Practical Stability of Au25(SR)18-1/0/+1.

Superatom electron shell and/or geometric shell filling underlies the thermodynamic stability of coinage and alkali metal clusters in both theoretical and experimental results. Factors beyond simple shell filling contribute substantially to the lifetime of ligated clusters in solution. Such factors include the nature of the solvent, the atmosphere and the steric size of the ligand shell. Here we systematically lay out a 'practical' stability model for ligated metal clusters, which includes both shell-closing aspects and colloidal stability aspects. Cluster decomposition may follow either fusion or fission pathways. Solvent polarity can be determinative of the decomposition pathway.

A Comparison of Five Brief Screening Tools for HIV-Associated Neurocognitive Disorders in the USA and South Africa.

Screening for HIV-associated neurocognitive disorders (HAND) is important to improve clinical outcomes. We compared the diagnostic sensitivity and specificity of the mini-mental state examination, International HIV dementia scale (IHDS), Montreal cognitive assessment, Simioni symptom questionnaire and cognitive assessment tool-rapid version (CAT-rapid) to a gold standard neuropsychological battery. Antiretroviral-experienced participants from Cape Town, South Africa, and Baltimore, USA, were recruited. The sensitivity and specificity of the five tools, as well as those of the combined IHDS and CAT-rapid, were established using 2 × 2 contingency tables and ROC analysis. More than a third (65165) had symptomatic HAND. In detecting HIV-D, the CAT-Rapid had good sensitivity (94 %) and weak specificity (52 %) (cut-point ≤10), while the IHDS showed fair sensitivity (68 %) and good specificity (86 %) (cut-point ≤10). The combined IHDS and CAT-rapid showed excellent sensitivity and specificity for HIV-D at a cut-off score of ≤16 (out of 20; 89 and 82 %). No tool was adequate in screening for any HAND. The combination IHDS and CAT-rapid tool appears to be a good screener for HIV-D but is only fairly sensitive and poorly specific in screening for any HAND. Screening for milder forms of HAND continues to be a clinical challenge.

High expression of connective tissue growth factor accelerates dissemination of leukaemia.

To improve treatment of acute lymphoblastic leukaemia (ALL), a better understanding of disease development is needed to tailor new therapies. Connective tissue growth factor (CTGF/CCN2) is highly expressed in leukaemia cells from the majority of paediatric patients with B-lineage ALL (pre-B ALL). CTGF is a matricellular protein and plays a role in aggressive cancers. Here we have genetically engineered leukaemia cells to modulate CTGF expression levels. Elevated CTGF levels accelerated disease dissemination and reduced survival in NOD/SCID mice. In vitro studies showed that CTGF protein induces stromal cell proliferation, promotes adhesion of leukaemia cells to stromal cells and leads to overexpression of genes associated with cell cycle and synthesis of extracellular matrix (ECM). Corresponding data from our leukaemia xenograft models demonstrated that CTGF leads to increased proliferation of non-leukaemia cells and deposition of ECM in the bone marrow. We document for the first time a functional role of CTGF in altering disease progression in a lymphoid malignancy. The findings provide support for targeting the bone marrow microenvironment in aggressive forms of leukaemia.

A novel BRD4-NUT fusion in an undifferentiated sinonasal tumor highlights alternative splicing as a contributing oncogenic factor in NUT midline carcinoma.

NUT midline carcinoma (NMC) is a fatal cancer that arises in various tissues along the upper midline of the body. The defining molecular feature of NMC is a chromosomal translocation that joins (in the majority of cases) the nuclear testis gene NUT (NUTM1) to the bromodomain protein family member 4 (BRD4) and thereby creating a fusion oncogene that disrupts cellular differentiation and drives the disease. In this study, we report the case of an adolescent NMC patient presenting with severe facial pain, proptosis and visual impairment due to a mass arising from the ethmoid sinus that invaded the right orbit and frontal lobe. Treatment involved radical resection, including exenteration of the affected eye with the view to consolidate treatment with radiation therapy; however, the patient experienced rapid tumor progression and passed away 79 days post resection. Molecular analysis of the tumor tissue identified a novel in-frame BRD4-NUT transcript, with BRD4 exon 15 fused to the last 124 nucleotides of NUT exon 2 (BRD4-NUT ex15:ex2Δnt1-585). The partial deletion of NUT exon 2 was attributed to a mid-exonic genomic breakpoint and the subsequent activation of a cryptic splice site further downstream within the exon. Inhibition of the canonical 3' acceptor splice site of NUT intron 1 in cell lines expressing the most common NMC fusion transcripts (PER-403, BRD4-NUT ex11:ex2; PER-624, BRD4-NUT ex15:ex2) induced alternative splicing from the same cryptic splice site as identified in the patient. Detection of low levels of an in-frame BRD4-NUT ex11:ex2Δnt1-585 transcript in PER-403 confirmed endogenous splicing from this alternative exon 2 splice site. Although further studies are necessary to assess the clinical relevance of the increasing number of variant fusions described in NMC, the findings presented in this case identify alternative splicing as a mechanism that contributes to this pathogenic complexity.

The lipaemic index: clinical observations.

The lipaemic index can be used to assess whether or not blood samples are suitable for laboratory analysis. However, little is known about which patients have a raised lipaemic index. In this article we study patient demographics and serum lipid concentrations in samples showing a raised lipaemic index. Of the 4271 patient samples measured in the month of July 2014, a total of 310 had a lipaemic index 0.4. Blood samples showing a raised lipaemic index were studied in a retrospective patient case review of laboratory results. Overall, 7.3% of all samples measured had a raised lipaemic index 0.4. This study found that males were more likely to have a high lipaemic index (56%) and neonates were the group most frequently producing lipaemic samples (30.6%). The correlation between the lipaemic index and the triglyceride concentration showed an r2 value of only 0.37 (r = 0.61), and the correlation between cholesterol and lipaemic index showed an r2 value of 0.16 (r = -0.41). Male and neonatal samples were most likely to show a raised lipaemic index. There was a positive correlation between sample triglyceride and lipaemic index and an inverse correlation with cholesterol concentration and the lipaemic index, although this did not account for all the variance. Thus, other factors may also be important in the expression of the lipaemic index.

Pro-protein convertase subtilisin/kexin 9 concentrations correlate with coronary artery disease atheroma burden in a Pakistani cohort with chronic chest pain.

OBJECTIVE: To determine the relationship between proprotein convertase subtilisin kexin 9 (PCSK9) levels and atheroma burden in Pakistanis presenting to an ambulatory centre with chest pain. METHODS: A prospective matched case-control study of 400 patients selected for presence/absence of angiographic disease referred between 2001 and 2003. A comprehensive cardiovascular disease risk factor profile was assessed including demographics, environmental and biochemical risk factors including insulin resistance and PCSK-9 levels. Coronary atheroma burden was quantified by Gensini score. RESULTS: In this population, PCSK-9 levels were weakly correlated (r = 0.23) with male gender (p = 0.06) and number of diabetes years (p = 0.09), and inversely with log10 of lipoprotein (a) concentration (p = 0.07) but not LDL-C. In multiple regression analysis, Gensini score was associated with age (p = 0.002), established angina (p = 0.001), duration of diabetes (p = 0.05), low HDL-C (p < 0.001), lipoprotein (a) (p = 0.01), creatinine (p < 0.001), C-Reactive Protein (p = 0.02) and PSCK-9 (p = 0.05) concentrations. PCSK9 added to the regression model. Neither total cholesterol nor LDL-C were significant risk factors in this study. CONCLUSIONS: Proprotein convertase subtilisin kexin 9 concentrations are correlated with atheroma burden in Indian Asian populations from the sub-continent, not taking statin therapy, independent of LDL-C or other CVD risk factors.

NUT protein immunoreactivity in ovarian germ cell tumours.

The aim of this study was to investigate NUT (nuclear protein in the testis) expression in ovarian germ cell tumours (GCTs). Immunostaining for NUT protein was performed in 10 mature cystic teratomas and in 49 malignant ovarian GCTs including 15 pure dysgerminomas, six dysgerminomas associated with gonadoblastoma, nine yolk sac tumours, 12 immature teratomas, and seven mixed malignant tumours. Only nuclear staining was considered a positive finding although cytoplasmic staining was noted when present. Thirty-seven (76%) malignant GCTs were NUT positive but staining was usually of weak to moderate intensity and observed in a relatively small proportion of neoplastic cells. Staining in immature teratomas and yolk sac tumours was restricted to foci of hepatoid and intestinal/glandular differentiation, where both nuclear and cytoplasmic reactivity were observed. In dysgerminoma associated with gonadoblastoma only the in situ and invasive germ cell elements were NUT positive. Nuclear staining was not seen in benign teratomas. Most malignant ovarian GCTs express NUT protein, albeit focally, and this should be considered when evaluating immunostaining in the differential diagnosis of poorly differentiated malignancies, particularly NUT midline carcinoma. Since NUT protein appears to play a role in normal germ cell maturation it may influence intestinal or hepatoid differentiation within malignant GCTs.

Angiographic coronary artery disease and high-sensitivity troponin-T in a native Pakistani cohort presenting with chronic chest pain.

OBJECTIVE: To determine the relationship between troponin-T levels and atheroma burden in Pakistanis presenting to an ambulatory centre with chest pain. METHODS: A prospective case-control study of 400 patients selected for presence/absence of angiographic disease referred between 2001 and 2003. A comprehensive cardiovascular disease (CVD) risk factor profile was assessed including demographics, environmental and biochemical risk factors including insulin resistance and troponin-T levels. Coronary atheroma burden was quantified by Gensini score. RESULTS: Clinically significant elevated troponin-T levels (> 30 pmol/l) were found in 40 patients (10%) with equal numbers in groups selected with or without angiographic disease. Troponin-T elevation (> 13 pmol/l) was present in 59 vs. 47 patients (30% vs. 24%; p = 0.04). Troponin-T levels did not correlate with any measured demographical, environmental, drug therapy or biochemical risk factor. No difference was found in concentrations of lipids, apolipoproteins, insulin resistance, C-reactive protein or sialic acid in cohorts stratified by troponin-T concentrations. In univariate analysis comparing patients with high (> 30 pmol/l) and low troponin-T levels (< 13 pmol/l) higher plasma total protein (91 g/l vs. 85 g/l; p = 0.01), increased immunoglobulin levels (41 g/l vs. 36 g/l; p = 0.02) and prevalence of hyperparathyroidism (40% vs. 21%; p = 0.04) were associated with higher troponin-T concentrations. CONCLUSIONS: This study shows that measurement of troponin-T is not an alternative to imaging in an Indian asian population, but that it does identify a separate potentially high-risk population that would not be identified by the use of imaging alone which is potentially at higher risk of CVD events.

Fascin expression in cervical normal squamous epithelium, cervical intraepithelial neoplasia, and superficially invasive (stage IA1) squamous carcinoma of the cervix.

The aims of this study were to: investigate fascin expression in normal cervix, cervical intraepithelial neoplasia (CIN), and stage IA1 squamous cell carcinoma (SCC).Fascin immunostaining was performed in cervical biopsies showing normal squamous epithelium (n=10), CIN 1 (n=10), CIN 2-3 without invasion (n=11), and CIN 2-3 adjacent to SCC (n=40); SCC was also present in 27 of the latter cases.Fascin expression in normal squamous epithelium was restricted to basal and parabasal cells, whereas there was increased staining in immature squamous metaplasia and in most CIN lesions. Full thickness staining was more frequent in high grade CIN adjacent to invasion than in CIN 2-3 alone. Eighteen SCCs (67%) were fascin positive and seven cases showed accentuated staining at the tumour-stromal interface (invasive front). There was no consistent relationship between fascin expression in CIN lesions and in corresponding carcinomas. Fascin staining in reactive stromal cells sometimes made identification of the invasive neoplastic cells difficult.Fascin is overexpressed in most CIN lesions and this may be a marker of increased invasive potential in high grade CIN. However, fascin staining does not distinguish low and high grade CIN or in situ and invasive squamous neoplasia. Therefore fascin has limited diagnostic utility in demonstrating superficial stromal invasion.

Fascin and cyclin D1 immunoreactivity in non-neoplastic vulvar squamous epithelium, vulvar intraepithelial neoplasia and invasive squamous carcinoma: correlation with Ki67 and p16 protein expression.

AIMS: To investigate cyclin D1 and fascin immunoreactivity in normal, reactive and neoplastic vulvar skin correlating the findings with p16 protein and Ki67 expression. METHODS: 66 vulvar biopsy or resection specimens demonstrating normal appearances, reactive epidermal changes, usual-type vulvar intraepithelial neoplasia (uVIN), differentiated-type VIN (dVIN), p16-positive squamous cell carcinoma (SCC) and p16-negative SCC were examined immunohistochemically for cyclin D1, fascin, Ki67 and p16 protein. Where applicable, expression patterns were compared in microanatomically distinct areas, particularly at the invasive front (deep tumour margin) of SCC. RESULTS: Normal epidermis showed parabasal Ki67 and cyclin D1 staining while fascin labelled cells in the lower one-third of the epithelium. Reactive and dVIN specimens demonstrated mildly increased Ki67 and cyclin D1 expression that maintained parabasal polarity, whereas uVIN and p16-positive SCC were characterised by loss of cyclin D1 staining. However, in 14 of 20 p16-positive SCC small infiltrative tumour groups and single infiltrating cells at the invasive front showed a cyclin D1-positive/ Ki67-negative phenotype. In contrast, p16-negative SCC generally showed diffuse and concordant cyclin D1 and Ki67 labelling, including at the invasive margin. Fascin expression was increased in all VIN and SCC lesions. CONCLUSIONS: Variations in cyclin D1 and Ki67 expression between p16-positive and p16-negative vulvar SCCs suggest different mechanisms of invasion in these tumour subgroups. Fascin is upregulated in vulvar squamous neoplasia but immunostaining does not discriminate in situ from invasive lesions nor putative human papilloma virus (HPV)-associated and HPV-independent SCCs.

Severe hypertriglyceridaemia in Type 2 diabetes mellitus: beneficial effect of continuous insulin infusion.

BACKGROUND: Severe hypertriglyceridaemia is a recognized complication of Type 2 diabetes mellitus (T2DM); however, there is no consensus on acute management despite the significant risk of developing associated complications such as acute pancreatitis and hyperviscosity syndrome. AIM: To identify the association between hyperglycaemia and severe hypertriglyceridaemia in patients with T2DM and assess the effect of continuous insulin infusion therapy on serum triglyceride (TG) concentrations and report any adverse events associated with this therapeutic approach. DESIGN: Retrospective review of case records. METHODS: Patients with uncontrolled hyperglycaemia and severe hypertriglyceridaemia (serum TG > 15 mmol/l) treated with continuous intravenous insulin infusion between October 2008 and September 2009 were retrospectively evaluated (n = 15). Details recorded included demographics, admission details, lipid profiles, glycaemic control, serum amylase and adverse events. Patients receiving treatment-dose unfractionated heparin infusion were excluded. RESULTS: Severe hypertriglyceridaemia is associated with hyperglycaemia in our heterogeneous group of patients with T2DM presenting with new-onset diabetes or established disease on pre-existing insulin or oral hypoglycaemic agents. Administration of continuous exogenous insulin not only achieved normoglycaemia but also dramatically corrected severe hypertriglyceridaemia in all patients (P = 0.001). CONCLUSION: The administration of continuous insulin in patients with T2DM with severe hypertriglyceridaemia is a simple and safe method of significantly reducing the immediate risk associated with this metabolic complication and should be considered in any T2DM patient presenting with severe hypertriglyceridaemia and hyperglycaemia.

Lipaemia: causes, consequences and solutions.

The detection of lipaemia in a patient blood sample can be a clinical conundrum as well as an analytical nuisance. With a reported prevalence of 0.7% in all blood samples received for lipid studies its finding has been suggested to be an underappreciated problem [1]. Its presence can have a significant impact on the validity of a number of routine blood tests. The intention of this report is to outline the causes of lipaemia, the clinical and analytical consequences of its presence and some of the tools the laboratory employ to reduce its effects. Both laboratory professionals and clinicians should have an appreciation of the analytical and clinical impact lipaemia may confer on routine biochemistry.

The risks of absolute medical confidentiality.

Some ethicists argue that patient confidentiality is absolute and thus should never be broken. I examine these arguments that when critically scrutinised, become porous. I will explore the concept of patient confidentiality and argue that although, this is a very important medical and bioethical issue, this needs to be wisely delivered to reduce third party harm or even detriment to the patient. The argument for absolute confidentiality is particularly weak when it comes to genetic information and inherited disease.