The absorption of regular human insulin from subcutaneous injection sites is delayed due to the self-association of insulin to multimeric forms. The insulin analogue insulin lispro has a weak ...self-association and a fast absorption rate. We examined the safety and efficacy of insulin lispro in the premeal treatment of patients with diabetes mellitus. A 12-month study was performed in 336 patients with insulin-dependent diabetes mellitus (IDDM) and 295 patients with non-insulin-dependent diabetes mellitus (NIDDM). The patients were randomized to inject either regular human insulin 30 to 45 minutes before eating, or insulin lispro immediately before each meal, in addition to basal insulin. The postprandial rise in serum glucose was lower in patients receiving insulin lispro than in those receiving regular human insulin therapy. At end point, the increment was significantly lower at 1 hour (35%) and at 2 hours (64%) after the meal in IDDM patients; in NIDDM patients, the increment was nonsignificantly lower at 1 hour (19%) and significantly lower at 2 hours (48%). IDDM patients receiving insulin lispro achieved significantly lower glycated hemoglobin (HbA
1c) levels in patients receiving regular human insulin (8.1% vs 8.3%. In NIDDM patients, HbA
1c levels decreased equally in both treatment groups. Due to its fast absorption rate, insulin lispro improves postprandial control in diabetes. Insulin lispro can be considered one step toward optimal insulin therapy and improved patient convenience.
Platelet-activating factor (PAF) acetylhydrolase, which inactivates PAF, has been detected in human and bovine seminal plasma and may represent a mechanism for regulating sperm-derived PAF. This ...study was designed to characterize further PAF acetylhydrolase in seminal plasma from domestic animal species. Sperm-free seminal plasma from the bull, stallion, rabbit, and rooster was assayed for acetylhydrolase activity based on the release of 3Hacetate from PAF. As reported previously for bud seminal plasma, activity in stallion, rabbit, and rooster seminal plasma was linear with both time and protein concentration, with specific activities of 97.4, 1.2, and 0.33 nmol PAF hydrolyzed/mg protein/min, respectively. Activity in seminal plasma from the bun, rabbit, and rooster was calcium-independent whereas activity in stallion seminal plasma increased with added calcium p 0.01). Addition of EDTA partially inhibited acetylhydrolase activity in stallion seminal plasma but increased the specific activity in rabbit seminal plasma (p 0.01). Enzyme activity in bull seminal plasma was nondialyzable (50 000 molecular weight cut-off), stable at pH 5.0, and heat-labile (greater than or equal to 60 degrees C). Very little activity was associated with bull seminal plasma lipoproteins isolated by KBr flotation or by precipitation with polyanions. These results demonstrate that PAF acetylhydrolase activity is present in seminal plasma from different species, with large differences in specific activity among species. These differences may be related to species differences in the physiological role of PAF and its regulation in sperm and male tract fluids
Aliphatic hydrocarbons exhibit an absorption feature at 3.4 km, observed toward sources that sample difftise regions of the interstellar medium (ISM). The absorbers responsible for this feature are ...assumed to reside in some component of interstellar dust, but the physical nature of the particles (size, shape, structure, etc.) is uncertain. Observations of interstellar polarization provide discrimination. Since the grains that carry the silicate absorption feature are known to be aligned, polarization across the 3.4 km hydrocarbon feature can be used to test the silicate-core organic refractory mantle grain theory. Although the 3.4 km feature has been observed to be devoid of polarization for one line of sight toward the Galactic center, a corresponding silicate polarization measurement for the same line of sight was not available. Here, we present spectropolarimetric observations of GCS 3-II and GCS 3-IV toward the Galactic center, where the 9.7 km silicate polarization has been previously observed. We show that polarization is not detected across the 3.4 km feature to a limit of 0.06% c 0.13% (GCS 3-II) and 0.15% c 0.31% (GCS 3-IV), well below the lowest available prediction of polarization on the basis of the core-mantle model. We conclude that the hydrocarbons in the diffuse ISM do not reside on the same grains as the silicates, and likely form a separate population of small grains.
Glutathione S-transferase P1 (GSTP1) is markedly downregulated in prostate cancer and prostatic intraepithelial neoplasia compared to normal prostate tissue. Downregulation of GSTP1 may, therefore, ...be an early event in prostate carcinogenesis. An A-->G polymorphism at nucleotide 313 results in an amino acid substitution (Ile105Val) in the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. In a study of 36 prostate cancer patients, Harries et al. reported that the Ile/Ile genotype is associated with a decreased risk of prostate cancer (odds ratio 0.4 (0.17-0.82)). We sought to confirm this finding and to examine the impact of this polymorphism together with several related polymorphisms implicated as risk factors for carcinogen-associated malignancies. One hundred and seventeen patients with prostate adenocarcinoma and 183 population-based controls were recruited to this case-control study. Genotyping of the GSTP1 (Ile105Val), GSTM1 (null), GSTT1 (null) and CYP1A1 (Ile462Val) genes was performed using polymerase chain reaction (PCR) based techniques on DNA prepared from peripheral blood. A questionnaire was used to collect demographic information from each subject. Cases were significantly older (P<0.0001) and had significantly greater family history of prostate cancer (P<0.0001), confirming known risk factors for this disease. By chi(2) analysis, none of the genotype distributions varied among cases and controls. Using a logistic regression model to control for known risk factors we were also unable to demonstrate a significant association with prostate cancer for any of the polymorphisms tested. This population fails to identify a relationship between the above polymorphisms and prostate adenocarcinoma.
: We used ENU mutagenesis in the mouse for the rapid generation of novel mutant phenotypes for both gene function studies and use as new animal models of human disease (Nolan et al. 2000b). One focus ...of the program was the development of a blood biochemistry screen. At 8–12 weeks of age, approximately 300 ml of blood was collected from F1 offspring of ENU mutagenized male mice. This yielded approximately 125 ml of plasma, used to perform a profile of 17 standard biochemical tests on an Olympus analyzer. Cohorts of F1 mice were also aged and then retested to detect late onset phenotypes. In total, 1,961 F1s were screened. Outliers were identified by running means and standard deviations. Of 70 mice showing consistent abnormalities in plasma biochemistry, 29 were entered into inheritance testing. Of these, 9 phenotypes were confirmed as inherited, 10 found not to be inherited, and 10 are still being tested. Inherited mutant phenotypes include abnormal lipid profiles (low total and HDL cholesterol, high triglycerides); abnormalities in bone and liver metabolism (low ALP, high ALP, high ALT, and AST); abnormal plasma electrolyte levels (high sodium and chloride); as well as phenotypes of interest for the study of diabetes (high glucose). The gene loci bearing the mutations are currently being mapped and further characterized. Our results have validated our biochemical screen, which is applicable to other mutagenesis projects, and we have produced a new set of mutants with defined metabolic phenotypes.
The normal human brain is characterized by a pattern of gross anatomical asymmetry. This pattern, known as the "torque", is associated with a sexual dimorphism: The male brain tends to be more ...asymmetric than that of the female. This fact, along with well-known sex differences in brain development (faster in females) and onset of psychosis (earlier with worse outcome in males), has led to the theory that schizophrenia is a disorder in which sex-dependent abnormalities in the development of brain torque, the correlate of the capacity for language, cause alterations in interhemispheric connectivity, which are causally related to psychosis (Crow TJ, Paez P, Chance SE. 2007. Callosal misconnectivity and the sex difference in psychosis. Int Rev Psychiatry. 19(4):449-457.). To provide evidence toward this theory, we analyze the geometry of interhemispheric white matter connections in adolescent-onset schizophrenia, with a particular focus on sex, using a recently introduced framework for white matter geometry computation in diffusion tensor imaging data (Savadjiev P, Kindlmann GL, Bouix S, Shenton ME, Westin CF. 2010. Local white geometry from diffusion tensor gradients. Neuroimage. 49(4):3175-3186.). Our results reveal a pattern of sex-dependent white matter geometry abnormalities that conform to the predictions of Crow's torque theory and correlate with the severity of patients' symptoms. To the best of our knowledge, this is the first study to associate geometrical differences in white matter connectivity with torque in schizophrenia.
Three experiments were conducted to determine the association between leaf number per tiller at defoliation, water-soluble carbohydrate (WSC) concentration and herbage mass of juvenile ryegrass ...plants when grown in a Mediterranean environment. Seedlings of ryegrass were grown in nursery pots arranged side-by-side and located outside in the open-air to simulate a mini-sward in Experiments 1 and 2, and a mixture of annual ryegrass and subterranean clover (Trifolium subterraneum L.) was grown in a small plot field study in Experiment 3. Swards were defoliated mechanically with the onset of defoliation commencing within 28 d of germination. Frequency of defoliation ranged from one to nine leaves per tiller, whilst defoliation height ranged from 30 mm of pseudostem height that removed all leaf laminae in Experiment 1, to 50 mm of pseudostem height with some leaf laminae remaining post-defoliation in Experiments 2 and 3.
The tree of life of fishes is in a state of flux because we still lack a comprehensive phylogeny that includes all major groups. The situation is most critical for a large clade of spiny-finned ...fishes, traditionally referred to as percomorphs, whose uncertain relationships have plagued ichthyologists for over a century. Most of what we know about the higher-level relationships among fish lineages has been based on morphology, but rapid influx of molecular studies is changing many established systematic concepts. We report a comprehensive molecular phylogeny for bony fishes that includes representatives of all major lineages. DNA sequence data for 21 molecular markers (one mitochondrial and 20 nuclear genes) were collected for 1410 bony fish taxa, plus four tetrapod species and two chondrichthyan outgroups (total 1416 terminals). Bony fish diversity is represented by 1093 genera, 369 families, and all traditionally recognized orders. The maximum likelihood tree provides unprecedented resolution and high bootstrap support for most backbone nodes, defining for the first time a global phylogeny of fishes. The general structure of the tree is in agreement with expectations from previous morphological and molecular studies, but significant new clades arise. Most interestingly, the high degree of uncertainty among percomorphs is now resolved into nine well-supported supraordinal groups. The order Perciformes, considered by many a polyphyletic taxonomic waste basket, is defined for the first time as a monophyletic group in the global phylogeny. A new classification that reflects our phylogenetic hypothesis is proposed to facilitate communication about the newly found structure of the tree of life of fishes. Finally, the molecular phylogeny is calibrated using 60 fossil constraints to produce a comprehensive time tree. The new time-calibrated phylogeny will provide the basis for and stimulate new comparative studies to better understand the evolution of the amazing diversity of fishes.
The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) is to formulate an evidence-based guidance for the use of neuromuscular blocking agents (NMBA) in adults with acute ...respiratory distress syndrome (ARDS). The panel comprised 20 international clinical experts from 12 countries, and 2 patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines and followed a strict conflict of interest policy. We convened panelists through teleconferences and web-based discussions. Guideline experts from the guidelines in intensive care, development, and evaluation Group provided methodological support. Two content experts provided input and shared their expertise with the panel but did not participate in drafting the final recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence and grade recommendations and suggestions. We used the evidence to decision framework to generate recommendations. The panel provided input on guideline implementation and monitoring, and suggested future research priorities. The overall certainty in the evidence was low. The ICM-RPG panel issued one recommendation and two suggestions regarding the use of NMBAs in adults with ARDS. Current evidence does not support the early routine use of an NMBA infusion in adults with ARDS of any severity. It favours avoiding a continuous infusion of NMBA for patients who are ventilated using a lighter sedation strategy. However, for patients who require deep sedation to facilitate lung protective ventilation or prone positioning, and require neuromuscular blockade, an infusion of an NMBA for 48 h is a reasonable option.
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