Studies on Rheumatic Carditis With Special Reference to Sub-Clinical Rheumatism

In a group of 175 with mitral valve disease submitted to valvotomy, changes suggesting an active disease process were present in 64 per cent of cases. Of the patients showing active disease 23 per cent showed lesions which do not appear to have reached the stage of developed Aschoff type lesions. In a proportion of patients (8%) the lesions are of the earliest type described in rheumatic disease as mucoid oedema, and 15% show lesions in which the earliest type of change in the collagen is present. The changes in the collagen correspond to the changes described by Gross and Ehrlich as preceding the formation of the coronal type of Aschoff body and differ in appearance from the reticular Aschoff body which I believe corresponds to the rheumatic "Fruhinfiltrat" of Klinge. A fibrin staining component was not detected in any of the auricular appendages, reliance being placed on Mallory's phosphotungstic acid haematoxylin stain which requires no differentiation. Preceding any detectable alteration in the collagen there is an accumulation of acid mucopolysaccharide in the tissue spaces and this persists but in reduced amount to the later tyres of lesions. The altered collagen appears to contain a variable amount of periodic-acid-Schiff positive material and possibly a tyrosine-containing protein. The staining reactions of the altered collagen in most cases are similar to those of collagen. Preservation of the fibrils is suggested by the preservation of birefringence in the altered collagen and the configuration of the material within some of the lesions. The healing process described by Gross and Ehrlich can be recognised but it is suggested that healing can occur with retention of the radiate arrangement of cells found in coronal lesions and also that a fibrillary stage may not occur in some cases, thickened collagen fibres being left in place of fibrillary scars. The early exudative phase appears to be much more extensive than the developed lesions would suggest. The differences between acute and sub-clinical rheumatic fever may lie in the extent of the exudativedegenerative phase tnd .also in the intensity of the alteration to the collagen. A close correlation was found between the presence of active lesions in the left auricular appendage and the ventricular myocardium. Skin and muscle from patients with active rheumatic lesions in the left auricular appendages showed no abnormality. In an autopsy series of 61 cases of rheumatic heart disease, active lesions were found in 12 cases. In 28 of these patients in the same age group and with valve lesions comparable to the biopsy series, 7 cases (25%) showed active rheumatism. As compared with a control series of non-rheumatic hearts, a large proportion of patients with rheumatic heart disease showed metachromasia in the auricular appendage and the left atrial wall. In a clinico-pathological correlation it has been shown that there is a marked difference in the incidence of lesions in patients with sinus rhythm and auricular fibrillation. The explanation for this has not been found but it applies at all age groups above the age of thirty. No evidence of clinical activity was found in the valvotomy cases and because the earliest changes of rheumatic disease can be found in some specimens this is put forward as proof that sub-clinical rheumatism is an entity and present clinical and laboratory methods are inadequate to detect this. The incidence of active rheumatism in the valvotomy series and the histories of these patients suggest that the acute attack of rheumatic fever is a rare occurrence in the course of the disease and that the bulk of the damage to the heart is the result of repeated episodes of sub-clinical rheumatic fever which may overlap, or to a continuous rheumatic process. One major difference is detected between the autopsy series and the valvotomy series. There is a marked change in the proportion of patients in auricular fibrillation and it is suggested that this factor may account at least in part for the low incidence of active lesions in the autopsy series. The majority of patients with rheumatic heart disease who die in this centre die in auricular fibrillation and show no histological evidence of active rheumatism. It is tentatively suggested that the increase in metachromasia in the hearts of patients with valvular disease who die with no evidence of rheumatic activity may be the result of early rheumatism. The results of chemical estimations of the hexosamine/ hydroxyproline ratio in auricular appendages showing active lesions and without active lesions were inconclusive

Mechanism of Honey Bacteriostatic Action Against MRSA and VRE Involves Hydroxyl Radicals Generated from Honey’s Hydrogen Peroxide

It has been recently reported that honey hydrogen peroxide in conjunction with unknown honey components produced cytotoxic effects resulting in bacterial growth inhibition and DNA degradation. The objective of this study was twofold: (a) to investigate whether the coupling chemistry involving hydrogen peroxide is responsible for a generation of hydroxyl radicals and (b) whether •OH generation affects growth of multi-drug resistant clinical isolates. The susceptibility of five different strains of methicillin-resistant Staphylococcus aureus (MRSA) and four strains of vancomycin-resistant Enterococcus faecium (VRE) isolates from infected wounds to several honeys was evaluated using broth microdilution assay. Isolates were identified to genus and species and their susceptibility to antibiotics was confirmed using an automated system (Vitek®, Biomérieux®). The presence of the mec(A) gene, nuc gene and van(A) and (B) genes were confirmed by polymerase chain reaction. Results showed that no clinical isolate was resistant to selected active honeys. The median difference in honeys MICs against these strains ranged between 12.5 and 6.25% v/v and was not different from the MIC against standard Escherichia coli and Bacillus subtilis. Generation of •OH during bacteria incubation with honeys was analyzed using 3′-(p-aminophenyl) fluorescein (APF) as the •OH trap. The •OH participation in growth inhibition was monitored directly by including APF in broth microdilution assay. The growth of MRSA and VRE was inhibited by •OH generation in a dose-dependent manner. Exposure of MRSA and VRE to honeys supplemented with Cu(II) augmented production of •OH by 30-fold and increased honey bacteriostatic potency from MIC90 6.25 to MIC90< 0.78% v/v. Pretreatment of honeys with catalase prior to their supplementation with Cu ions fully restored bacterial growth indicating that hydroxyl radicals were produced from H2O2 via the Fenton-type reaction. In conclusion, we have demonstrated for the first time that bacteriostatic effect of honeys on MRSA and VRE was dose-dependently related to generation of •OH from honey H2O2

Therapeutic targeting of p90 ribosomal S6 kinase

The Serine/Threonine protein kinase family, p90 ribosomal S6 kinases (RSK) are downstream effectors of extracellular signal regulated kinase 1/2 (ERK1/2) and are activated in response to tyrosine kinase receptor or G-protein coupled receptor signaling. RSK contains two distinct kinase domains, an N-terminal kinase (NTKD) and a C-terminal kinase (CTKD). The sole function of the CTKD is to aid in the activation of the NTKD, which is responsible for substrate phosphorylation. RSK regulates various homeostatic processes including those involved in transcription, translation and ribosome biogenesis, proliferation and survival, cytoskeleton, nutrient sensing, excitation and inflammation. RSK also acts as a major negative regulator of ERK1/2 signaling. RSK is associated with numerous cancers and has been primarily studied in the context of transformation and metastasis. The development of specific RSK inhibitors as cancer therapeutics has lagged behind that of other members of the mitogen-activated protein kinase signaling pathway. Importantly, a pan-RSK inhibitor, PMD-026, is currently in phase I/1b clinical trials for metastatic breast cancer. However, there are four members of the RSK family, which have overlapping and distinct functions that can vary in a tissue specific manner. Thus, a problem for transitioning a RSK inhibitor to the clinic may be the necessity to develop isoform specific inhibitors, which will be challenging as the NTKDs are very similar to each other. CTKD inhibitors have limited use as therapeutics as they are not able to inhibit the activity of the NTKD but could be used in the development of proteolysis-targeting chimeras

Tyrosine Kinase Growth Factors in Gastric Cancer

In the West of Scotland in the last thirty years there has been a definite decrease in the incidence and mortality from gastric cancer but the survival of patients who develop adenocarcinoma of the stomach remains poor. This thesis is introduced by an audit of gastric cancer in a single centre over a period of twenty years. This aims to describe changes in the presentation, diagnosis and management of the condition during the period of study. Overall, despite improvements in investigation the disease still presents at an advanced stage and rates of curative resection are low. Advances in surgical technique and post-operative care have not improved long term survival with little significant additional benefit from current adjuvent medical therapy. The tyrosine kinase growth factor receptors have been investigated in a number of human cancers including breast, colon, ovarian and squamous carcinoma. In gastric cancer, the level of expression and prognostic value of EGFr and c-erbB-2 have been reported with some considerable variation using standard immunohistochemistry. To assess the use of growth factors as tumour markers or potential therapeutic targets, reliable quantitative and reproducible measurements of expression must be established. This study reports the quantitative expression of EGFr and c-erbB-2 using radioimmunohistochemistry (RIHC) and compares the results with expression using conventional immunohistochemistry (IHC). The correlation of established clinico- pathological factors with EGFr, c-erbB-2 and the gene amplification of c-erbB-2 using fluorescence in situ hybridisation is investigated. In both EGFr and c-erbB-2 expression there is good overall correlation analysis using RIHC and IHC (p<0.0005) but the separation of results is significantly better with RIHC particularly in the higher expressing tumours. In comparing tumour to mucosal samples, 22.4% of tumours expressed c-erbB-2 at a higher level, using RIHC and 43.3% with IHC. EGFr was expressed in 22.4% of cases more than the mucosal range with RIHC and 41. 8% with IHC. There was no correlation of EGFr and c-erb-2 (r2 = 0.004, p = 0.594). In this study there is significant correlation of c-erbB-2 with well and moderately well differentiated tumours (p=0.008) and no serosal involvement (p=0.066). EGFr in this study also appears to correlate with well and moderately well differentiated tumours (p=0.079). There was no correlation between EGFr, c-erbB-2 and patient survival. This thesis has demonstrated IGF-I induced cellular proliferation with a dose dependent inhibition by the tyrophostin RG13022. IGF-I is found to be a less potent stimulator of the MAP kinase pathway than EGF and RG13022 is less able to inhibit this pathway

Variation in the management of elderly patients in two neighboring breast units is due to preferences and attitudes of health professionals

Introduction: Elderly breast cancer patients have been shown to be managed less aggressively than younger patients. There is evidence that their management varies between institutions. We audited the management of elderly patients in two neighboring units in Glasgow and aimed to identify reasons for any differences in practice found. Methods: Patients aged ≥70 years, who were managed for a new diagnosis of breast cancer in the two units between 2009 and 2013, were identified from a prospectively maintained database. Tumor pathology, treatment details, postcode and consultant in charge of care were obtained from the same database. Comorbidities were obtained from each patient’s electronic clinical record. Questionnaires were distributed to members of each multidisciplinary teams. Results: 487 elderly patients in Unit 1 and 467 in Unit 2 were identified. 76.2% patients in Unit 1 were managed surgically compared to 63.7% in Unit 2 (p&lt;0.0001). There was no difference between the two units in patient age, tumor pathology, deprivation or comorbidity. 16.2% patients managed surgically in Unit 1 had a comorbidity score of 6 and above compared to 11% of surgically managed patients in Unit 2 (p=0.036). Responses to questionnaires suggested that staff at Unit 1 were more confident of the safety of general anesthetic in elderly patients and were more willing to consider local anesthetic procedures. Conclusion: A higher proportion of patients aged &gt;70 years with breast cancer were managed surgically in Unit 1 compared to Unit 2. Reasons for variation in practice seem to be related to attitudes of medical professionals toward surgery in the elderly, rather than patient or pathological factors

Impact of large-scale automation on healthcare staff

New technological advancements are often a driver for change in the redesign of services. More research is needed to better understand the impact of socio-technical dimensions on the implementation of new technological systems in hospital pharmacy. This paper aims to analyse the experiences arising from the large-scale automation of medicines distribution. The introduction of new technology may not only lead to unintended first-order consequences, but can also generate potentially serious adverse feedback loops between the social and technical dimensions. In addition, the longer-term impact of new technology may be quite different for different groups of healthcare staff

The relationship between oestrogen receptor-alpha phosphorylation and the tumour microenvironment in patients with primary operable ductal breast cancer

Aims: Although the role of phosphorylation of oestrogen receptor (ER) at serines 118 (p-S118) and 167 (p-S167) has been studied, the relationship between p-S118, p-S167 and the tumour microenvironment in ER-positive primary operable ductal breast cancers have not been investigated. The aims of this study are to investigate (i) the relationship between p-S118/p-S167 and the tumour microenvironment, and (ii) the effect of p-S118/167 on survival and recurrence in ER-positive primary operable ductal breast cancers. Methods and results: Patients presenting at three Glasgow hospitals between 1995 and 1998 with invasive ductal ER-positive primary breast cancers were studied (n = 294). Immunohistochemical staining of p-S118 and p-S167 was performed and their association with clinicopathological characteristics, cancer-specific survival (CSS) and recurrence-free interval (RFI) were examined. In the whole cohort, tumour size (P &lt; 0.05) and microvessel density (P &lt; 0.05) were associated with high p-S118 while increased micovessel density (P &lt; 0.05), apoptosis (P &lt; 0.05), general inflammatory infiltrate measured using the Klintrup–Makinen score (P &lt; 0.05) and macrophage infiltrate (P &lt; 0.05) were found to be associated with high p-S167. Only high p-S167 was associated with shorter CSS (P &lt; 0.005) and shorter RFI in the whole cohort (P = 0.001) and separately in the luminal A (P &lt; 0.05) and B tumours (P &lt; 0.05). Conclusions: This study showed that both p-S118 and p-S167 were associated with several microenvironmental factors, including increased microvessel density. In particular, p-S167 was associated with reduced RFI and CSS in the whole cohort and RFI in luminal A and B tumours and could possibly be employed to predict response to kinase inhibitors

Regulation of Virulence of Entamoeba histolytica by the URE3-BP Transcription Factor

It is not understood why only some infections with Entamoeba histolytica result in disease. The calcium-regulated transcription factor upstream regulatory element 3-binding protein (URE3-BP) was initially identified by virtue of its role in regulating the expression of two amebic virulence genes, the Gal/GalNac lectin and ferredoxin. Here we tested whether this transcription factor has a broader role in regulating virulence. A comparison of in vivo to in vitro parasite gene expression demonstrated that 39% of in vivo regulated transcripts contained the URE3 motif recognized by URE3-BP, compared to 23% of all promoters (P < 0.0001). Amebae induced to express a dominant positive mutant form of URE3-BP had an increase in an elongated morphology (30% ± 6% versus 14% ± 5%; P = 0.001), a 2-fold competitive advantage at invading the intestinal epithelium (P = 0.017), and a 3-fold increase in liver abscess size (0.1 ± 0.1 g versus 0.036 ± 0.1 g; P = 0.03). These results support a role for URE3-BP in virulence regulation