MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by Leishmania mexicana

In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2+/+ but not from MKP-2−/− mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2−/− macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE2 production. However surprisingly, in MKP-2−/− macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2−/− mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2−/− T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2−/− bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage

Assessment of the centre of pressure pattern and moments about S2 in scoliotic subjects during normal walking

Background Context: Research employing gait measurements indicate asymmetries in ground reaction forces and suggest relationships between these asymmetries, neurological dysfunction and spinal deformity. Although, studies have documented the use of centre of pressure (CoP) and net joint moments in gait assessment and have assessed centre of mass (CoM)-CoP distance relationships in clinical conditions, there is a paucity of information relating to the moments about CoM. It is commonly considered that CoM is situated around S2 vertebra in normal upright posture and hence this study uses S2 vertebral prominence as reference point relative to CoM. Purpose: To assess and establish asymmetry in the CoP pattern and moments about S2 vertebral prominence during level walking and its relationship to spinal deformity in adolescents with scoliosis. Patient sample: Nine Adolescent Idiopathic Scoliosis subjects (8 females and 1 male with varying curve magnitudes and laterality) scheduled for surgery within 2-3 days after data collection, took part in this study. Outcome measures: Kinetic and Kinematic Gait assessment was performed with an aim to estimate the CoP displacement and the moments generated by the ground reaction force about the S2 vertebral prominence during left and right stance during normal walking. Methods: The study employed a strain gauge force platform to estimate the medio-lateral and anterior-posterior displacement of COP and a six camera motion analysis system to track the reflective markers to assess the kinematics. The data were recorded simultaneously. Results: Results indicate wide variations in the medio lateral direction CoP, which could be related to the laterality of both the main and compensation curves. This variation is not evident in the anterior-posterior direction. Similar results were recorded for moments about S2 vertebral prominence. Subjects with higher left compensation curve had greater displacement to the left. Conclusion: Although further longitudinal studies are needed, results indicate that the variables identified in this study are applicable to initial screening and surgical evaluation of scoliosis. © 2008 Chockalingam et al; licensee BioMed Central Ltd

Economies of (Alleged) Deviance: Sex Work and the Sport Mega Event

Based on ethnographic data collected during the 2014 FIFA World Cup and 2016 Olympic Games in Rio de Janeiro, Brazil, thisarticle is interested to examine urban processes which reinvent the changing (sexual) landscape. Focusing on the way (host) citiesshape sex work both imaginatively and physically, we explore the (lived) realities of neoliberal imaginaries that shape urbanspace. Often thought to exist in the urban shadow as an absent-presence in cosmopolitan processes, we demonstrate the manner inwhich sexualized and racialized women creatively resist the political and economic trajectories of neoliberal urbanism that seek toexpropriate land and dispossess certain bodies. In the context of Rio de Janeiro—as in other host cities—this is particularlyevident in the routine encounter between sexual minorities and local law enforcement. Mindful of the literature on state incursioninto social-sexual life, we remain attentive to the everyday strategies through which those deemed sexually deviant and/or victimnavigate local authorities in search of new opportunities for economic salvation in the midst of the sport mega-event

Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor

Bortezomib inhibits nuclear factor-κB (NF-κB). Cetuximab is a chimeric mouse–human antibody targeted against epidermal growth factor receptor (EGFR). We hypothesised that concomitant blockade of NF-κB and EGFR signalling would overcome EGFR-mediated resistance to single-agent bortezomib and induce apoptosis through two molecular pathways. The aim of this phase I trial was to establish the maximum tolerated dose (MTD) for bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumours. The 21-day treatment cycle consisted of bortezomib administered on days 1 and 8 through dose escalation (1.3–2 mg m−2). Cetuximab was delivered at a dose of 250 mg m−2 on days 1, 8 and 15 (400 mg m−2 day 1 cycle 1). A total of 37 patients were enroled and given a total 91 cycles. No grade ⩾3 haematological toxicity was noted. Non-hematological grade ⩾3 toxicities included fatigue (22% of patients), dyspnoea (16%) and infection (11%). The MTD was not reached at the highest tested bortezomib dose (2.0 mg m−2). Efficacy outcomes included disease progression in 21 patients (56.7%) and stable disease (SD) at 6 weeks in 16 patients (43.3%). Five of the six patients with SD at 12 weeks were diagnosed with cancers of the lungs or head and neck. This combination therapy was moderately effective in extensively pretreated patients with non-small cell lung or head and neck cancers and warrants further investigation

Sexual and reproductive health outcomes among female sex workers in Johannesburg and Pretoria, South Africa: Recommendations for public health programmes

Abstract Background The sexual and reproductive health (SRH) status of female sex workers is influenced by a wide range of demographic, behavioural and structural factors. These factors vary considerably across and even within settings. Adopting an overly standardised approach to sex worker programmes may compromise its impact on some sub-groups in local areas. Methods Records of female sex workers attending clinic-, community-, or hotel-based health services in Johannesburg (n = 1422 women) and Pretoria (n = 408 women), South Africa were analysed. We describe the population’s characteristics and identified factors associated with sexual and reproductive health outcomes, namely HIV status; previous symptomatic sexually transmitted infection (STI); modern contraceptive use and number of child dependents. Results The women in Johannesburg were less likely than those in Pretoria to have HIV (42.2% vs 52.9%), or previous symptomatic STIs (44.3% vs. 8.3%), and were 1.4 fold less likely to have child dependents (20.1% vs. 15.3%). About 43% of women in Johannesburg were Zimbabwean and 40% in Pretoria. Of concern, only about 15% of women in both sites were using modern contraceptives. Johannesburg women were also more likely to access health services at a hotel (85.0% vs. 80.6%) or clinic (5.7% vs. 0.5%), to have completed secondary education (57.1% vs. 36.0%), and moved house more than twice during the past year (19.6 vs. 2.0%). In both cities, risk of HIV rose rapidly with age (23.8%–58.2% vs. 22.0%–64.8%). Of interest, HIV prevalence was considerably higher in those with consistent condom use with one’s main partner than inconsistent users. Conclusions Sex worker populations are heterogeneous. Local health programmes must prioritise services that reflect the variety and complexity of sex worker needs and behaviours, and should be designed in consultation with sex workers. Segmenting sex worker populations according to age, country of origin and place of service delivery, and training healthcare providers accordingly, could help prevent new HIV infections, improve adherence to antiretroviral treatment and increase uptake of SRH services

p21WAF1/CIP1 Upregulation through the Stress Granule-Associated Protein CUGBP1 Confers Resistance to Bortezomib-Mediated Apoptosis

p21(WAF1/CIP1) is a well known cyclin-dependent kinase inhibitor induced by various stress stimuli. Depending on the stress applied, p21 upregulation can either promote apoptosis or prevent against apoptotic injury. The stress-mediated induction of p21 involves not only its transcriptional activation but also its posttranscriptional regulation, mainly through stabilization of p21 mRNA levels. We have previously reported that the proteasome inhibitor MG132 induces the stabilization of p21 mRNA, which correlates with the formation of cytoplasmic RNA stress granules. The mechanism underlying p21 mRNA stabilization, however, remains unknown.We identified the stress granules component CUGBP1 as a factor required for p21 mRNA stabilization following treatment with bortezomib ( =  PS-341/Velcade). This peptide boronate inhibitor of the 26S proteasome is very efficient for the treatment of myelomas and other hematological tumors. However, solid tumors are sometimes refractory to bortezomib treatment. We found that depleting CUGBP1 in cancer cells prevents bortezomib-mediated p21 upregulation. FISH experiments combined to mRNA stability assays show that this effect is largely due to a mistargeting of p21 mRNA in stress granules leading to its degradation. Altering the expression of p21 itself, either by depleting CUGBP1 or p21, promotes bortezomib-mediated apoptosis.We propose that one key mechanism by which apoptosis is inhibited upon treatment with chemotherapeutic drugs might involve upregulation of the p21 protein through CUGBP1

The ‘Stolen Generations' of Mothers and Daughters: Child Apprehension and Enhanced HIV Vulnerabilities for Sex Workers of Aboriginal Ancestry

The number of children in care of the state continues to grow in BC, Canada with a historical legacy of child apprehension among criminalized and marginalized populations, particularly women of Aboriginal ancestry and sex workers. However, there is a paucity of research investigating child apprehension experiences among marginalized mothers. The objective of the current analysis is to examine the prevalence and correlates of child apprehensions among female sex workers in Vancouver, Canada.Analyses were drawn from the AESHA (An Evaluation of Sex Workers Health Access, 2010-present), a prospective cohort of street and off-street SWs, through outreach and semi-annual visits to the research office. Bivariate and multivariate logistic regression were used to examine correlates of child apprehension.Of a total of 510 SWs, 350 women who had given birth to at least one child were included in the analyses (median age = 37 yrs: IQR: 31-44 yrs). The prevalence of child apprehension among mothers was 38.3%, with 37.4% reporting having been apprehended themselves by child welfare services. In multivariable analysis, servicing clients in outdoor public spaces (versus formal sex work establishments or informal indoor settings) (adjusted odds ratio, (aOR) = 2.73; 95%CI 1.27-5.90), history of injecting drugs (aOR  = 2.53; 95%CI 1.42-4.49), Aboriginal ancestry (aOR = 1.66; 95%CI 1.01-2.74) were associated with increased odds of child apprehension.Child apprehension rates are high, particularly among the most marginalized sex workers, including sex workers who use drugs and sex workers of Aboriginal ancestry. Structural reforms to child protection are urgently needed, that support family-based care address the historical legacy of colonization affecting Aboriginal peoples