Quantifying Argonaute 2 (Ago2) expression to stratify breast cancer.

BACKGROUND: Argonaute-2 (Ago2) is an essential component of microRNA biogenesis implicated in tumourigenesis. However Ago2 expression and localisation in breast cancer remains undetermined. The aim was to define Ago2 expression (mRNA and protein) and localisation in breast cancer, and investigate associations with clinicopathological details. METHODS: Ago2 protein was stained in breast cancer cell lines and tissue microarrays (TMAs), with intensity and localization assessed. Staining intensity was correlated with clinicopathological details. Using independent databases, Ago2 mRNA expression and gene alterations in breast cancer were investigated. RESULTS: In the breast cancer TMAs, 4 distinct staining intensities were observed (Negative, Weak, Moderate, Strong), with 64.2% of samples stained weak or negatively for Ago2 protein. An association was found between strong Ago2 staining and, the Her2 positive or basal subtypes, and between Ago2 intensity and receptor status (Estrogen or Progesterone). In tumours Ago2 mRNA expression correlated with reduced relapse free survival. Conversely, Ago2 mRNA was expressed significantly lower in SK-BR-3 (HER2 positive) and BT-20 (Basal/Triple negative) cell lines. Interestingly, high levels of Ago2 gene amplification (10-27%) were observed in breast cancer across multiple patient datasets. Importantly, knowledge of Ago2 expression improves predictions of breast cancer subtype by 20%, ER status by 15.7% and PR status by 17.5%. CONCLUSIONS: Quantification of Ago2 improves the stratification of breast cancer and suggests a differential role for Ago2 in breast cancer subtypes, based on levels and cellular localisation. Further investigation of the mechanisms affecting Ago2 dysregulation will reveal insights into the molecular differences underpinning breast cancer subtypes.

Greater yogurt consumption is associated with increased bone mineral density and physical function in older adults.

In this cohort of community dwelling older adults (>60 years), we observed significant positive associations between the frequencies of yogurt intake with measures of bone density, bone biomarkers, and indicators of physical function. Improving yogurt intakes could be a valuable health strategy for maintaining bone health in older adults. INTRODUCTION: The associations of yogurt intakes with bone health and frailty in older adults are not well documented. The aim was to investigate the association of yogurt intakes with bone mineral density (BMD), bone biomarkers, and physical function in 4310 Irish adults from the Trinity, Ulster, Department of Agriculture aging cohort study (TUDA). METHODS: Bone measures included total hip, femoral neck, and vertebral BMD with bone biochemical markers. Physical function measures included Timed Up and Go (TUG), Instrumental Activities of Daily Living Scale, and Physical Self-Maintenance Scale. RESULTS: Total hip and femoral neck BMD in females were 3.1-3.9% higher among those with the highest yogurt intakes (n = 970) compared to the lowest (n = 1109; P < 0.05) as were the TUG scores (-6.7%; P = 0.013). In males, tartrate-resistant acid phosphatase (TRAP 5b) concentrations were significantly lower in those with the highest yogurt intakes (-9.5%; P < 0.0001). In females, yogurt intake was a significant positive predictor of BMD at all regions. Each unit increase in yogurt intake in females was associated with a 31% lower risk of osteopenia (OR 0.69; 95% CI 0.49-0.96; P = 0.032) and a 39% lower risk of osteoporosis (OR 0.61; 95% CI 0.42-0.89; P = 0.012) and in males, a 52% lower risk of osteoporosis (OR 0.48; 95% CI 0.24-0.96; P = 0.038). CONCLUSION: In this cohort, higher yogurt intake was associated with increased BMD and physical function scores. These results suggest that improving yogurt intakes could be a valuable public health strategy for maintaining bone health in older adults.

Hospitalisations for fracture and associated costs between 2000 and 2009 in Ireland: a trend analysis.

UNLABELLED: In Ireland, the absolute numbers of hospitalisations for all osteoporotic-type fractures including hip fractures increased between 2000 and 2009 along with the mean length of stay. The cost of hospitalisations for these fractures also increased between 2003 and 2008. INTRODUCTION: The purposes of the study were to carry out a trend analyses of the total number of osteoporotic-type fractures in males and females aged 50 years and over in Ireland between 2000 and 2009 and to project the number of osteoporotic-type fractures in the Republic of Ireland expected by 2025. METHODS: Age- and gender-specific trends in the absolute numbers and direct age-standardised rates of hospitalisations for all osteoporotic-type fractures in men and women ≥ 50 years were analysed, along with the associated hospitalisation costs and length of stay using the Hospital In-Patient Enquiry system database. Future projections of absolute numbers of osteoporotic-type fractures in years 2015, 2020 and 2025 were computed based on the 2009 incidence rates applied to the projected populations. RESULTS: Between 2000 and 2009, the absolute numbers of all osteoporotic-type fractures increased by 12 % in females and by 15 % in males while the absolute numbers of hip fractures increased by 7 % in women and by 20 % in men. The age-specific rates for hip fractures decreased in all age groups with the exception of the 55-59-year age group which showed an increase of 4.1 % (p = 0.023) within the study period. The associated hospitalisation costs and length of stay increased. Assuming stable age-standardised incidence rates from 2009 over the next 20 years, the number of all types of osteoporotic-type fractures is projected to increase by 79 % and the number of hip fractures is expected to increase by 88 % by 2025. CONCLUSIONS: Hospitalisations for osteoporotic-type fractures continued to increase in Ireland. Hip fractures increased by 7 % in women and 20 % in men.

Quantifying Tip60 (Kat5) stratifies breast cancer.

Breast cancer is stratified into four distinct clinical subtypes, using three key biomarkers (Her2/Neu gene status, Estrogen and Progesterone receptor status). However, each subtype is a heterogeneous group, displaying significant variation in survival rates and treatment response. New biomarkers are required to provide more precise stratification of breast cancer cohorts to inform personalised treatment options/predict outcomes. Tip60 is a member of the MYST sub-family of histone acetyltransferases (HATs), and is directly involved in genome maintenance, gene regulation and DNA damage response/repair pathways (key chemotherapeutic influencing mechanisms). We aimed to determine if quantifying Tip60 staining patterns improved breast cancer stratification. We defined Tip60 protein in vivo, quantifying location (cytoplasmic, nuclear), percent of cells and staining intensity in a breast cancer tissue microarray (n = 337). A significant association of specific Tip60 staining patterns with breast cancer subtype, ER or PR status and Tumour grade was found. Importantly, low Tip60 mRNA expression correlated with poor overall survival and relapse free survival. We found Tip60 is a biomarker able to stratify breast cancer patients, and low Tip60 expression is a significant risk factor indicating a higher chance of disease reoccurrence. This work highlights Tip60 regulation as a key factor influencing the development of breast cancer.

Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): kindred disorders of autonomic regulation.

Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS) were long considered rare disorders of respiratory control and more recently have been highlighted as part of a growing spectrum of disorders within the rubric of autonomic nervous system (ANS) dysregulation (ANSD). CCHS typically presents in the newborn period with a phenotype including alveolar hypoventilation, symptoms of ANSD and, in a subset of cases, Hirschsprung disease and later tumors of neural crest origin. Study of genes related to autonomic dysregulation and the embryologic origin of the neural crest led to the discovery of PHOX2B as the disease-defining gene for CCHS. Like CCHS, SIDS is thought to result from central deficits in control of breathing and ANSD, although SIDS risk is most likely defined by complex multifactorial genetic and environmental interactions. Some early genetic and neuropathological evidence is emerging to implicate serotonin systems in SIDS risk. The purpose of this article is to review the current understanding of the genetic basis for CCHS and SIDS, and discuss the impact of this information on clinical practice and future research directions.

Dairy Intakes in Older Irish Adults and Effects on Vitamin Micronutrient Status: Data from the TUDA Study.

BACKGROUND: Consumption of dairy products has been associated with positive health outcomes including a lower risk of hypertension, improved bone health and a reduction in the risk of type 2 diabetes. The suggested dairy intake for health in older adults is three servings per day but recent analysis of the NHANES data for older adults reported 98% were not meeting these recommendations. No studies have investigated the consequences of such declines in the dairy intakes of Irish older adults and the subsequent effects on vitamin micronutrient status. OBJECTIVES: To study the daily dairy intakes of older Irish adults and to examine how the frequency of dairy food consumption affects vitamin micronutrient status. METHODS: Participants (n 4,317) were from the Trinity Ulster Department of Agriculture (TUDA) Study, a large study of older Irish adults (aged >60 yrs) designed to investigate gene-nutrient interactions in the development of chronic diseases of aging. The daily intake portion for milk, cheese and yoghurt was calculated from food frequency questionnaire (FFQ) responses. Blood samples were analysed for vitamin biomarkers as follows: vitamin B12 (total serum cobalamin and holotranscobalamin (holoTC)), folate (red cell folate (RCF) and serum folate), vitamin B2 (erythrocyte glutathione reductase activation coefficient (EGRac)), vitamin B6 (serum pyridoxal phosphate) and vitamin D (serum 25(OH)D). RESULTS: The mean total reported dairy intake was 1.16 (SD 0.79) portions per day with males consuming significantly fewer total dairy portions compared to females (1.07 vs 1.21 respectively) (P<0.05). There was no significant difference in total daily dairy serving intakes by age decade (60-69, 70-79, >80 yrs). Overall, only 3.5% of the total population (n 151) achieved the recommended daily dairy intake of three or more servings per day. A significantly higher proportion of females (4%) compared to males (2.4%) met these dairy requirements (P=0.011). Blood concentrations of vitamin B12 biomarkers, RCF, vitamin B2 and vitamin B6 were significantly worse in those with the lowest tertile of dairy intake (0-0.71 servings) compared to those in the highest tertile (1.50-4.50 servings) (P<0.05). CONCLUSION: This study found that more than 96% of the older adults sampled did not meet current daily dairy intake recommendations. The study is the largest to-date examining dairy intakes in older Irish adults, and provides evidence that daily dairy intakes (in particular yogurt) contribute significantly to the B-vitamin and vitamin D biomarker status of older adults. These results suggest that older adults who are already vulnerable to micronutrient inadequacies, are forgoing the nutritional advantages of vitamin-rich dairy products.

Immunohistochemistry of carbonic anhydrase isozyme IX (MN/CA IX) in human gut reveals polarized expression in the epithelial cells with the highest proliferative capacity.

MN/CA IX is a recently discovered member of the carbonic anhydrase (CA) gene family that has been identified in the plasma membranes of certain tumor and epithelial cells and found to promote cell proliferation when transfected into NIH3T3 cells. This study presents localization of MN/CA IX in human gut and compares its distribution to those of CA I, II, and IV, which are known to be expressed in the intestinal epithelium. The specificity of the monoclonal antibody for MN/CA IX was confirmed by Western blots and immunostaining of COS-7 cells transfected with MN/CA IX cDNA. Immunohistochemical stainings of human gut revealed prominent polarized staining for MN/CA IX in the basolateral surfaces of the enterocytes of duodenum and jejunum, the reaction being most intense in the crypts. A moderate reaction was also seen in the crypts of ileal mucosa, whereas the staining became generally weaker in the large intestine. The results indicate isozyme-specific regulation of MN/CA IX expression along the cranial-caudal axis of the human gut and place the protein at the sites of rapid cell proliferation. The unique localization of MN/CA IX on the basolateral surfaces of proliferating crypt enterocytes suggests that it might serve as a ligand or a receptor for another protein that regulates intercellular communication or cell proliferation. Furthermore, MN/CA IX has a completely conserved active site domain of CAs suggesting that it could also participate in carbon dioxide/bicarbonate homeostasis.

Lymphoma associated bone marrow necrosis with raised anticardiolipin antibody.

A case of high grade B cell lymphoma presented with bone marrow necrosis, followed by development of extensive marrow fibrosis, the evolution of which was documented by serial magnetic resonance imaging and bone marrow trephine histology. A markedly raised anticardiolipin antibody titre at diagnosis suggests that lymphoma associated antiphospholipid syndrome may have contributed to the aetiology of the bone marrow necrosis.

Non-operative management of diverticular perforation in a patient with suspected Ehlers-Danlos syndrome.

INTRODUCTION: No consensus exists regarding definitive management of colonic perforation in Ehlers-Danlos syndrome (EDS), with various authors advocating different operative techniques. Spontaneous colonic perforation is a recognised complication of vascular-type EDS (type IV), with many reported cases in the literature. No such cases have been reported concerning classical-type EDS (type I/II). PRESENTATION OF CASE: A 55-year-old male with a family history of EDS presented with acute lower abdominal pain and signs of localised peritonitis. Following resuscitation, computerised tomography identified perforation of a sigmoid diverticulum with localised intraperitoneal air. Considering the potential complications associated with laparotomy in a patient with EDS, a trial of conservative management was undertaken including image-guided drainage of a mesenteric abscess. Intensive care monitoring, nutritional support and intravenous antibiotics also facilitated successful non-operative management. Following discharge, molecular studies confirmed COL5A1 mutation, and a diagnosis of classical Ehlers-Danlos syndrome was established. DISCUSSION: This is the first reported case of successful conservative management of colonic diverticular perforation in a patient with classical Ehlers-Danlos syndrome. CONCLUSION: EDS is highly significant in the surgical context, with the causative genetic factors serving to further complicate the course of surgical intervention. In the absence of consensus regarding best surgical management, due consideration should be given to non-operative management of benign colonic perforation.

Farm-related trauma in the west of Ireland: an occupational hazard.

BACKGROUND: Farm fatalities in Ireland remain at their highest recorded levels despite the introduction and implementation of several farm safety initiatives during recent years. AIMS: The aim of this study was to examine all farm-related morbidity and mortality presenting to a general hospital in the west of Ireland. METHODS: A consecutive series of all farm-related fatal and non-fatal injuries presenting to our institution over a 7-year period (2005-2011) was compiled by examining the hospital inpatient enquiry system and mortuary records. RESULTS: One hundred and thirty patients were admitted to Mayo General Hospital with non-fatal farm-related injuries during the study period. This cohort was comprised 104 males and 26 females with an average age at presentation of 46 (range 19-75) years. The most common mechanism of non-fatal injury was animal attack. The mean length of hospital stay, mean length of ICU stay and total number of bed days used were 5.2, 5.3 and 677 days, respectively. There were seven farm-related fatalities during the same study period. Four were livestock-related, two due to machinery accident and one due to fall of a heavy object. The post-mortem findings were analysed in each case. CONCLUSIONS: This analysis outlines the incidence and severity of fatal and non-fatal injuries sustained in the farming workplace and presenting to a general hospital serving a rural catchment population. Greater awareness of our results may help reduce the longterm incidence and magnitude of such injuries.

Vitamin D deficiency is associated with inflammation in older Irish adults.

CONTEXT: Inadequate vitamin D status is common within elderly populations and may be implicated in the etiology of autoimmune disease and inflammation. Few studies have investigated the relationship between vitamin D status and age-related immune dysfunction in humans. OBJECTIVE: The aim of this study was to investigate the association between vitamin D status and immune markers of inflammation in a large sample of older adults. DESIGN, SETTING, AND PARTICIPANTS: An observational investigation of 957 Irish adults (>60 years of age) recruited in Northern Ireland (55°N latitude) as part of the Trinity Ulster Department of Agriculture aging cohort study. MAIN OUTCOME MEASURE: We measured serum 25-hydroxyvitamin D (25(OH)D) by liquid chromatography tandem mass spectrometry and serum cytokines IL-6, TNF-α, IL-10, and C-reactive protein (CRP) by ELISA. RESULTS: Concentrations of IL-6, CRP, and the ratios of IL-6 to IL-10 and CRP to IL-10 were significantly higher in individuals with deficient (<25 nmol/L) serum 25(OH)D compared with those with sufficient (>75 nmol/L) status after adjustment for age, sex, and body mass index (P < .05). Vitamin D status was a significant predictor of the IL-6 to IL-10 cytokine ratio, and those participants defined as deficient were significantly more likely to have an IL-6 to IL-10 ratio >2:1 compared with those defined as sufficient. CONCLUSIONS: This study demonstrated significant associations between low vitamin D status and markers of inflammation (including the ratio of IL-6 to IL-10) within elderly adults. These findings suggest that an adequate vitamin D status may be required for optimal immune function, particularly within the older adult population.

Comparison of prescribing and adherence patterns of anti-osteoporotic medications post-admission for fragility type fracture in an urban teaching hospital and a rural teaching hospital in Ireland between 2005 and 2008.

INTRODUCTION: Poor adherence reduces the potential benefits of osteoporosis therapy, lowering gains in bone mineral density resulting in increased risk of fractures. AIM: To compare prescribing and adherence patterns of anti-osteoporotic medications in patients admitted to an urban teaching hospital in Ireland with a fragility type fracture to patients admitted to a rural hospital in the North Western region. METHODOLOGY: We identified all patients >55 years admitted to Sligo General Hospital between 2005 and 2008 with a fragility fracture (N = 744) using the hospital in-patient enquiry system (HIPE). The medical card number of those patients eligible for the primary care reimbursement services scheme (PCRS) facilitated the linkage of the HSE-PCRS scheme database to the HIPE database which enabled a study to identify persistence rates of patients prescribed osteoporosis therapy after discharge. The results were compared to the findings of a similar study carried out in St. James's Hospital, Dublin. RESULTS: The 12 months post-fracture prescribing increased from 11.0 % (95 % CI 9.6, 12.4) in 2005 to 47 % (95 % CI 43.6, 50.3) in 2008 in the urban setting and from 25 % (95 % CI 21.5, 28.9) to 39 % (95 % CI 34.5, 42.7) in the rural setting. Adherence levels to osteoporosis medications at 12 months post-initiation of therapy was <50 % in both study groups. Patients on less frequent dosing regimes were better adherers. CONCLUSION: The proportion of patients being discharged on anti-osteoporosis medications post-fragility fracture increased between 2005 and 2008 in both patient groups. Sub-optimal adherence levels to osteoporosis medications continue to be a major concern.

Patient profile in a bone health and osteoporosis prevention service in Ireland.

OBJECTIVES: To (1) characterise a cohort of patients attending a major osteoporosis clinic in Ireland and (2) examine the prescribing of preventative therapies amongst these patients. METHODS: Data were taken from 2006-2007 on patients attending the Osteoporosis Clinic at St. James's Hospital, Dublin. Information gathered included age, gender, fracture history, past medical and surgical history, co-morbidities, the results of the first DXA scans, anti-resorptive therapies along with other medications prescribed. RESULTS: Of all patients 87.6% were female and the mean age was 68 years (SD = 14.31). In total 166 (74%) patients had osteoporosis, 40 (17.8%) had osteopenia and 18 patients (8%) had normal T-score values, 163 (72.7%) had a history of a fracture. Only 13.7% of the patients did not have a documented history of other co-morbidities. CONCLUSION: Comprehensive services such as the Osteoporosis Clinic at St. James's Hospital can provide the necessary screening, monitoring and prescribing of appropriate osteoporosis medications with additional follow-up if required to this at risk group reducing the unnecessarily traumatic effects of the disease on patients.

Audit of patients on oral anticoagulants with International normalized ratios of eight or above.

We reviewed retrospectively the medical records of all patients (n = 77, mean age 74.2) on oral anticoagulants with an International normalized ratio (INR) of eight or above in a 12-month period in the Leicestershire District Health Authority (DHA). From a total of 55,625 INRs, 131 (0.24%) were > or = 8. A major cause of over-anticoagulation was unsatisfactory dose loading during in-hospital commencement of oral anticoagulation. The incidence of major bleeding was 12.9% of total episodes of INR > or = 8 with two haemorrhage-related fatalities. Therapy of major haemorrhage with fresh frozen plasma (FFP) and intravenous (i.v) vitamin K proved effective but was not given in a majority of such cases. In conclusion, improvements in initial dose loading of oral anticoagulation and in the management of major haemorrhage are required. Severely over-anticoagulated patients without obvious bleeding should nevertheless receive small dose vitamin K therapy to reduce the risk of haemorrhage related morbidity and mortality without compromising subsequent oral anti-coagulant control.

Microangiopathic Hemolytic Anemia Associated with the use of both Cyclosporin A and FK506 (Tacrolimus) in the Same Patient.

Microangiopathic hemolytic anemia (MAHA) is a well recognized complication of cyclosporin A (CyA) immunosupressive therapy post bone marrow and solid organ transplant but has rarely been reported in association with FK506 (tacrolimus), we describe a unique patient in whom both CyA and FK506 appear to have caused microangiopathy following an allogeneic peripheral stem cell transplant.