Enantio-selectivity of human nucleoside monophosphate kinases.

Over recent years, there has been a renewed interest in the development of L-nucleosides as safe and efficacious drugs for the treatment of viral infections. Biological activity of these compounds requires phosphorylation to their triphosphate form, involving nucleoside monophosphate kinases in the second step. In order to characterize the activation pathway of L-nucleosides of the pyrimidine series, we studied the enantio-selectivity of human uridylate-cytidylate and thymidylate kinases. The results showed that these enzymes are only weakly enantio-selective and are thus probably involved in the activation of L-nucleosides in vivo. An activation pathway for telbivudine (L-dT) was therefore proposed.

Technological Analysis of the World's Earliest Shamanic Costume: A Multi-Scalar, Experimental Study of a Red Deer Headdress from the Early Holocene Site of Star Carr, North Yorkshire, UK.

Shamanic belief systems represent the first form of religious practice visible within the global archaeological record. Here we report on the earliest known evidence of shamanic costume: modified red deer crania headdresses from the Early Holocene site of Star Carr (c. 11 kya). More than 90% of the examples from prehistoric Europe come from this one site, establishing it as a place of outstanding shamanistic/cosmological significance. Our work, involving a programme of experimental replication, analysis of macroscopic traces, organic residue analysis and 3D image acquisition, metrology and visualisation, represents the first attempt to understand the manufacturing processes used to create these artefacts. The results produced were unexpected--rather than being carefully crafted objects, elements of their production can only be described as expedient.

[Non-radioimmunometric NT-ProBNP and BNP assays: impact of diluent, age, gender, BMI]. / Corrélation BNP-NT-proBNP: rôle du diluant, influence de l'âge, du sexe et de l'indice de masse corporelle.

We examined the analytical correlation between non-radioimmunometric plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) and evaluated whether NT-proBNP or BNP was influenced by age, gender and/or body mass index (BMI). Electro-chemiluminescence (Elecsys, Roche diagnostic) and a single use fluorescence (Triage, Biosite) immunoassays were used to measure NT-proBNP and BNP levels respectively. As a preliminary, seven different diluents usually used in immunoassays were tested and the "speciality diluent" (Ortho Clinical Diagnostic) was validated to increase the linearity of BNP immunoassay above 5000 pg/mL. Data were collected prospectively from patients admitted to the emergency department for acute dyspnea. Plasma BNP and NT-proBNP were measured at admission. Reference diagnosis was adjudicated by 2 independent cardiologists using the European Society of Cardiology guidelines. One hundred and sixty consecutive patients were included: 84 females and 76 males, mean age 80.1 +/- 13.5 (16-98). The analytical correlation between NT-proBNP and BNP was satisfactory using the equation: log10(NT-proBNP) = 1.1xlog10(BNP) + 0.57 and a correlation r = 0.93. This was established over a wide range of concentration (5-6400 pg/mL for BNP). Age and gender were known to influence circulating BNP levels. We showed that the correlation between BNP and NT-proBNP was not influenced by age, gender and body mass index of patients which suggests that the distribution of both peptides was similarly affected by these parameters. We conclude that NT-proBNP, as assayed in the present study, correlates closely with BNP. Used in conjunction with other clinical information, rapid measurement of BNP or NT-proBNP is useful in establishing or excluding the diagnosis of congestive heart failure in patients with acute dyspnea.

Combination of long-acting furosemide and instant-acting amiloride: pharmacokinetics and pharmacodynamics in human subjects.

The pharmacokinetics and pharmacodynamics of the combination of amiloride (2 x 2.5 mg) and long-acting furosemide (2 x 10 mg) were compared with amiloride (5 mg) and furosemide (20 mg) in 12 healthy male volunteers aged 26.2 +/- 1.6 years and weighing 68.8 +/- 6.2 kg, after random order administration. Furosemide and amiloride plasma or urine concentrations were determined by HPLC with fluorimetric detection. The rate of absorption (tmax = 3 h) and the bioavailability of the two diuretics were not significantly modified by their combination. Furosemide plasma half-life was 2.77 +/- 1.04 h after the combination treatment and 2.76 +/- 0.98 h alone, amiloride plasma half-life was respectively 15.7 +/- 4.6 h and 14.6 +/- 3.7 h. The urinary elimination of furosemide was significantly higher in the 2-4 h interval in the combination treatment, accompanying its delayed maximum effect of diuresis. A synergistic effect was observed after the combination administration of the two diuretics; between the 2nd and the 8th hour, the sodium elimination was significantly increased (P less than 0.01) and the potassium excretion was significantly decreased (P = 0.05). After a single dose, no modification of plasma or erythrocyte magnesium levels was observed. This study shows that the combination of the two drugs entails a synergy of their activities which does not involve pharmacokinetic changes.

[Protein profile and iron deficiency: value of the study of the albumin-transferrin couple]. / Profil protéique et carence martiale: intérêt de l'étude du couple albumine-transferrine.

From a clinical standpoint, the search for iron deficiency is based upon serum ferritin. However, serumferritin values may be pathologic in other numerous pathological conditions such as inflammation, liver diseases, malignant hematologic disorders, hemolysis, etc. Proteic profile combines the analyze of proteins variations: protein results are converted in percent of normal values referenced for the technique used. It has been suggested that on the protein profile, an increase in serum transferrin level compared to a normal serum albumin level (DAT: difference albumin-transferrin), appears early in the course of iron deficiency. In order to know the value of a pathologic DAT > or = 28% in the diagnosis of iron deficiency, we prospectively studied 156 patients consecutively hospitalized in an internal medicine department. Iron deficiency was defined by a low serum ferritin level. Diagnosis performance (sensitivity, specificity, positive and negative predictive values) of different biologic markers of iron deficiency (serum iron, saturation of total iron-binding capacity, low mean erythrocyte volume) and DAT was compared to the performance of low serum ferritin values. With the exception of low serum ferritin (which have by definition a specificity and a positive predictive value of 100%), pathologic DAT appeared as the best index of iron deficiency with the highest sensitivity (67.4%), specificity (97.3%), positive predictive value (91.2%), negative predicitive value (87.7%) and diagnosis efficacy (sensitivity x specificity = 0.66). A pathologic DAT associated to a low serum ferritin level increased the diagnosis performance of both tests to 0.72. Diagnosis efficacy of DAT was not changed (0.66) in 83 patients with a confounding factor for serum ferritin analysis (inflammation, liver diseases, malignant hematologic disorders, hemolysis) when diagnosis efficacy of all other tests decreased. There was a negative correlation between serum ferritin level and DAT level (r = 0.55; P < 0.0001). In conclusion, an increase of serum transferrin of more than 28% compared to serum albumin on a proteic profile gives a significant benefit for the diagnosis of iron deficiency. This benefit increases when data of both DAT and serum ferritin are associated.

European Hernia Society classification of parastomal hernias.

PURPOSE: A classification of parastomal hernias (PH) is needed to compare different populations described in various trials and cohort studies, complete the previous inguinal and ventral hernia classifications of the European Hernia Society (EHS) and will be integrated into the EuraHS database (European Registry of Abdominal Wall Hernias). METHODS: Several members of the EHS board and invited experts gathered for 2 days to discuss the development of an EHS classification of PH. The discussions were based on a literature review and critical appraisal of existing classifications. RESULTS: The classification proposal is based on the PH defect size (small is ≤5 cm) and the presence of a concomitant incisional hernia (cIH). Four types were defined: Type I, small PH without cIH; Type II, small PH with cIH; Type III, large PH without cIH; and Type IV, large PH with cIH. In addition, the classification grid includes details about whether the hernia recurs after a previous PH repair or whether it is a primary PH. Clinical validation is needed in the future to assess if the classification allows us to differentiate the treatment strategy and if the classification impacts outcome in these different subgroups. CONCLUSION: A classification of PH divided into subgroups according to size and cIH was formulated with the aim of improving the ability to compare different studies and their results.

Adaptations to keep a thyrotropin immunoradiometric assay "supersensitive" with automated pipetting.

The sensitivity of the immunoradiometric kit "RIA-gnost hTSH" (Behring) is poorer with a common automated pipetting station than with careful manual pipetting, principally because of tracer contamination of the inner wall of the tube, above the level reached by the wash solution. This can be eliminated by adapting the wash buffer volume so as to fill the entire tube. In this way, one can detect as little thyrotropin as 0.02 milli-int. unit/L, which is better than the 0.03 milli-int. unit/L claimed by the manufacturer. Cross-contamination from pipetting can induce overestimation of "suppressed" thyrotropin values. Prolonging the counting time to obtain an optimal counting error is of no practical value in the thyrotropin range where activity is low.

[Pharmacokinetics of aspirin in African children with normal nutrition and malnutrition]. / Pharmacocinétique de l'aspirine chez l'enfant africain normonutri et malnutri.

Pharmacokinetics of aspirin given orally at antipyretic dose (12 mg/kg) were studied in 11 African children aged 4-48 months. In order to examine the influence of nutritional status on aspirin kinetics, children were classified according to Waterlow criteria. Blood samples were collected during the 8 hours following the initial dose. Albumin, prealbumin and transferrin plasma levels were measured and plasma salicylic acid (SA) concentrations determined by a fluorometric method. Nutritional status seemed to have no prominent effect on plasma concentrations of SA. The volume of distribution found in our study was lower than those obtained in other studies. This could be explained by lower plasma aspirin esterase activities in black children. There were large individual variations in plasma salicylate concentrations. For example, even at antipyretic doses, saturation phenomena appeared in two children.

Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin genes.

We describe a large family with a connective-tissue disorder that exhibits some of the skeletal and cardiovascular features seen in Marfan syndrome. However, none of the 19 affected individuals displayed ocular abnormalities and therefore did not comply with recognized criteria for this disease. These patients could alternatively be diagnosed as MASS (mitral valve, aorta, skeleton, and skin) phenotype patients or represent a distinct clinical entity, i.e., a new autosomal dominant connective-tissue disorder. The fibrillin genes located on chromosomes 15 and 5 are clearly involved in the classic form of Marfan syndrome and a clinically related disorder (congenital contractural arachnodactyly), respectively. To test whether one of these genes was also implicated in this French family, we performed genetic analyses. Blood samples were obtained for 56 family members, and four polymorphic fibrillin gene markers, located on chromosomes 15 (Fib15) and 5 (Fib5), respectively, were tested. Linkage between the disease allele and the markers of these two genes was excluded with lod scores of -11.39 (for Fib15) and -13.34 (for Fib5), at theta = .001, indicating that the mutation is at a different locus. This phenotype thus represents a new connective-tissue disorder, overlapping but different from classic Marfan syndrome.