An analytical study of one hundred cases of rheumatic heart disease in children

In this Thesis are given the results of an investigation into the social and medical histories of one hundred cases of rheumatic heart disease.In the first section of the Thesis are given the clinical findings upon which the diagnosis of heart disease has been based. In the next section follows the incidence rates of acute arthritis, chorea, growing pains, tonsillitis and scarlet fever, discovered in the histories of these patients. The results of tonsillectomy in the prevention of rheumatism are given. In other sections the subjects of enquiry are the social circumstances of the patients, and the relationship between the environment of the patients and the incidence of rheumatism among them.Two series of control cases have been used in these investigations, the first control series was a group of 600 children drawn from the same localities and schools as the rheumatic heart cases, and the second control series a group of 500 boys from a public school in the City.The examination of all these cases was carried out in the schools and school clinics in Hull, and in compiling their case- histories, use was made of Medical Âecords from the Maternity and Child Welfare Department and the School Medical Department of Hull. These records gave a very full account of the past illnesses of the children and added greatly to the reliability of the histories recorded.In the final section of the thesis are discussed and summarised the results from this enquiry

Borrelia burgdorferi Enolase Is a Surface-Exposed Plasminogen Binding Protein

Borrelia burgdorferi is the causative agent of Lyme disease, the most commonly reported arthropod-borne disease in the United States. B. burgdorferi is a highly invasive bacterium, yet lacks extracellular protease activity. In order to aid in its dissemination, B. burgdorferi binds plasminogen, a component of the hosts' fibrinolytic system. Plasminogen bound to the surface of B. burgdorferi can then be activated to the protease plasmin, facilitating the bacterium's penetration of endothelial cell layers and degradation of extracellular matrix components. Enolases are highly conserved proteins with no sorting sequences or lipoprotein anchor sites, yet many bacteria have enolases bound to their outer surfaces. B. burgdorferi enolase is both a cytoplasmic and membrane associated protein. Enolases from other pathogenic bacteria are known to bind plasminogen. We confirmed the surface localization of B. burgdorferi enolase by in situ protease degradation assay and immunoelectron microscopy. We then demonstrated that B. burgdorferi enolase binds plasminogen in a dose-dependent manner. Lysine residues were critical for binding of plasminogen to enolase, as the lysine analog εaminocaproic acid significantly inhibited binding. Ionic interactions did not play a significant role in plasminogen binding by enolase, as excess NaCl had no effects on the interaction. Plasminogen bound to recombinant enolase could be converted to active plasmin. We conclude that B. burgdorferi enolase is a moonlighting cytoplasmic protein which also associates with the bacterial outer surface and facilitates binding to host plasminogen

The relationship between oxidised LDL, endothelial progenitor cells and coronary endothelial function in patients with CHD

Objective The balance between coronary endothelial dysfunction and repair is influenced by many protective and deleterious factors circulating in the blood. We studied the relationship between oxidised low-density lipoprotein (oxLDL), circulating endothelial progenitor cells (EPCs) and coronary endothelial function in patients with stable coronary heart disease (CHD). Methods 33 patients with stable CHD were studied. Plasma oxLDL was measured using ELISA, coronary endothelial function was assessed using intracoronary acetylcholine infusion and EPCs were quantified using flow cytometry for CD34+/KDR+ cells. Results Plasma oxLDL correlated positively with the number of EPCs in the blood (r=0.46, p=0.02). There was a positive correlation between the number of circulating EPCs and coronary endothelial function (r=0.42, p=0.04). There was no significant correlation between oxLDL and coronary endothelial function. Conclusions Plasma levels of oxLDL are associated with increased circulating EPCs in the blood of patients with CHD, which may reflect a host-repair response to endothelial injury. Patients with stable CHD had a high prevalence of coronary endothelial dysfunction, which was associated with lower numbers of circulating EPCs, suggesting a mechanistic link between endothelial dysfunction and the pathogenesis of atherosclerosis

Epidermal stem cells are retained in vivo throughout skin aging

In healthy individuals, skin integrity is maintained by epidermal stem cells which self-renew and generate daughter cells that undergo terminal differentiation. It is currently unknown whether epidermal stem cells influence or are affected by skin aging. We therefore compared young and aged skin stem cell abundance, organization, and proliferation. We discovered that despite age-associated differences in epidermal proliferation, dermal thickness, follicle patterning, and immune cell abundance, epidermal stem cells were maintained at normal levels throughout life. These findings, coupled with observed dermal gene expression changes, suggest that epidermal stem cells themselves are intrinsically aging resistant and that local environmental or systemic factors modulate skin aging

Shape-Induced Terminal Differentiation of Human Epidermal Stem Cells Requires p38 and Is Regulated by Histone Acetylation

Engineered model substrates are powerful tools for examining interactions between stem cells and their microenvironment. Using this approach, we have previously shown that restricted cell adhesion promotes terminal differentiation of human epidermal stem cells via activation of serum response factor (SRF) and transcription of AP-1 genes. Here we investigate the roles of p38 MAPK and histone acetylation. Inhibition of p38 activity impaired SRF transcriptional activity and shape-induced terminal differentiation of human keratinocytes. In addition, inhibiting p38 reduced histone H3 acetylation at the promoters of SRF target genes, FOS and JUNB. Although histone acetylation correlated with SRF transcriptional activity and target gene expression, treatment with the histone de-acetylase inhibitor, trichostatin A (TSA) blocked terminal differentiation on micro-patterned substrates and in suspension. TSA treatment simultaneously maintained expression of LRIG1, TP63, and ITGB1. Therefore, global histone de-acetylation represses stem cell maintenance genes independent of SRF. Our studies establish a novel role for extrinsic physical cues in the regulation of chromatin remodeling, transcription, and differentiation of human epidermal stem cells

Functional characterization of an alkaline exonuclease and single strand annealing protein from the SXT genetic element of Vibrio cholerae

<p>Abstract</p> <p>Background</p> <p>SXT is an integrating conjugative element (ICE) originally isolated from <it>Vibrio cholerae</it>, the bacterial pathogen that causes cholera. It houses multiple antibiotic and heavy metal resistance genes on its ca. 100 kb circular double stranded DNA (dsDNA) genome, and functions as an effective vehicle for the horizontal transfer of resistance genes within susceptible bacterial populations. Here, we characterize the activities of an alkaline exonuclease (S066, SXT-Exo) and single strand annealing protein (S065, SXT-Bet) encoded on the SXT genetic element, which share significant sequence homology with Exo and Bet from bacteriophage lambda, respectively.</p> <p>Results</p> <p>SXT-Exo has the ability to degrade both linear dsDNA and single stranded DNA (ssDNA) molecules, but has no detectable endonuclease or nicking activities. Adopting a stable trimeric arrangement in solution, the exonuclease activities of SXT-Exo are optimal at pH 8.2 and essentially require Mn²⁺or Mg²⁺ions. Similar to lambda-Exo, SXT-Exo hydrolyzes dsDNA with 5'- to 3'-polarity in a highly processive manner, and digests DNA substrates with 5'-phosphorylated termini significantly more effectively than those lacking 5'-phosphate groups. Notably, the dsDNA exonuclease activities of both SXT-Exo and lambda-Exo are stimulated by the addition of lambda-Bet, SXT-Bet or a single strand DNA binding protein encoded on the SXT genetic element (S064, SXT-Ssb). When co-expressed in <it>E. coli </it>cells, SXT-Bet and SXT-Exo mediate homologous recombination between a PCR-generated dsDNA fragment and the chromosome, analogous to RecET and lambda-Bet/Exo.</p> <p>Conclusions</p> <p>The activities of the SXT-Exo protein are consistent with it having the ability to resect the ends of linearized dsDNA molecules, forming partially ssDNA substrates for the partnering SXT-Bet single strand annealing protein. As such, SXT-Exo and SXT-Bet may function together to repair or process SXT genetic elements within infected <it>V. cholerae </it>cells, through facilitating homologous DNA recombination events. The results presented here significantly extend our general understanding of the properties and activities of alkaline exonuclease and single strand annealing proteins of viral/bacteriophage origin, and will assist the rational development of bacterial recombineering systems.</p

Effect of suspension systems on the physiological and psychological responses to sub-maximal biking on simulated smooth and bumpy tracks

The aim of this study was to compare the physiological and psychological responses of cyclists riding on a hard tail bicycle and on a full suspension bicycle. Twenty males participated in two series of tests. A test rig held the front axle of the bicycle steady while the rear wheel rotated against a heavy roller with bumps (or no bumps) on its surface. In the first series of tests, eight participants (age 19 – 27 years, body mass 65 – 82 kg) were tested on both the full suspension and hard tail bicycles with and without bumps fitted to the roller. The second series of test repeated the bump tests with a further six participants (age 22 – 31 years, body mass 74 – 94 kg) and also involved an investigation of familiarization effects with the final six participants (age 21 – 30 years, body mass 64 – 80 kg). Heart rate, oxygen consumption (VO&lt;sub&gt;2&lt;/sub&gt;), rating of perceived exertion (RPE) and comfort were recorded during 10 min sub-maximal tests. Combined data for the bumps tests show that the full suspension bicycle was significantly different (P &#60; 0.001) from the hard tail bicycle on all four measures. Oxygen consumption, heart rate and RPE were lower on average by 8.7 (s &#61; 3.6) ml · kg&lt;sup&gt;-1&lt;/sup&gt; · min&lt;sup&gt;-1&lt;/sup&gt;, 32.1 (s &#61; 12.1) beats · min&lt;sup&gt;-1&lt;/sup&gt; and 2.6 (s &#61; 2.0) units, respectively. Comfort scores were higher (better) on average by 1.9 (s &#61; 0.8) units. For the no bumps tests, the only statistically significant difference (P &#61; 0.008) was in VO&lt;sub&gt;2&lt;/sub&gt;, which was lower for the hard tail bicycle by 2.2 (s &#61; 1.7) ml · kg-1 · min&lt;sup&gt;-1&lt;/sup&gt;. The results indicate that the full suspension bicycle provides a physiological and psychological advantage over the hard tail bicycle during simulated sub-maximal exercise on bumps

How should an infected perinephric haematoma be drained in a tetraplegic patient with baclofen pump implanted in the abdominal wall? – A case report

BACKGROUND: We present a case to illustrate controversies in percutaneous drainage of infected, perinephric haematoma in a tetraplegic patient, who had implantation of baclofen pump in anterior abdominal wall on the same side as perinephric haematoma. CASE PRESENTATION: A 56-year-old male with C-4 tetraplegia had undergone implantation of programmable pump in the anterior abdominal wall for intrathecal infusion of baclofen to control spasticity. He developed perinephric haematoma while he was taking warfarin as prophylactic for deep vein thrombosis. Perinephric haematoma became infected with a resistant strain of Pseudomonas aeruginosa, and required percutaneous drainage. Positioning this patient on his abdomen without anaesthesia, for insertion of a catheter from behind, was not a realistic option. Administration of general anaesthesia in this patient in the radiology department would have been hazardous. RESULTS AND CONCLUSION: Percutaneous drainage was carried out by anterior approach under propofol sedation. The site of entry of percutaneous catheter was close to cephalic end of baclofen pump. By carrying out drainage from anterior approach, and by keeping this catheter for ten weeks, we took a risk of causing infection of the baclofen pump site, and baclofen pump with a resistant strain of Pseudomonas aeruginosa. The alternative method would have been to anaesthetise the patient and position him prone for percutaneous drainage of perinephric collection from behind. This would have ensured that the drainage track was far away from the baclofen pump with minimal risk of infection of baclofen pump, but at the cost of incurring respiratory complications in a tetraplegic subject

Should there be a female age limit on public funding for Assisted Reproductive Technology? Differing conceptions of justice in resource allocation

Should there be a female age limit on public funding for assisted reproductive technology (ART)? The question bears significant economic and sociopolitical implications and has been contentious in many countries. We conceptualise the question as one of justice in resource allocation, using three much-debated substantive principles of justice—the capacity to benefit, personal responsibility, and need—to structure and then explore a complex of arguments. Capacity-to-benefit arguments are not decisive: There are no clear cost-effectiveness grounds to restrict funding to those older women who still bear some capacity to benefit from ART. Personal responsibility arguments are challenged by structural determinants of delayed motherhood. Nor are need arguments decisive: They can speak either for or against a female age limit, depending on the conception of need used. We demonstrate how these principles can differ not only in content but also in the relative importance they are accorded by governments. Wide variation in ART public funding policy might be better understood in this light. We conclude with some inter-country comparison. New Zealand and Swedish policies are uncommonly transparent and thus demonstrate particularly well how the arguments we explore have been put into practice