Variation in mitochondrial DNA in a cline of allele frequencies and shell phenotype in the dog-whelk Nucella lapillus (L.)

Genetic constitution in the intertidal gastropod Nucella lapillus (L.) influences shell shape, growth rate and physiology. Clinal variation in these traits along a 5 km stretch of coastline in south Devon can be related to environmental variation in temperature and desiccation stress. We have examined mtDNA variation along this shore to investigate whether the cline represents primary or secondary contact. Two distinct mtDNA haplotypes were found which exhibit coincident step clines with karyotypic, allozymic and phenotypic variation and covary with the environmental pressures of temperature and desiccation. These results are interpreted in the context of the wider scale distribution of genetic and phenotypic variation in N. lapillus. It is suggested that the shore studied may represent one of a number of regions of secondary contact within a mosaic hybrid zone in N. lapillus , where coadapted phenotypic variation correlates with habitat and the position of the clines represents an environmental transition.     

Echocardiographic assessment and percutaneous closure of multiple atrial septal defects

Percutaneous coronary intervention can be associated with distal embolization of thrombotic material causing myocardial necrosis and infarction. We discuss the role of intravascular imaging to guide the use of a distal protection device by describing the outcome of a young woman presenting with non-ST elevation myocardial infarction. Coronary angiography demonstrated an isolated minor stenosis in the proximal left anterior descending coronary artery with slight haziness beyond the lesion. Intravascular ultrasound confirmed an extensive thrombus overlying a bulky atherosclerotic plaque. A distal filter wire was therefore successfully used to reduce the risk of distal embolization. The use of intravascular ultrasound in patients presenting with acute coronary syndrome may reveal large thrombi that are difficult to image using conventional angiographic techniques. Intravascular ultrasound can therefore be used as a tool to select lesions requiring distal protection.     

Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1

Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.     

When What's Left Is Right: Visuomotor Transformations in an Aged Population

Background

There has been little consensus as to whether age-related visuomotor adaptation effects are readily observable. Some studies have found slower adaptation, and/or reduced overall levels. In contrast, other methodologically similar studies have found no such evidence of aging effects on visuomotor adaptation. A crucial early step in successful adaptation is the ability to perform the necessary transformation to complete the task at hand. The present study describes the use of a viewing window paradigm to examine the effects of aging in a visuomotor transformation task.

Methods

Two groups of participants, a young adult control group (age range 18–33 years old, mean age = 22) and an older adult group (age range 62–74, mean age = 68) completed a viewing window task that was controlled by the user via a computer touchscreen. Four visuomotor “flip” conditions were created by varying the relationship between the participant''s movement, and the resultant on-screen movement of the viewing window: 1) No flip 2) X-Axis and Y-axis body movements resulted in the opposite direction of movement of the viewing window. In each of the 3) Flip-X and 4) Flip-Y conditions, the solitary X- or Y-axes were reversed. Response times and movement of the window were recorded.

Conclusions

Older participants demonstrated impairments in performing a required visuomotor transformation, as evidenced by more complex scanning patterns and longer scanning times when compared to younger control participants. These results provide additional evidence that the mechanisms involved in visuomotor transformation are negatively affected by age.     

Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors

Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC₅₀ = 4 nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.     

Monocyte matrix metalloproteinase production in Type 2 diabetes and controls – a cross sectional study

Background

Even mild hyperglycemia is associated with future acute and chronic complications. Nevertheless, many cases of diabetes in the community go unrecognized. The aim of the study was to determine if national electronic patient records could be used to identify patients with diabetes in a health management organization.

Methods

The central district databases of Israel's largest health management organization were reviewed for all patients over 20 years old with a documented diagnosis of diabetes mellitus (DM) in the chronic disease register or patient file (identified diabetic patients) or a fasting serum glucose level of >126 mg/100 ml according to the central laboratory records (suspected diabetic patients). The family physicians of the patients with suspected diabetes were asked for a report on their current diabetic status.

Results

The searches yielded 1,694 suspected diabetic patients; replies from the family physicians were received for 1,486. Of these, 575 (38.7%) were confirmed to have diabetes mellitus. Their addition to the identified patient group raised the relative rate of diabetic patients in the district by 3.2%.

Conclusion

Cross-referencing existing databases is an efficient, low-cost method for identifying hyperglycemic patients with unrecognized diabetes who require preventive treatment and follow-up. This model can be used to advantage in other clinical sites in Israel and elsewhere with fully computerized databases.     

Sequence variations in small-subunit ribosomal RNAs of Hartmannella vermiformis and their phylogenetic implications

Evidence of associations between free-living amoebas and human disease has been increasing in recent years. Knowledge about phylogenetic relationships that may be important for the understanding of pathogenicity in the genera involved is very limited at present. Consequently, we have begun to study these relationships and report here on the phylogeny of Hartmannella vermiformis, a free-living amoeba that can harbor the etiologic agent of Legionnaires' disease. Our analysis is based on studies of small-subunit ribosomal RNA genes (srDNA). Nucleotide sequences were determined for nuclear srDNA from three strains of H. vermiformis isolated from the United Kingdom, Germany, and the United States. These sequences then were compared with a sequence previously obtained for a North American isolate by J. H. Gunderson and M. L. Sogin. The four genes are 1,840 bp long, with an average GC content of 49.6%. Sequence differences among the strains range are 0.38%-0.76%. Variation occurs at 19 positions and includes 2 single-base indels plus 14 monotypic and 3 ditypic single-base substitutions. Variation is limited to eight helix/loop structures according to a current model for srRNA secondary structure. Parsimony, distance, and bootstrap analyses used to examine phylogenetic relationships between the srDNA sequences of H. vermiformis and other eukaryotes indicated that Hartmannella sequences were most closely related to those of Acanthamoeba and the alga Cryptomonas. All ditypic sites were consistent with a separation between European and North American strains of Hartmannella, but results of other tests of this relationship were statistically inconclusive.      

Human leukocyte granule elastase: rapid isolation and characterization.

Human granulocytic elastases have been purified by a two-step procedure involving affinity chromatography of crude extracts of leukocytic granules on Sepharose-Trasylol, followed by ion-exchange chromatography on CM-cellulose to resolve the isoelastases. All of these enzymes were found to be glycoproteins with the carbohydrate content of the major form being composed essentially of only neutral sugars. The molecular weight of this form was found to be near 30 000 daltons with the other forms being slightly higher. Preliminary structural analyses indicate that all of the elastase isozymes have identical NH2-terminal sequences suggesting that the differences in mobility of the four proteins are not due to different degrees of activation from a common zymogen but, more likely, from minor changes in carbohydrate content. Human granulocytic elastases are less active on ligament elastin than porcine pancreatic elastase, but both are inhibited by synthetic elastase active-site directed low molecular weight compounds (Tuhy, P. M., and Powers, J. C. (1975), FEBS Lett. 50, 359) as well as by plasma alpha-1-proteinase inhibitor (formerly called alpha-1-antitrypsin). In the latter case a stable complex with mol wt of 78 000 daltons is formed indicating the formation of a 1:1 complex.