Meta-analysis of tumour burden in pre-operative axillary ultrasound positive and negative breast cancer patients

Management of the axilla in breast cancer is becoming increasingly conservative. Patients identified with a low axillary nodal burden (two or fewer involved nodes) at sentinel node biopsy (SNB) can avoid completion axillary node clearance (cANC). 'Fast track' to ANC in patients with involved nodes on pre-operative ultrasound may be over-treating a subgroup of these patients with low nodal burden, which would have precluded their need for ANC. This systematic review assesses the proportion of patients with involved nodes on pre-operative axillary ultrasound, which would fit low axillary burden criteria. Meta-analysis of studies comparing axillary burden of breast cancer patients identified as pre-operative ultrasound negative versus positive was performed. The primary outcome measure was the number of patients with two or fewer involved nodes (macrometastases only). Pooled odds ratio (OR), 95% confidence intervals (CIs), means and probabilities of identifying two or fewer involved nodes versus greater than two were calculated. Six studies reported the axillary burden in 4271 patients who were either directed straight to ANC or cANC after SNB. There was a significantly greater axillary burden in the ultrasound positive versus negative groups (OR 5.95, 95% CI 5.80-6.11) with mean nodal retrieval values of 2.9 [standard error (SE) 0.2] and 1.6 (SE 0.2) nodes, respectively. Cumulative probabilities identified 78.9% of ultrasound negative and 43.2% of ultrasound positive patients possessed low axillary burden. Pre-operative ultrasound positive patients have significantly higher axillary burden. However, nearly half do fit the criteria of low axillary burden and could be considered for omission of ANC

An Essential Role for the Proximal but Not the Distal Cytoplasmic Tail of Glycoprotein M in Murid Herpesvirus 4 Infection

Murid herpesvirus-4 (MuHV-4) provides a tractable model with which to define common, conserved features of gamma-herpesvirus biology. The multi-membrane spanning glycoprotein M (gM) is one of only 4 glycoproteins that are essential for MuHV-4 lytic replication. gM binds to gN and is thought to function mainly secondary envelopment and virion egress, for which several predicted trafficking motifs in its C-terminal cytoplasmic tail could be important. We tested the contribution of the gM cytoplasmic tail to MuHV-4 lytic replication by making recombinant viruses with varying C-terminal deletions. Removing an acidic cluster and a distal YXXΦ motif altered the capsid distribution somewhat in infected cells but had little effect on virus replication, either in vitro or in vivo. In contrast, removing a proximal YXXΦ motif as well completely prevented productive replication. gM was still expressed, but unlike its longer forms showed only limited colocalization with co-transfected gN, and in the context of whole virus appeared to support gN expression less well. We conclude that some elements of the gM cytoplasmic tail are dispensible for MuHV-4 replication, but the tail as a whole is not

Promoting mental health in small-medium enterprises: An evaluation of the "Business in Mind" program

<p>Abstract</p> <p>Background</p> <p>Workplace mental health promotion (WMHP) aims to prevent and effectively manage the social and economic costs of common mental illnesses such as depression. The mental health of managers and employees within small-medium enterprises (SMEs) is a neglected sector in occupational health research and practice, despite the fact that this sector is the most common work setting in most economies. The availability and propensity of SME staff to attend face-to-face training/therapy or workshop style interventions often seen in corporate or public sector work settings is a widely recognised problem. The 'Business in Mind' program employs a DVD mode of delivery that is convenient for SME managers, particularly those operating in regional and remote areas where internet delivery may not be optimal. The objective of the intervention program is to improve the mental health of SME managers, and examine whether employees of managers' whose mental health improves, report positive change in their psychosocial work environment. The mechanisms via which we aim to improve managers' mental health are through the development of their psychological capital (a higher order construct comprised of hope, self efficacy, resilience and optimism) and their skills and capacities for coping with work stress.</p> <p>Methods/Design</p> <p>The effectiveness of two versions of the program (self administered and telephone facilitated) will be assessed using a randomised trial with an active control condition (psychoeducation only). We aim to recruit a minimum of 249 managers and a sample of their employees. This design allows for 83 managers per group, as power analyses showed that this number would allow for attrition of 20% and still enable detection of an effect size of 0.5. The intervention will be implemented over a three month period and postal surveys will assess managers and employees in each group at baseline, intervention completion, and at 6 month follow up. The intervention groups (managers only) will also be assessed at 12 and 24 month follow-up to examine maintenance of effects. Primary outcomes are managers' levels of psychological capital (hope, resilience, self-efficacy and optimism), coping strategies, anxiety and depression symptoms, self-reported health, job satisfaction and job tension. Secondary outcomes are participating managers subordinates' perceptions of manager support, relational justice, emotional climate and job tension. In order to provide an economic evaluation of the intervention, both employees and manager rates of absenteeism and presenteeism will also be assessed.</p> <p>Discussion</p> <p>The intervention being trialled is expected to improve both primary and secondary outcomes. If proven efficacious, the intervention could be disseminated to reach a much larger proportion of the business community.</p> <p>Trial registration</p> <p>Current controlled trials ISRCTN 62853520</p

Lifespan extension without fertility reduction following dietary addition of the autophagy activator Torin1 in Drosophila melanogaster

Autophagy is a highly conserved mechanism for cellular repair that becomes progressively down-regulated during normal ageing. Hence, manipulations that activate autophagy could increase lifespan. Previous reports show that manipulations to the autophagy pathway can result in longevity extension in yeast, flies, worms and mammals. Under standard nutrition, autophagy is inhibited by the nutrient sensing kinase Target of Rapamycin (TOR). Therefore, manipulations of TOR that increase autophagy may offer a mechanism for extending lifespan. Ideally, such manipulations should be specific and minimise off-target effects, and it is important to discover additional methods for ‘clean’ lifespan manipulation. Here we report an initial study into the effect of up-regulating autophagy on lifespan and fertility in Drosophila melanogaster by dietary addition of Torin1. Activation of autophagy using this selective TOR inhibitor was associated with significantly increased lifespan in both sexes. Torin1 induced a dose-dependent increase in lifespan in once-mated females. There was no evidence of a trade-off between longevity and fecundity or fertility. Torin1-fed females exhibited significantly elevated fecundity, but also elevated egg infertility, resulting in no net change in overall fertility. This supports the idea that lifespan can be extended without trade-offs in fertility and suggest that Torin1 may be a useful tool with which to pursue anti-ageing research

Notch Signaling Regulates Late-Stage Epidermal Differentiation and Maintains Postnatal Hair Cycle Homeostasis

Notch signaling involves ligand-receptor interactions through direct cell-cell contact. Multiple Notch receptors and ligands are expressed in the epidermis and hair follicles during embryonic development and the adult stage. Although Notch signaling plays an important role in regulating differentiation of the epidermis and hair follicles, it remains unclear how Notch signaling participates in late-stage epidermal differentiation and postnatal hair cycle homeostasis.We applied Cre/loxP system to generate conditional gene targeted mice that allow inactivation of critical components of Notch signaling pathway in the skin. Rbpj, the core component of all four Notch receptors, and Pofut1, an essential factor for ligand-receptor interactions, were inactivated in hair follicle lineages and suprabasal layer of the epidermis using the Tgfb3-Cre mouse line. Rbpj conditional inactivation resulted in granular parakeratosis and reactive epidermal hyperplasia. Pofut1 conditional inactivation led to ultrastructural abnormalities in the granular layer and altered filaggrin processing in the epidermis, suggesting a perturbation of the granular layer differentiation. Disruption of Pofut1 in hair follicle lineages resulted in aberrant telogen morphology, a decrease of bulge stem cell markers, and a concomitant increase of K14-positive keratinocytes in the isthmus of mutant hair follicles. Pofut1-deficent hair follicles displayed a delay in anagen re-entry and dysregulation of proliferation and apoptosis during the hair cycle transition. Moreover, increased DNA double stand breaks were detected in Pofut1-deficent hair follicles, and real time PCR analyses on bulge keratinocytes isolated by FACS revealed an induction of DNA damage response and a paucity of DNA repair machinery in mutant bulge keratinocytes.our data reveal a role for Notch signaling in regulating late-stage epidermal differentiation. Notch signaling is required for postnatal hair cycle homeostasis by maintaining proper proliferation and differentiation of hair follicle stem cells

A Gammaherpesviral Internal Repeat Contributes to Latency Amplification

BACKGROUND: Gammaherpesviruses cause important infections of humans, in particular in immunocompromised patients. The genomes of gammaherpesviruses contain variable numbers of internal repeats whose precise role for in vivo pathogenesis is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We used infection of laboratory mice with murine gammaherpesvirus 68 (MHV-68) to explore the biological role of the 40 bp internal repeat of MHV-68. We constructed several mutant viruses partially or completely lacking this repeat. Both in vitro and in vivo, the loss of the repeat did not substantially affect lytic replication of the mutant viruses. However, the extent of splenomegaly, which is associated with the establishment of latency, and the number of ex vivo reactivating and genome positive splenocytes were reduced. Since the 40 bp repeat is part of the hypothetical open reading frame (ORF) M6, it might function as part of M6 or as an independent structure. To differentiate between these two possibilities, we constructed an N-terminal M6STOP mutant, leaving the repeat structure intact but rendering ORF M6 unfunctional. Disruption of ORF M6 did neither affect lytic nor latent infection. In contrast to the situation in lytically infected NIH3T3 cells, the expression of the latency-associated genes K3 and ORF72 was reduced in the latently infected murine B cell line Ag8 in the absence of the 40 bp repeat. CONCLUSIONS/SIGNIFICANCE: These data suggest that the 40 bp repeat contributes to latency amplification and might be involved in the regulation of viral gene expression

Differential Effects of Pravastatin and Simvastatin on the Growth of Tumor Cells from Different Organ Sites

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins

Consumer trust and confidence in the compliance of Islamic banks

Islamic banks compete with traditional (non-Islamic) banks for customers. This article aims to provide insight into why some Muslims choose to bank with Islamic banks in Pakistan, while others do not. Specifically, it addresses the questions: to what extent are trust and confidence active influencers in the decision-making process, are they differentiated or are they one of the same? Also how does the Pakistani collective cultural context further complicate the application of these concepts? For the purposes of this article trust refers to people and their interpersonal or social relations whereas confidence concerns institutions such as banks. Drawing on interviews with Muslim consumers in Pakistan, this study provides further insight into consumer behaviour within financial services and specifically Islamic banking and contributes to our theoretical understanding of the concepts of trust and confidence

Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment

Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral nucleus of the amygdala (BLA) and prelimbic (PL) medial prefrontal cortex have been implicated in reward-seeking and fear-related responses, but how information flows between these reciprocally connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task wherein competing shock- and sucrose-predictive cues were simultaneously presented. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, BLA neurons optogenetically identified as projecting to PL more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally photostimulation of the BLA→PL projection increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. Therefore, the BLA→PL circuit is critical in governing the selection of behavioral responses in the face of competing signals.National Institutes of Health (U.S.) (Award 1R25-MH092912-01)National Institute of Mental Health (U.S.) (Grant R01- MH102441-01)National Institutes of Health (U.S.) (Award DP2- DK-102256-01

Medical Therapies for Uterine Fibroids - A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials

BACKGROUND: Uterine fibroids are common, often symptomatic and a third of women need repeated time off work. Consequently 25% to 50% of women with fibroids receive surgical treatment, namely myomectomy or hysterectomy. Hysterectomy is the definitive treatment as fibroids are hormone dependent and frequently recurrent. Medical treatment aims to control symptoms in order to replace or delay surgery. This may improve the outcome of surgery and prevent recurrence. PURPOSE: To determine whether any medical treatment can be recommended in the treatment of women with fibroids about to undergo surgery and in those for whom surgery is not planned based on currently available evidence. STUDY SELECTION: Two authors independently identified randomised controlled trials (RCT) of all pharmacological treatments aimed at the treatment of fibroids from a list of references obtained by formal search of MEDLINE, EMBASE, Cochrane library, Science Citation Index, and ClinicalTrials.gov until December 2013. DATA EXTRACTION: Two authors independently extracted data from identified studies. DATA SYNTHESIS: A Bayesian network meta-analysis was performed following the National Institute for Health and Care Excellence-Decision Support Unit guidelines. Odds ratios, rate ratios, or mean differences with 95% credible intervals (CrI) were calculated. RESULTS AND LIMITATIONS: A total of 75 RCT met the inclusion criteria, 47 of which were included in the network meta-analysis. The overall quality of evidence was very low. The network meta-analysis showed differing results for different outcomes. CONCLUSIONS: There is currently insufficient evidence to recommend any medical treatment in the management of fibroids. Certain treatments have future promise however further, well designed RCTs are needed