The pharmacokinetic and pharmacodynamic properties of different formulations of biphasic insulin aspart: a randomized, glucose clamp, crossover study.

BACKGROUND: Type 2 diabetes patients on premixed insulin are commonly prescribed biphasic insulin with low prandial insulin content, such as biphasic insulin aspart (BIAsp) 30, comprising 30% insulin aspart (IAsp). The new formulations BIAsp 50 and BIAsp 70 contain 50% and 70% soluble IAsp, respectively. We compared the pharmacodynamics (PD) and pharmacokinetics (PK) of BIAsp 30, 50, and 70 and IAsp in a glucose clamp trial. METHODS: In this randomized, double-blind, crossover study at a clinical research institute, 32 type 1 diabetes patients on basal-bolus therapy each underwent four glucose clamps (clamp level 5 mmol/L, duration 28 h post-dosing [12 h for IAsp]) and received a single dose of 0.4 U/kg BIAsp 30, 50, or 70 and IAsp. Main PD/PK outcome parameters measured were early- and late-phase glucose disposal (area under the curve of glucose infusion rate [AUC(GIR)]), nonesterified fatty acid concentrations, and IAsp concentrations. RESULTS: With increasing proportions of soluble IAsp, the insulin formulations showed significantly higher early metabolic activity (ratio of AUC(GIR) 0-6 h: BIAsp 50/BIAsp 30 = 1.28 [P < 0.001], BIAsp 70/BIAsp 50 = 1.18 [P < 0.001), IAsp/BIAsp 70 = 1.15 [P < 0.01]) and lower late metabolic activity (ratio of AUC(GIR) 12-28 h: BIAsp 50/BIAsp 30 = 0.17 [P < 0.01], BIAsp 70/BIAsp 50 = 0.21 [P < 0.05]). Likewise, early IAsp levels were significantly greater and late PK concentrations were significantly lower with increasing proportion of soluble IAsp. CONCLUSIONS: There are significant differences between the early and late PD and PK effects among BIAsp 30, 50, and 70 and IAsp that should allow tailored treatment with the convenience of prandial and basal insulin in each injection.

Molecular factors of 5-fluorouracil metabolism in colorectal cancer: analysis of primary tumor and lymph node metastasis.

Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) are predictive markers for tumor response to 5-fluorouracil-based therapies. To determine whether gene expression values measured in primary cancer tissue would be useful for prediction of response of lymph node metastases, the expressions of these genes were quantitatively analyzed in 35 pairs of primary colorectal cancer (CRC) and corresponding lymph node metastases using real-time PCR. DPD and TP mRNA levels were significantly lower in the primary colorectal tumor and lymph node metastases compared with the normal adjacent stroma tissue (p<0.01), whereas TS mRNA levels were significantly higher in the primary tumor and lymph node metastases than in the normal adjacent tissue (p<0.001). Median gene expression levels of TP and TS did not differ significantly between primary colorectal tumor and corresponding lymph node metastasis but median DPD gene expression levels in the lymph node metastases were significantly higher compared to matched primary colorectal tumors (p=0.015). There was a significant correlation for DPD, TP and TS gene expression levels between primary colorectal tumor specimens and the matched lymph node metastasis. These results suggest that biopsies of the tumor of origin may be valid for determining predictive markers for chemotherapy response in patients with metastatic CRC.

Fiber type-specific expression of GLUT4 in human skeletal muscle: influence of exercise training.

The fiber type-specific expression of skeletal muscle GLUT4 and the effect of 2 weeks of low-intensity training were investigated in 8 young untrained male subjects. Single muscle fibers were dissected from a vastus lateralis biopsy sample. Based on myosin heavy chain (MHC) expression, fibers were pooled into 3 groups (MHC I, MHC IIA, and MHC IIX), and the GLUT4 content of 15-40 pooled fibers was determined using SDS-PAGE and immunological detection. The GLUT4 content in pooled muscle fibers expressing MHC I was approximately 20% higher (P < 0.05) than that in muscle fibers expressing MHC IIA or MHC IIX. No difference in GLUT4 could be detected between fibers expressing MHC IIA or MHC IIX. Two weeks of exercise training increased (P < 0.05) the peak power output of the knee extensors by 13%, the maximal activities of citrate synthase and 3-hydroxyacyl-CoA dehydrogenase by 21 and 18%, respectively, and the GLUT4 protein content by 26% in a muscle homogenate. Furthermore, a 23% increase (P < 0.05) in GLUT4 was seen in fibers expressing the MHC I isoform after exercise training for 2 weeks. No change was seen in fibers expressing MHC IIA or MHC IIX. In conclusion, our data directly demonstrate that GLUT4 is expressed in a fiber type-specific manner in human skeletal muscle, although fiber type differences are relatively small. In addition, low-intensity exercise training recruiting primarily fibers expressing MHC I increased GLUT4 content in these fibers but not in fibers expressing MHC IIA or MHC IIX, indicating that GLUT4 protein content is related more to activity level of the fiber than to its fiber type, which is defined by expression of contractile protein.

Omega-3 fatty acids inhibit an increase of proinflammatory cytokines in patients with active Crohn's disease compared with omega-6 fatty acids.

BACKGROUND: Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract. Polyunsaturated omega-3 fatty acids given orally may reduce the secretion of proinflammatory cytokines and hereby downregulate the inflammatory process. AIM: To assess the effects of enteral fatty acids, in the form of Impact Powder (Novartis, Switzerland), as adjuvant therapy to corticosteroid treatment on the proinflammatory and anti-inflammatory cytokine profiles in patients with active Crohn's disease. METHODS: The proinflammatory and anti-inflammatory cytokines were measured in plasma from 31 patients with active Crohn's disease. Patients were randomized for oral intake of omega-3 fatty acid (3-Impact Powder) or omega-6 fatty acids (6-Impact Powder). Clinical and biochemical markers of inflammation were studied at baseline and after 5 and 9 weeks. RESULTS: Within the 3-Impact Powder group, no significant changes in concentrations of interleukin-6, interferon-gamma, monocyte chemoattractant protein-1, interleukin-2, interleukin-5 and interleukin-10, whereas a significant differences in concentration of interleukin-1beta and interleukin-4 were observed during therapy. Within the 6-Impact Powder group a significant changes in concentrations of interleukin-1beta, interleukin-6, interferon-gamma, monocyte chemoattractant protein-1, interleukin-2, interleukin-4, interleukin-5 and interleukin-10 were observed. CONCLUSIONS: The 3-Impact Powder showed immunomodulatory properties and might inhibit an increase of proinflammatory cytokines in contrast to the 6-Impact Powder.

The association between daytime attendance and out-of-hours frequent attendance among adult patients in general practice.

BACKGROUND: Frequent attenders (FAs) account for a large proportion of daytime consultations in general practice. However, no studies have so far been conducted to establish whether daytime FAs are also out-of-hours FAs. AIM: To analyse the association between daytime attendance and out-of-hours frequent attendance. DESIGN OF STUDY: A registry-based study of individual face-to-face contacts with general practice during daytime and out of hours, based on National Health Insurance files. SETTING: General practices in Aarhus County, Denmark (630,000 inhabitants). METHOD: A total of 416,172 adults, i.e. all adults registered with a general practice during a 12-month period from November 1997 to October 1998 were included. Odds ratios (OR) for frequent attendance out of hours were stratified for age, sex, and frequency of contacts during daytime were calculated. RESULTS: A strong association was observed between daytime level of attendance and out-of-hours level of attendance (OR = 2.9-6.3 among patients with low daytime attendance, OR = 33.7-99.8 among daytime FAs). Daytime FAs accounted for one-third of the daytime contacts, one-third of the out-of-hours contacts, and 42% of out-of-hours FAs. More than half of the daytime FAs did not attend out of hours. Two per cent of the out-of-hours FAs had no contacts during the daytime. CONCLUSION: Frequent attendance in daytime was very strongly associated with frequent attendance out of hours, and daytime FAs accounted for a large proportion of all contacts with general practice.

Etiologic studies on late-term swine abortions.

One hundred thirty-eight swine abortions were studied in detail in an effort to identify an etiologic agent. A viral agent was implicated in 7 cases. Bacteria were isolated in less than half of the examined cases: however, in 61% of the cases, motile, filamentous organisms were observed in tissues and fluids. Although swine sera from farms experiencing reproductive problems had a high reactor rate to Leptospira bratislava antigen, electron microscopy of the observed organism revealed a wall-free prokaryote morphologically typical of the class Mollicutes.

Reproductive failure associated with Leptospira interrogans serovar bratislava infection of swine.

Specimens from 17 swine herds experiencing reproductive failure were examined for Leptospira interrogans serovar bratislava. Clinical signs observed in these herds included stillborn pigs, weak neonatal pigs, and abortion. Diagnostic tests used to determine L. interrogans serovar bratislava infection were bacteriologic culture, serologic assays to detect antibodies, and immunofluorescence. Examination of fetal serum for antibodies against serovar bratislava and a fluorescent antibody test were the most practical diagnostic procedures.

Physiological response to acute endotoxemia in swine: effect of genotype on energy metabolites and leptin.

Certain high lean gain swine genotypes have greater sensitivity to pathogen and nonpathogen stressors evident by reduced productivity and increased mortality during disease stress or in suboptimal production environments. Saline (control) and an immunologic challenge (LPS; 25 microg lipopolysaccharide/kg BW) were administered to three genetic populations (each pig used as its own control): high lean (H), moderate lean terminal cross (MT), and moderate lean maternal cross (MM). LPS induced anorexia, and significantly increased body temperature and circulating TNF-alpha, cortisol, and NEFA in all genotypes (P < 0.0004). LPS reduced circulating glucose, insulin, and IGF-1 in all genotypes (P < 0.05). The LPS-induced hypoglycemia was significantly greater in MM versus MT and H pigs (P < 0.03). The hypoinsulinemia was significantly greater in MM versus H pigs (P < 0.02). MM pigs recovered from hypoinsulinemia slower than MT pigs (P < 0.03). Control insulin was higher in H versus MT pigs (P < 0.08), but relative to basal, the insulin response to LPS was similar. Plasma haptoglobin response to LPS was lower for MM versus MT and H pigs (P < 0.02), and tended to be lower in MT versus H pigs (P < 0.09). LPS treatment caused similar decreases in plasma IGF-1 concentrations among genotypes. Ten hours after LPS treatment, leptin mRNA abundance in adipose tissue was significantly reduced (relative to control) in MM and H pigs (P < 0.02) but not in MT pigs (P > 0.05). Physiological differences in leptin, a potent regulator of food intake and energy metabolism, may be important factors in the genetic variation in sensitivity to environmental stress.

Leptospira interrogans serovar bratislava infection in two dogs.

Two dogs with clinical histories suggestive of leptospirosis were examined serologically and culturally for evidence of leptospiral infection. Antibodies to Leptospira interrogans serovar bratislava were detected in serum from one dog, and the organism was isolated from urine of that dog. In a serologic survey of dogs in the state of Illinois, reactor rates to bratislava were higher than those to canicola or icterohaemorrhagiae. In cases of suspect canine leptospirosis, serovars such as bratislava, not contained in canine vaccines, should be considered in a differential diagnosis.

A comparison of the routine medical examination of pilots in 12 air forces.

All air forces use routine medical examination to ensure the health of their pilots and flying safety. I compared pilot physicals in 12 air forces, and reviewed literature dealing mainly with routine medical examination of asymptomatic individuals. The discussion considers what should be done during the routine pilot examination to ensure flying safety, health and mission completion. General recommendations are given on ways to keep cost and effort within limits without failing to achieve the objective. Methods to achieve this include differentiating the intervals between examinations in different age groups and inclusion of procedures only beyond a certain age. Caution is advised when considering the inclusion of new procedures, and attention should be paid to whether such a test can be expected to produce unacceptable numbers of false positive results.

[Does a computerized price comparison module reduce prescribing costs in general practice?]. / Reducerer et computerbaseret modul til prissammenligning udgifter til medicin i almen praksis?

The aim was to assess the trends in prescribed defined daily doses (DDD) and drug expenses before and after the introduction of a computerized cost containment module. On January 1993 the module was introduced in 20 practices in Aarhus County that used the computer record system APEX. Two control groups were made. From the Public Health Insurance in Aarhus County (600,000 inhabitants) data were collected during 1992 and 1993. Compared with te controls there were no changes in prescribed DDD, reimbursement for prescribed drugs, and reimbursement per prescribed DDD in the intervention group after the introduction of the module. Cost containment procedures should be more intensive than just giving the doctors a computer-assisted decision aid.

The insulin-like growth factor system and markers of inflammation in adult patients with inflammatory bowel disease.

BACKGROUND AND OBJECTIVES: Catabolism and growth impairment are well-known complications of inflammatory bowel disease (IBD). Recent studies have demonstrated significant changes in the IGF system in IBD patients. The aim of the present study was to investigate correlations between the IGF system and markers of inflammation in IBD. METHODS: A cross-sectional study comprising 99 IBD patients (Crohn's disease (CD, n = 50) and ulcerative colitis (UC, n = 49)). Correlations between markers of inflammation and IGF-I, IGF-II and IGFBP-3 were examined in CD and UC patients in remission and relapse. The patients were clinically scored using Crohn's Disease Activity Index (CDAI) for CD patients and Activity Index (AI) for UC patients. RESULTS: In the UC group we found correlations between IGF-I and CRP (r(s) = Spearman's rho) (r(s) = -0.40, p < 0.01) and albumin (r(s) = 0.46, p < 0.001), IGFBP-3 and albumin (r(s) = 0.36, p < 0.01) and AI score (r(s) = -0.31, p < 0.05). IGF-II correlated with CRP (r(s) = -0.42, p < 0.01), IL-6 (r(s) = -0.65, p < 0.001), albumin (r(s) = 0.41, p < 0.01), AI score (r(s) = -0.30, p < 0.05) and orosomucoid (r(s) = -0.47, p < 0.001). In the CD group we found correlations between IGF-I and CRP (r(s) = -0.40, p < 0.05), and albumin (r(s) = -0.46, p < 0.01), IGFBP-3 and albumin (r = 0.36, p < 0.01). IGF-II correlated with IL-6 (r(s) = -0.65, p < 0.001), albumin (r(s) = 0.41, p < 0.01), CDAI score (r(s) = -0.30, p < 0.05) and orosomucoid (r(s) = -0.47, p < 0.001). CONCLUSIONS: IGF-I, IGF-II and IGFBP-3 are correlated to albumin and IGF-I and IGF-II are correlated to CRP in IBD patients. Further, IGF-II is correlated to IL-6 in IBD patients. This may suggest a correlation between inflammation and the IGF system with involvement in muscle and bone catabolism in IBD.

Regulation of glycogen synthase in skeletal muscle during exercise.

Glycogen synthase (GS) catalyses the incorporation of uridine diphosphate-glucose into glycogen in skeletal muscle. In concert with the glucose transport step, GS activity is thought to be rate-limiting in the disposal of glucose as muscle glycogen. Glycogen synthase is regulated by both allosteric factors (primarily glucose 6-phosphate) and covalent modification by reversible phosphorylation and dephosphorylation leading to inactivation and activation of GS, respectively. Exercise activates both stimulatory and inhibitory regulators of GS and it is thought that the resultant activity of GS during exercise depends on the relative strength of opposing signals. However, the mechanisms by which exercise regulates GS activity are not fully understood. Glycogen breakdown, the GM-protein phosphatase 1 complex and possibly cellular relocalization of GS may be considered important factors involved in the stimulation of GS activity during exercise, while adenosine monophosphate-activated protein kinase and plasma adrenaline (via protein kinase A) can be considered as essential for the exercise-induced inhibitory signals to GS.

Relationship among selected Leptospira interrogans serogroups as determined by nucleic acid hybridization.

Leptospiral DNAs from a variety of Leptospira interrogans serogroups of veterinary significance, as well as a nonpathogenic leptospira, were compared by Southern blot hybridization of EcoRI-digested genomic DNA. The serogroups examined could be assigned to one of three groups on the basis of the degree of cross-hybridization between genomic DNAs. Only a few restriction fragments hybridized between the three groups, and most of these were shown to contain ribosomal DNA. The restriction fragment length polymorphism observed among the intergroup hybridizations allowed differentiation among serogroups and, in some cases, serovars. Under the hybridization conditions used, no hybridization was observed between leptospiral DNA and Leptonema, Escherichia coli, or porcine DNA.

Does a computerized price comparison module reduce prescribing costs in general practice?

OBJECTIVE: We aimed to assess the trends in prescribed defined daily doses (DDD) and drug expenses before and after the introduction of a computerized cost containment module into the computer record system of a defined group of GPs. The GPs' expectations for and experiences with the module were examined. METHOD: We performed a controlled follow-up study on antecedent data before and after intervention. A questionnaire was administered to the intervention group at the introduction and 1 year later. Data on prescribing were collected in the database of the Health Insurance Aarhus County, as a normal routine for accounting. The GPs were not aware of the ongoing cost supervision study. Additional cost information software was introduced on 1 January 1993 to 20 practices with 28 GPs. The software assisted the GPs in a semiautomatic way to identify and prescribe the cheapest drugs. The subjects comprised 158 practices including 231 GPs in Aarhus County, Denmark. Questionnaires were sent to the 20 intervention practices. The main outcome measures were prescribed DDD, reimbursement for prescribed drugs, and reimbursement per prescribed DDD quarterly during 1992 and 1993. RESULTS: Compared with the controls there were no changes in prescribed DDD, reimbursement for prescribed drugs, and reimbursement per prescribed DDD in the intervention group after the introduction of the module. CONCLUSION: Simply giving a random group of GPs computer assistance to choose less expensive drugs did not reduce expenditure per DDD. Cost containment procedures should be more intensive than just giving the doctors a computer-assisted decision aid.

Additional assignment of the human 5S rRNA genes to chromosome region 1q31.

A major fraction of the human 5S rRNA genes has previously been assigned to chromosome region 1q42.11-->q42.13 (Sørensen et al., 1991). Through in situ hybridization of different tritiated probes to metaphase spreads, we have demonstrated that a minor fraction of the 5S rRNA genes is localized at band 1q31. This fraction amounts to 25-30% of the genes found in the region 1q42.11-->q42.13. Results obtained with the chromosomes of a balanced translocation carrier involving this region indicate that the major cluster is localized in band 1q42.13.

Crystal structure of a peptide nucleic acid (PNA) duplex at 1.7 A resolution.

The crystal structure of a PNA duplex reveals both a right- and a left-handed helix in the unit cell. The helices are wide (28A), large pitched (18bp) with the base pairs perpendicular to the helix axis, thereby demonstrating that PNA besides adapting to oligonucleotide partners also has a unique structure by itself.

A trauma-like elevation of plasma cytokines in humans in response to treadmill running.

1. Elevated levels of cytokines, especially interleukin (IL)-6 and IL-1ra, can be measured in the plasma of athletes after exhaustive long term exercise. 2. The present study investigates the kinetics of several cytokines and chemokines in ten male athletes before, during and after 2.5 h of treadmill running at 75 % of maximal oxygen consumption (VO2,max). Blood was sampled before, every half-hour during running and every hour in the following 6 h recovery period. 3. The plasma concentration of IL-6 increased after 30 min of running, and peaked at the end of running with a 25-fold increase compared with the pre-exercise value. IL-1ra increased only after running, and peaked after 2 h of rest with an 18-fold increase compared with the pre-exercise value. No changes were found in the concentrations of IL-1beta, tumour necrosis factor (TNF)alpha, IL-15 and macrophage inflammatory protein (MIP)-1beta, and the concentrations of IL-8 and MIP-1alpha were below detection limits. 4. The results suggest that very early events in exercise trigger the release of IL-6, and that the cytokine response to exercise has similarities to that observed after trauma.