Skiing and snowboarding head injury: A retrospective centre-based study and implications for helmet test standards.

BACKGROUND: Head injury occurs in up to 47% of skiing or snowboarding injuries and is the predominant cause of death in these sports. In most existing literature reporting injury type and prevalence, head injury mechanisms are underreported. Thus, protective equipment design relies on safety evaluation test protocols that are likely oversimplified. This study aims to characterize severity and mechanism of head injuries suffered while skiing and snowboarding in a form appropriate to supplement existing helmet evaluation methods. METHODS: A 6-year, multicentre, retrospective clinical record review used emergency databases from two major trauma centres and Coroner's reports to identify relevant cases which indicated head impact. Records were investigated to understand the relationships between helmet use, injury type and severity, and injury mechanism. Descriptive statistics and odds ratios aided interpretation of the data. FINDINGS: The snow sport head injury database included 766 cases. "Simple fall", "jump impact" and "impact with object" were the most common injury mechanisms while concussion was observed to be the most common injury type. Compared to "edge catch", moderate or serious head injury was more common for "fall from height" (OR = 4.69; 95% CI = 1.44-16.23; P = 0.05), "jump impact" (OR = 3.18; 95% CI = 1.48-7.26; P = 0.01) and "impact with object" (OR = 2.44; 95% CI = 1.14-5.56; P = 0.05). Occipital head impact was associated with increased odds of concussion (OR = 7.46; 95% CI = 4.55-12.56; P = 0.001). INTERPRETATION: Snow sport head injury mechanisms are complex and cannot be represented through a single impact scenario. By relating clinical data to injury mechanism, improved evaluation methods for protective measures and ultimately better protection can be achieved.

Overall survival and risk of second malignancies with cancer chemotherapy and G-CSF support.

Background: The use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently recommended by several clinical practice guidelines. However, in a previous meta-analysis, G-CSF prophylaxis was associated with an increased risk of secondary malignancies while reducing long-term mortality. We present here an updated systematic review and meta-analysis. Materials and methods: A systematic literature search was carried out to identify randomized controlled trials of cancer patients receiving conventional-dose chemotherapy, assigned to primary G-CSF support or a control group without initial G-CSF, with at least 2 years of follow-up. Studies were categorized into one of the four groups, based on the chemotherapy regimen and study design. An updated meta-analysis was carried out; relative risk (RR) and 95% confidence intervals (CIs) for all-cause mortality and secondary malignancies were calculated. Results: Of 2604 articles screened, 14 eligible studies were identified and combined with studies identified in the previous systematic literature searches. The updated meta-analysis included a total of 68 studies presenting 71 separate comparisons. Survival was significantly improved in patients receiving primary G-CSF support, compared with patients without primary G-CSF support (mortality RR=0.92; 95% CI 0.90-0.95; ARD=-3.3%; 95% CI -4.2--2.4; P < 0.0001). The largest improvement in survival was observed with dose-dense chemotherapy regimens with G-CSF support, compared with controls receiving no G-CSF support (mortality RR=0.86; 95% CI 0.80-0.92; P < 0.0001). Patients who received primary G-CSF support experienced a significantly higher risk of secondary malignancies, compared with controls (RR=1.85; 95% CI 1.19-2.88; ARD=0.47; 95% CI 0.21-0.73; P < 0.01). Conclusions: Our findings demonstrate that overall survival is improved in patients receiving intensified chemotherapy with primary G-CSF support, compared with those receiving standard chemotherapy. Primary G-CSF support was also associated with a higher risk of developing secondary malignancies, including secondary acute myeloid leukemia and myelodysplastic syndrome.

Long-term efficacy and safety of once-daily fosamprenavir 1400 mg boosted by ritonavir 100 mg: the BOLD100 study.

In a retrospective database study at two HIV treatment centres, medical records were accessed to evaluate long-term efficacy and safety parameters in all HIV-infected adults who had achieved HIV-1 RNA <50 copies/mL following the initiation of fosamprenavir (FPV)/ritonavir (RTV) 1400 mg/100 mg once-daily (QD)-containing regimens between January 2004 and January 2006. Data were available for 20 antiretroviral (ARV)-naïve patients (baseline median HIV-1 RNA 5.0 log(10) copies/mL; CD4+ cell count 307 cells/mm(3)), 30 protease inhibitor (PI)-naïve, ARV-experienced patients (HIV-1 RNA 3.6 log(10) copies/mL; CD4+ count 348 cells/mm(3)) and 25 PI-experienced patients switching to FPV/RTV100 for reasons other than virological failure (HIV-1 RNA 2.7 log(10) copies/mL; CD4+ count 328 cells/mm(3)). HIV-1 RNA <50 copies/mL was achieved in 100% of the ARV-naïve cohort (median monitoring period, 2.4 years; range, 1.4-3.2 years), 87% of the PI-naïve cohort (2.4 years; range, 1.2-3.4 years) and 88% of the PI-experienced cohort (2.2 years; range, 1.0-3.2 years). Virological failure occurred in 0%, 7% and 8% of the cohorts, respectively, and median CD4+ count increased above baseline by 224, 155 and 115 cells/mm(3), respectively. Change from baseline in median fasting lipids was: total cholesterol +12, -6, -2 mg/dL; low-density lipoprotein-cholesterol 0, -5, +12 mg/dL; high-density lipoprotein-cholesterol +4, +2, +7 mg/dL; triglycerides +9, -21, -65 mg/dL, respectively. In conclusion, FPV/RTV 1400/100 mg QD-containing regimens remained effective long-term in all ARV-naïve and most PI-naïve and PI-experienced HIV-infected patients.

A comprehensive training programme for nurse endoscopist performing flexible sigmoidoscopy in Hong Kong.

AIMS: To describe the process and explore the feasibility of training a colorectal nurse in Hong Kong to perform flexible sigmoidoscopy. BACKGROUND: Given the shortage and high turnover rate of medical staff, a pilot programme was designed to train and expand the role of colorectal nurse clinicians. It was hoped that such nurses could share some of the clinical duties of the medical staff. An advanced practice nurse was selected for the programme. One of the training components was the performance of flexible sigmoidoscopy. DESIGN: This was a descriptive, case review study. METHOD: A one-year-structured endoscopic training programme was designed for the nurse clinician. Weekly sessions were conducted by one of the trainers. The training process included the following: (1) procedural observation; (2) supervised withdrawal, advancement and manipulation of the sigmoidoscope and (3) a final assessment of the nurse's competency in performing sigmoidoscopy independently. RESULTS: In total, 119 outpatients (58 male and 61 female) with a mean age of 57·02 years (SD 14·6 years; range: 18-83 years) underwent flexible sigmoidoscopy by the nurse over 11 months. The mean procedural time was 9·38 minutes (SD 3·5 minutes; range 3-26 minutes). The procedure was terminated prematurely if it could not be tolerated by the patient or if the bowel preparation was inadequate. The mean depth of insertion was 53·5 cm (SD 12·2 cm; range 6-60 cm). In total, 82 patients had a normal exam, 32 patients had abnormalities. There were no procedural complications, and no patient required an unplanned hospital admission after the procedure. CONCLUSION: In Queen Mary Hospital, nurses can be trained to perform flexible sigmoidoscopy in a safe and effective manner. RELEVANCE TO CLINICAL PRACTICE: Nurse endoscopists could increase the use of flexible sigmoidoscopy in colorectal cancer screening and can also enhance the professional development of colorectal nurses.

Long-term efficacy and safety of fosamprenavir plus ritonavir versus lopinavir/ritonavir in combination with abacavir/lamivudine over 144 weeks.

PURPOSE: The KLEAN study extension assessed the long-term efficacy and safety of fosamprenavir-ritonavir (FPV/r) and lopinavir-ritonavir (LPV/r), both administered with abacavir/lamivudine (ABC/3TC) fixed dose combination, over 144 weeks. METHODS: KLEAN was an open-label, noninferiority study that randomised antiretroviral-naïve patients to FPV/r twice daily (bid) or LPV/r bid with ABC/3TC once daily (qd). Patients with a viral load of <400 copies/mL at Week 48 were eligible to participate in the KLEAN study extension (up to 144 weeks) and continued with their previously randomised therapy. RESULTS: The KLEAN study extension (48 to 144 weeks) randomized 199 patients. The proportion of TLOVR responders (HIV-1 RNA <50 copies/mL) at Week 144 was 73% and 60% in the FPV/r and LPV/r arms, respectively. The proportion of TLOVR responders (<50 copies/mL) was the same irrespective of baseline HIV-1 RNA (>100,000 or 100,000 copies/mL). The Week 144 median (interquartile range) change from baseline CD4+ cell count was 300 (236-433) cells/mm3 and 335 (225-444) cells/mm3 in the FPV/r and LPV/r arms, respectively. Diarrhea was the most frequently reported adverse event. A small proportion of patients (FPV/r, 13%; LPV/r, 9%) discontinued study medication due to adverse events. Three patients (FPV/r, 1; LPV/r, 2) experienced virological failure between Week 48 and Week 144. CONCLUSION: The findings of the KLEAN study extension (48 to 144 weeks) support durable viral suppression with both FPV/r and LPV/r treatment regimens when used in combination with ABC/3TC irrespective of viral load at baseline. Both regimens were well tolerated and had similar safety profiles.

Evaluation of the impact of highly active antiretroviral therapy on immune recovery in antiretroviral naive patients.

OBJECTIVES: To examine the extent of immune reconstitution in treatment-naive patients with CD4 T-cell counts <500 cells/microL following 48 weeks of highly active antiretroviral therapy (HAART). METHODS: Thirteen antiretroviral naive patients were evaluated longitudinally for 48 weeks on HAART utilizing immune functional and lymphocyte phenotyping assays, including lymphocyte proliferation assay, flow cytometric evaluation of cell surface markers, and delayed type hypersensitivity skin tests. Virologic responses were monitored using commercially available viral load assays and gag/pol mRNA quantification using simultaneous immunophenotyping/UltraSensitive fluorescence in situ hybridization (ViroTect In Cell HIV-1 Detection Kit; Invirion, Frankfort, MI). Thymic function was evaluated for a subset of four patients using real-time polymerase chain reaction (PCR) for T-cell receptor excision circle (TREC) quantification and thymic scans using computerized axial tomography (CT) of the thymus. RESULTS: HAART initiation resulted in a significant decline in plasma viremia and percentage of infected peripheral blood cells, and a rise in CD4 T cells from a baseline median of 207 cells/microL to a week-48 median of 617 cells/microL. The rise was predominately in CD4 memory cells. Naive T cells also increased in number, but at a slower rate. Activated (HLA-DR CD38) CD4 and CD8 T cells were elevated at baseline (24 and 62%, respectively) and declined by week 48 (17 and 36%, respectively) but did not reach normal levels. The number of Fas CD4 T cells increased from a baseline median of 169 to 381 cells/microL at week 48. Both soluble interleukin (IL)-2 and tumour necrosis factor (TNF) II receptors declined by week 48. HIV p24 lymphocyte proliferation assay responses were transiently detected in three patients. TREC values increased from a median 6400 copies/microg at baseline to a week-48 median value of 26 697 copies/microg. CONCLUSION: Immune functional reconstitution was not achieved in these HAART naive patients.

Bradykinin receptor antagonists attenuate neointimal proliferation postangioplasty.

Bradykinin has been linked to the development of restenosis in response to vascular injury. We therefore examined the effect of bradykinin on vascular smooth muscle cell growth and neointimal formation in organ culture. Bradykinin stimulated both RNA and DNA synthesis (by 175%) in smooth muscle cells from either porcine or human coronary arteries and increased cell number in a concentration-dependent manner. Both p42/44 mitogen-activated protein kinase (MAPK) and p38 kinase were also activated. Treatment with [Hyp(3),Tyr(Me)(8)]bradykinin, a B(2) receptor agonist, stimulated thymidine incorporation by 146%, whereas B(1)-selective Lys-des-Arg(9)-bradykinin had no effect. Addition of the B(2) antagonist HOE-140 reduced the stimulation by 56%, whereas B(1)-selective des-Arg-HOE-140 had no significant effect. Similarly, HOE-140 attenuated angioplasty-induced neointimal formation in organ culture with an efficacy approaching 100% inhibition. These experiments suggest that bradykinin promotes smooth muscle proliferation after vascular injury, presumably via B(2) receptor-dependent activation of MAPK family pathways, and may explain the negative outcome of angiotensin converting enzyme inhibitor therapy on restenosis in nonrodent models.

Insulin-like growth factor-I (IGF-I)-dependent activation of pp42/44 mitogen-activated protein kinase occurs independently of IGF-I receptor kinase activation and IRS-1 tyrosine phosphorylation.

The proliferation and metabolism of H4IIE hepatoma cells is apparently mediated through the insulin receptor. These cells, however, also have high-affinity binding sites for insulin-like growth factor-I (IGF-I). Addition of insulin to H4IIE cells increased RNA synthesis, DNA synthesis and cell number. IGF-I, on the other hand, was ineffective at concentrations equivalent to the lowest effective insulin dose, although stimulation was observed with concentrations 100-fold higher. Similar results were obtained when glucose uptake was measured. Western blot analysis demonstrated that tyrosine phosphorylation patterns produced by insulin and IGF-I differed. In particular, phosphorylation of insulin receptor substrate-1 (IRS-1) was evident after treatment with insulin, but not after treatment with IGF-I. Correspondingly, insulin, but not IGF-I, stimulated receptor tyrosine kinase activity. In contrast with these results, both insulin and IGF-I induced mitogen-activated protein (MAP) kinase phosphorylation and activity at a concentration of 10 nM. The correlation between insulin-dependent and IGF-I-dependent MAP kinase activation was confirmed by Western blot analysis of phosphorylated MAP kinase kinase (MEK). These results suggest that phosphorylation of IRS-1 is essential for both cell proliferation and glucose metabolism, but is uncoupled from the MAP kinase cascade. Furthermore, stimulation of MEK and MAP kinase is independent of receptor tyrosine kinase activity.

Modulation of the vascular smooth muscle angiotensin subtype 2 (AT2) receptor by angiotensin II.

The angiotensin subtype 2 (AT2) receptor is scarce in most adult vascular tissues except after injury. Since angiotensin II (AngII) is released upon injury, we examined the possibility that AngII governs AT2 receptor expression in smooth muscle cells (SMC). A polyclonal antiserum, raised to a peptide corresponding to the AT2 receptor C-terminus, recognized a approximately 45-kDa protein after transfection of cos-7 cells with AT2 receptor cDNA. Detection of a approximately 65-kDa band in extracts of SMC indicated that the AT2 receptor was glycosylated. Treatment of SMCs with AngII increased AT2 receptor levels fourfold over 24 h. This response was abrogated by losartan, but not by PD123319, indicating AT1 receptor involvement. AngII-dependent increases in AT2 receptor levels were also prevented by LY294002, an inhibitor of phosphatidyinositol 3-kinase, but not by rapamycin. These results indicate AngII influences AT2 receptor expression through the AT1 receptor via a signaling pathway that includes PI3K.

Expression and regulation of the insulin-like growth factor-1 receptor by growing and quiescent H4IIE hepatoma.

Recent evidence that insulin-like growth factor-1 (IGF-1) influences certain properties of H4IIE hepatoma cells independent of insulin led us to examine whether H4IIE cells express IGF-1 receptors. Competitive binding experiments demonstrated IGF-1, but not insulin or IGF-II, could compete with [125I]IGF-1. Chemical crosslinking detected a protein with an apparent mass of 175 kDa and its identity as the IGF-1 receptor alpha-subunit was confirmed by Western blotting. The apparent molecular mass of this protein decreased to 135 kDa following deglycosylation. Immunofluorescence microscopy verified that both insulin and IGF-1 receptors were present, although measurement of IGF-1 receptor quantity revealed they were less abundant than insulin receptors. Binding of IGF-1 was low in growing cells and higher in a quiescent cell population. Scatchard analysis confirmed that receptor density was increased in non-growing H4IIE cells while there was no apparent difference in receptor affinity. Western blot analysis and RT-PCR revealed that both protein and mRNA levels were elevated as cell growth ceased. Interestingly, addition of insulin to quiescent H4IIE cells, which stimulates cell proliferation, further increased IGF-1 receptor protein levels with a peak at 12-24 h. Distinct modes of regulating IGF-1 receptor expression are indicated.

Vancomycin-resistant and vancomycin-susceptible enterococcal bacteremia: comparison of clinical features and outcomes.

Vancomycin-resistant Enterococcus (VRE) is a major nosocomial pathogen. We collected clinical and laboratory data on 93 hospitalized adults with VRE bacteremia and 101 adults with vancomycin-susceptible enterococcal (VSE) bacteremia. Risk factors for VRE bacteremia included central venous catheterization, hyperalimentation, and prolonged hospitalization prior to the initial blood culture. VRE-infected patients were less likely to have undergone recent surgery or have polymicrobial bacteremia, suggesting a pathogenesis distinct from traditional VSE bacteremia. Prior exposure to metronidazole was the only significant pharmacologic risk factor for VRE bacteremia. Animal studies suggest metronidazole potentiates enterococcal overgrowth in the gastrointestinal tract and translocation into the bloodstream. An increasing APACHE II score was the major risk factor for death in a multivariate analysis, with VRE status being of only borderline significance.

Repression of phosphoenolpyruvate carboxykinase gene activity by insulin is blocked by 3-aminobenzamide but not by PD128763, a selective inhibitor of poly(ADP-ribose) polymerase.

Expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is induced by 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase. Synthesis of PEPCK mRNA is repressed by insulin, but remains detectable in H4IIE hepatoma cells exposed simultaneously to both 3-aminobenzamide and insulin. This capability of 3-aminobenzamide to block the inhibitory actions of insulin suggests that ADP-ribosylation is required for the regulation of PEPCK gene expression by insulin. Furthermore, neither changes in chromatin condensation nor cell growth status were linked to these events. The inability of 3,4-dihydro-5-methylisoquinolinone (PD128763), a selective inhibitor of poly(ADP-ribose) polymerase, to impede insulin-dependent repression of PEPCK gene expression, however, indicated that 3-aminobenzamide does not operate by inhibiting poly(ADP-ribosyl)ation. The potential involvement of mono(ADP-ribosyl)ation, a process that is also inhibited by 3-aminobenzamide, in the regulation of PEPCK gene activity was then evaluated. Analysis of poly(ADP-ribose) polymerase activity and poly(ADP-ribosyl)ation confirmed that there were no significant changes in response to insulin, while microsomal mono(ADP-ribosyl)transferase activity was elevated approximately fourfold. An increase in protein hydroxylamine-sensitive mono(ADP-ribosyl)ation was observed following insulin treatment. The sensitivity of the mono(ADP-ribosyl)transferase activity to 3-aminobenzamide but not PD128763 makes it plausible that mono(ADP-ribosyl)ation rather than poly(ADP-ribosyl)ation contributes to the regulation of PEPCK gene expression.

Immunodetection of activated mitogen-activated protein kinase in vascular tissues.

Mitogen-activated protein kinase (MAPK) is a key modulator of cytoplasmic-nuclear signal transmission, and for this reason measurement of MAPK activity has become very popular. Monitoring of MAPK activity may be particularly relevant to the cardiovascular system where it has already been shown that the stimulation of cardiomyocytes and smooth muscle cells by stretch and by growth factors activates MAPK. Since both growth factors and mechanical stress are causal agents for certain pathologies, enhanced MAPK activity may be a good predictor of disease progression. A variety of methods have been designed to measure the activation of this enzyme including an in vitro assay coupled to either gel electrophoresis or binding to P81 paper, an activity gel assay to detect p42/44 isoforms and, more recently, monitoring MAPK phosphorylation using immunoblot detection. The validity of the latter method is based on the correlation between MAPK activity and the degree of phosphorylation. The antibodies have also been of use in the detection of MAPK translocation in cell monolayers. In this report, we discuss the advantages and disadvantages of all MAPK detection methods and demonstrate an additional application for the MAPK antibodies using an in vitro restenosis model. In addition, the utility of MAPK measurements to smooth muscle pathophysiology and vascular injury (as a predictor of injury) has been assessed.

Intent-to-treat analysis for longitudinal studies with drop-outs.

We consider intent-to-treat (IT) analysis of clinical trials involving longitudinal data subject to drop-out. Common methods, such as Last Observation Carried Forward imputation or incomplete-data methods based on models that assume random dropout, have serious drawbacks in the IT setting. We propose a method that involves multiple imputation of the missing values following drop-out based on an "as treated" model, using actual dose after drop-out if this is known, or imputed doses that incorporate a variety of plausible alternative assumptions if unknown. The multiply-imputed data sets are then analyzed using IT methods, were subjects are classified by randomization group rather than by the dose actually received. Results from the multiply-imputed data sets are combined using the methods of Rubin (1987, Multiple Imputation for Nonresponse in Surveys). A novel feature of the proposed method is that the models for imputation differ from the model used for the analysis of the filled-in data. The method is applied to data on a clinical trial for Tacrine in the treatment of Alzheimer's disease.

Stimulation of protein synthesis by phosphatidic acid in rat cardiomyocytes.

Phosphatidic acid (PA) was observed to stimulate protein synthesis in adult cardiomyocytes in a time- and concentration-dependent manner. The maximal stimulation in protein synthesis (142 +/- 12% vs 100% as the control) was achieved at 10 microM PA within 60 min and was inhibited by actinomycin D (107 +/- 4% of the control) or cycloheximide (105 +/- 6% of the control). The increase in protein synthesis due to PA was attenuated or abolished by preincubation of cardiomyocytes with a tyrosine kinase inhibitor, genistein (94 +/- 9% of the control), phospholipase C inhibitors 2-nitro-4-carboxyphenyl N,N-diphenyl carbamate or carbon-odithioic acid O-(octahydro-4,7-methanol-1H-inden-5-yl (101 +/- 6 and 95 +/- 5% of the control, respectively), protein kinase C inhibitors staurosporine or polymyxin B (109 +/- 3 and 93 +/- 3% of the control), and chelators of extracellular and intracellular free Ca2+ EGTA or BAPTA/AM (103 +/- 6 and 95 +/- 6% of the control, respectively). PA at different concentrations (0.1 to 100 microM) also caused phosphorylation of a cell surface protein of approximately 24 kDa. In addition, mitogen-activated protein kinase was stimulated by PA in a concentration-dependent manner; maximal stimulation (217 +/- 6% of the control) was seen at 10 microM PA. These data suggest that PA increases protein synthesis in adult rat cardiomyocytes and thus may play an important role in the development of cardiac hypertrophy.

Inhibition of RNA synthesis by bradykinin involves both the B1 and B2 receptor subtypes.

The efficacy of angiotensin converting enzyme inhibitors in the treatment of heart disease is due in part to the accumulation of bradykinin (BK). Since BK can exert its effect by influencing cell proliferation, we chose to study the effect of BK on the growth of A10 vascular smooth muscle cells. Ligand binding studies to determine which BK receptor subtypes are present on A10 cells showed that both B1 and B2 receptors were present in approximately equal numbers. Examination of RNA synthesis demonstrated that BK inhibits uridine incorporation in a dose-dependent manner. This decrease in RNA synthesis was blocked by both B1 and B2 receptor antagonists, as well as by addition of indomethacin, a cyclooxygenase inhibitor. The latter result suggested that prostaglandins mediate the biological actions of BK. Consequently, we examined the direct effect of two prostaglandins, PGE2 and PGI2 (prostacyclin), on A10 cells. PGE2 caused a decrease in RNA synthesis, thus mimicking the effect of BK, while PGI2 did not. Therefore, the inhibition of RNA synthesis in A10 vascular smooth muscle cells by BK requires both B1 and B2 receptor subtypes and this action of BK is apparently mediated by de novo synthesis of prostaglandins.

ADP-ribosylation and gene expression.

Gene expression can be defined as the conversion of information existing in a molecule of DNA into a mature RNA or protein product and each step in the process, which requires the concerted action of several macromolecules for completion, may be perturbed by the post-translational modification of specific proteins with ADP-ribose. The participation of poly(ADP-ribose) in the regulation of transcription initiation was examined using cell-free systems for both ribosomal RNA and ribosomal proteins. The presence or absence of poly(ADP-ribose) polymerase did not influence the transcription process. Similarly, under conditions optimal for poly(ADP-ribose) polymerase activity, no change in transcription was observed. A direct contribution of poly(ADP-ribosyl)ation to gene transcription thus could not be detected. In contrast, the addition of 3-aminobenzamide to quiescent hepatoma cells treated with insulin inhibited the stimulation of rRNA synthesis. The high concentrations necessary for this effect suggest that a mono(ADP-ribosyl)ation event participates in the cellular action of insulin. A role in the signal transduction pathway leading to activation of rRNA gene expression has been proposed.

A microcomputer-based, net-lending interlibrary loan system.

A microcomputer-based, net-lending interlibrary loan system was developed at Lane Medical Library, Stanford University. The system, designed to generate the monthly billing invoices and all necessary statistical reports, has reduced the time required for logging-in procedures and compilation of monthly, quarterly, and annual statistics. User menus, help screens, and choice fields were developed explicitly for library staff who have little or no computer experience. The program was written using the DataEase database management software running on IBM PC, XT, AT, or compatible with a minimum of 512K RAM. Described are features of this automated interlibrary loan management system and its use in a net-lending interlibrary loan department. It focuses on data entry in the "Library Directory" and "ILL Log Sheet," details of billing invoices, and statistical reports, and flexibility in modifying tax rates, borrowing fees, and other parameters.

Glucose effect on drug action, metabolism, and pharmacokinetic parameters in mice.

The glucose effect on hepatic drug metabolism (decreased) of barbiturates was maximum after 2 days of increased glucose intake as indicated by increased barbiturate sleep time in mice. However, this effect was not observed after 5 days of glucose treatment, and barbiturate sleep time was similar to the control after 6 days of treatment. Serum glucose and liver glycogen were, in general, not significantly different from control, even after chronic glucose intake, indicating that neither hypoglycemia nor alteration of liver glycogen levels were required for the glucose effect on drug action. However, in contrast to the decreased metabolism of barbiturate, there was increased metabolism of glucose in the glucose-treated animals. Brain levels of barbiturate in 48 hours glucose-treated mice were higher and declined at approximately half the rate of controls (Ke(G) 0.009 vs Ke(C) 0.015). A similar trend in barbiturate blood concentration indicated decreased metabolism of the barbiturate and/or decreased clearance of drug and metabolites. The glucose treatment altered the pentobarbital dose response curve, but there appeared to be no alteration of the sensitivity to insulin; exogenase insulin still produced significant hypoglycemia and prolonged barbiturate S.T. after 7 days of glucose treatment. Other factors may be involved in the glucose effect; increased permeability of the brain to barbiturate, decreased permeability to outflow so that brain concentrations remain higher for a long period of time.