A Rare Cause of Myoclonus: A Cupric Conundrum

A woman aged 22 years presented with a 3-year history of jerks when brushing her teeth and a tremor when carrying drinks. Examination revealed a bilateral jerky tremor, stimulus-sensitive myoclonus, and difficulty with tandem gait. Thyroid and liver function test results were normal, but she had rapidly progressive renal failure. Serum copper, ceruloplasmin, and manganese levels were normal, but her urinary copper level was elevated on 2 occasions. Pathological findings on organ biopsy prompted genetic testing to confirm the diagnosis. The differential diagnosis, tissue biopsy findings, and final genetic diagnosis are discussed.

Chromosome 9p21.3 is associated with early-onset coronary heart disease in the Irish population

Coronary heart disease (CHD) remains a leading cause of death across the world. A region on chromosome 9p21.3 has been recently reported to be associated with CHD. We evaluated 3 SNPs and 3 common haplotypes in the 9p21.3 region in 1494 individuals from 580 Irish families, where at least 1 member had early-onset (males

Bereavement: A behavioural process

Sixty-seven widows whose husbands had been killed in the context of sectarian violence in Northern Ireland were assessed in relation to the cause of death, the quality of their marital relationship and the level of worry prior to the loss. Results reported here show that the violent cause of death led to a greater level of long-term psychological distress than other causes of death. Furthermore, widows who reported happiness regarding their marital relationship showed more signs of distress after the loss than those who reported less happiness. Widows who had not worried about their husband showed less signs of psychological distress after the loss than those who had worried. The interpretation of the findings is based on recent thinking in behaviour analysis.

Home medication management practices and associated factors among patients with selected chronic diseases in a community pharmacy in Uganda

ABSTRACT: BACKGROUND: Chronic diseases are rapidly increasing and are currently the major cause of death and disability worldwide. Patients with chronic diseases experience many challenges including medicine-related problems. However, there is limited information about the home management of medicines among these patients. This study therefore was to determine home medication management practices and associated factors among patients with chronic diseases seeking care in a community pharmacy in Uganda. METHODS: A cross-sectional study was conducted in a community pharmacy in Kampala from June to July 2010. A total of 207 consenting chronic disease patients or caregivers of children with chronic disease were consecutively sampled. The patients were visited at home to evaluate their drug management practices and to check their medical forms for disease types and drugs prescribed. An interviewer-administered questionnaire and an observation checklist were used to collect the data. RESULTS: Overall home medication management was inappropriate for 70% (n = 145) of the participants (95% CI = 63.3-76.2) and was associated with perceived severity of disease (not severe OR =0.40, moderately severe OR = 0.35), duration of disease >5 years (OR = 2.15), and health worker not assessing for response to treatment (OR = 2.53). About 52% (n = 107) had inappropriate storage which was associated with inadequate information about the disease (OR = 2.39) and distance to the health facility >5 kilometres (OR = 2.82). Fifteen percent (n = 31) had no drug administration schedule and this was associated with increasing age (OR = 0.97), inadequate information about the disease (OR = 2.96), and missing last appointment for medical review (OR = 6.55). About 9% (n = 18) had actual medication duplication; 1.4% (n = 3) had expired medicines; while 18.4% (n = 38) had drug hoarding associated with increasing number of prescribers (OR = 1.34) and duration of disease (OR = 2.06). About 51% (n = 105) had multiple prescribers associated with perceiving the disease to be non severe (OR = 0.27), and having more than one chronic disease (OR = 2.37). CONCLUSIONS: Patients with chronic disease have poor home management of medicines. In order to limit the occurrence of poor outcomes of treatment or drug toxicity, health providers need to strengthen the education of patients with chronic disease on how to handle their medicines at home.

Investigating local relationships between trace elements in soils and cancer data

Medical geology research has recognised a number of potentially toxic elements (PTEs), such as arsenic, cobalt, chromium, copper, nickel, lead, vanadium, uranium and zinc, known to influence human disease by their respective deficiency or toxicity. As the impact of infectious diseases has decreased and the population ages, so cancer has become the most common cause of death in developed countries including Northern Ireland. This research explores the relationship between environmental exposure to potentially toxic elements in soil and cancer disease data across Northern Ireland. The incidence of twelve different cancer types (lung, stomach, leukaemia, oesophagus, colorectal, bladder, kidney, breast, mesothelioma, melanoma and non melanoma(NM) both basal and squamous, were examined in the form of twenty-five coded datasets comprising aggregates over the 12 year period from 1993 to 2006. A local modelling technique,geographically weighted regression (GWR) is usedto explore the relationship between environmental exposure and cancer disease data. The results show comparisons of the geographical incidence of certain cancers (stomach and NM squamous skin cancer) in relation to concentrations of certain PTEs (arsenic levels in soils and radon were identified). Findings from the research have implications for regional human health risk assessments.

Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia

Rationale: Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied.

Objective: This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia.

Methods and results: Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli. 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p<0.05 for MSC vs 3T3 and PBS groups) and lung injury compared with control mice. In addition, wild-type MSCs enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups. The antibacterial effect with MSCs was due, in part, to their upregulation of the antibacterial protein lipocalin 2.

Conclusions: Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs

Mortality in Barrett's oesophagus:Results from a population based study

Background: Patients with Barrett's oesophagus have an increased risk of oesophageal adenocarcinoma but this cancer only accounts for a small proportion of deaths in these patients. Other causes of death are reportedly raised in this group. We examined cause specific mortality among individuals in a population based Barrett's oesophagus register. Methods: We constructed a register of all patients diagnosed with columnar mucosa (including specialised intestinal metaplasia) of the oesophagus within Northern Ireland between 1993 and 1999. Deaths occurring within this cohort until 31 December 2000 were identified and mortality rates were compared with the general population. Results: Overall mortality was not raised in Barrett's patients. During 7413 person years of follow up in 2373 patients there were 253 deaths (standardised mortality ratio (SMR) 96 (95% confidence interval (CI) 84-107)). Mortality from oesophageal cancer was raised in patients with specialised intestinal metaplasia (SMR 774 (95% CI 317-1231 )) but only 4.7% of patients died from this cancer. Mortality from stroke (SMR 65 (95% CI 37-93)) was significantly lower than the general population while mortality from non-cancerous digestive system diseases was significantly higher (SMR 211 (95% CI 111-311)). Mortality rates from all other causes were similar to those of the general population. Conclusions: This study demonstrates that the overall mortality rate in patients with Barrett's oesophagus is closely similar to that of the general population. Oesophageal cancer mortality was raised but is an uncommon cause of death in these patients who also appear to have a reduced risk of death from stroke.

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2)

Targeting Siglecs with a sialic acid-decorated nanoparticle abrogates inflammation

Sepsis is the most frequent cause of death in hospitalized patients, and severe sepsis is a leading contributory factor to acute respiratory distress syndrome (ARDS). At present, there is no effective treatment for these conditions, and care is primarily supportive. Murine sialic acid-binding immunoglobulin-like lectin-E (Siglec-E) and its human orthologs Siglec-7 and Siglec-9 are immunomodulatory receptors found predominantly on hematopoietic cells. These receptors are important negative regulators of acute inflammatory responses and are potential targets for the treatment of sepsis and ARDS. We describe a Siglec-targeting platform consisting of poly(lactic-co-glycolic acid) nanoparticles decorated with a natural Siglec ligand, di(α2→8) N-acetylneuraminic acid (α2,8 NANA-NP). This nanoparticle induced enhanced oligomerization of the murine Siglec-E receptor on the surface of macrophages, unlike the free α2,8 NANA ligand. Furthermore, treatment of murine macrophages with these nanoparticles blocked the production of lipopolysaccharide-induced inflammatory cytokines in a Siglec-E-dependent manner. The nanoparticles were also therapeutically beneficial in vivo in both systemic and pulmonary murine models replicating inflammatory features of sepsis and ARDS. Moreover, we confirmed the anti-inflammatory effect of these nanoparticles on human monocytes and macrophages in vitro and in a human ex vivo lung perfusion (EVLP) model of lung injury. We also established that interleukin-10 (IL-10) induced Siglec-E expression and α2,8 NANA-NP further augmented the expression of IL-10. Indeed, the effectiveness of the nanoparticle depended on IL-10. Collectively, these results demonstrated a therapeutic effect of targeting Siglec receptors with a nanoparticle-based platform under inflammatory conditions.

Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis

BACKGROUND: Colorectal cancer (CRC) is a leading cause of death in the United States. Increased level of interleukin-8 (IL-8) and CXCR2 on tumours and in the tumour microenvironment has been associated with CRC growth, progression and recurrence in patients. Here, we aimed to evaluate the effects of tissue microenvironment-encoded IL-8 and CXCR2 on colon cancer progression and metastasis.

METHODS: A novel immunodeficient, skin-specific IL-8-expressing transgenic model was generated to evaluate colon cancer growth and metastasis. Syngeneic mouse colon cancer cells were grafted in CXCR2 knockout (KO) mice to study the contribution of CXCR2 in the microenvironment to cancer growth.

RESULTS: Elevated levels of IL-8 in the serum and tumour microenvironment profoundly enhanced the growth of human and mouse colon cancer cells with increased peri-tumoural angiogenesis, and also promoted the extravasation of the cancer cells into the lung and liver. The tumour growth was inhibited in CXCR2 KO mice with significantly reduced tumour angiogenesis and increased tumour necrosis.

CONCLUSION: Increased expression of IL-8 in the tumour microenvironment enhanced colon cancer growth and metastasis. Moreover, the absence of its receptor CXCR2 in the tumour microenvironment prevented colon cancer cell growth. Together, our study demonstrates the critical roles of the tumour microenvironment-encoded IL-8/CXCR2 in colon cancer pathogenesis, validating the pathway as an important therapeutic target.