Cerebrospinal Fluid Biomarkers are Differentially Related to Structural and Functional Changes in Dementia of the Alzheimer's Type

The two cardinal pathologies of Alzheimer’s disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer’s type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks

"Half plate of rice to a male casual sexual partner, full plate belongs to the husband": Findings from a qualitative study on sexual behaviour in relation to HIV and AIDS in northern Tanzania

A thorough understanding of the contexts of sexual behaviour of the people who are vulnerable to HIV infection is an important component in the battle against AIDS epidemic. We conducted a qualitative study to investigate perceptions, attitudes and practices of sexually active people in three districts of northern Tanzania with the view of collecting data to inform the formulation of appropriate complementary interventions against HIV and AIDS in the study communities. We conducted 96 semi-structured interviews and 48 focus group discussions with sexually active participants (18-60 years of age) who were selected purposively in two fishing and one non-fishing communities. The study revealed a number of socio-economic and cultural factors which act as structural drivers of HIV epidemic. Mobility and migration were mentioned to be associated with the risk of HIV acquisition and transmission. Sexual promiscuous behaviour was common in all study communities. Chomolea, (a quick transactional sex) was reported to exist in fishing communities, whereas extramarital sex in the bush was reported in non-fishing community which was predominantly Christian and polygamous. Traditional practices such as Kusomboka (death cleansing through unprotected sex) was reported to exist. Other risky sexual behaviour and traditional practices together with their socio-economic and cultural contexts are presented in details and discussed. Knowledge of condom was low as some people mistook them for balloons to play with and as decorations for their living rooms. Acute scarcity of condoms in some remote areas such as vizingani (fishing islands) push some people to make their own condoms locally known as kondomu za pepsi using polythene bags. HIV prevention efforts can succeed by addressing sexual behaviour and its socio-economic and cultural contexts. More innovative, interdisciplinary and productive structural approaches to HIV prevention need to be developed in close collaboration with affected communities and be closely related to policy-making and implementation; to go beyond the limited success of traditional behavioural and biomedical interventions to particularly address the underlying social and structural drivers of HIV risk and vulnerability in the study communities

Luminal and basal-like breast cancer cells show increased migration induced by hypoxia, mediated by an autocrine mechanism

<p>Abstract</p> <p>Background</p> <p>Some breast cancer patients receiving anti-angiogenic treatment show increased metastases, possibly as a result of induced hypoxia. The effect of hypoxia on tumor cell migration was assessed in selected luminal, post-EMT and basal-like breast carcinoma cell lines.</p> <p>Methods</p> <p>Migration was assessed in luminal (MCF-7), post-EMT (MDA-MB-231, MDA-MB-435S), and basal-like (MDA-MB-468) human breast carcinoma cell lines under normal and oxygen-deprived conditions, using a collagen-based assay. Cell proliferation was determined, secreted cytokine and chemokine levels were measured using flow-cytometry and a bead-based immunoassay, and the hypoxic genes HIF-1α and CA IX were assessed using PCR. The functional effect of tumor-cell conditioned medium on the migration of neutrophil granulocytes (NG) was tested.</p> <p>Results</p> <p>Hypoxia caused increased migratory activity but not proliferation in all tumor cell lines, involving the release and autocrine action of soluble mediators. Conditioned medium (CM) from hypoxic cells induced migration in normoxic cells. Hypoxia changed the profile of released inflammatory mediators according to cell type. Interleukin-8 was produced only by post-EMT and basal-like cell lines, regardless of hypoxia. MCP-1 was produced by MDA-MB-435 and -468 cells, whereas IL-6 was present only in MDA-MB-231. IL-2, TNF-α, and NGF production was stimulated by hypoxia in MCF-7 cells. CM from normoxic and hypoxic MDA-MB-231 and MDA-MB-435S cells and hypoxic MCF-7 cells, but not MDA-MB-468, induced NG migration.</p> <p>Conclusions</p> <p>Hypoxia increases migration by the autocrine action of released signal substances in selected luminal and basal-like breast carcinoma cell lines which might explain why anti-angiogenic treatment can worsen clinical outcome in some patients.</p

Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Prostaglandin E₂(PGE₂) is the major product of Cyclooxygenase-2 (COX-2) in colorectal cancer (CRC). We aimed to assess PGE₂cell surface receptors (EP 1–4) to examine the mechanisms by which PGE₂regulates tumour progression.</p> <p>Methods</p> <p>Gene expression studies were performed by quantitative RT-PCR. Cell cycle was analysed by flow cytometry with cell proliferation quantified by BrdU incorporation measured by enzyme immunoassay. Immunohistochemistry was employed for expression studies on formalin fixed paraffin embedded tumour tissue.</p> <p>Results</p> <p>EP4 was the most abundant subtype of PGE₂receptor in HT-29 and HCA7 cells (which show COX-2 dependent PGE₂generation) and was consistently the most abundant transcript in human colorectal tumours (n = 8) by qRT-PCR (ANOVA, p = 0.01). G0/G1 cell cycle arrest was observed in HT-29 cells treated with SC-236 5 μM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE₂(1 μM). G0/G1 arrest was also seen with a specific EP4 receptor antagonist (EP4A, L-161982) (p = 0.01). Treatment of HT-29 cells with either SC-236 or EP4A caused reduction in intracellular cAMP (ANOVA, p = 0.01). Early induction in p21^WAF1/CIP1expression (by qRT-PCR) was seen with EP4A treatment (mean fold increase 4.4, p = 0.04) while other genes remained unchanged. Similar induction in p21^WAF1/CIP1was also seen with PD153025 (1 μM), an EGFR tyrosine kinase inhibitor, suggesting EGFR transactivation by EP4 as a potential mechanism. Additive inhibition of HCA7 proliferation was observed with the combination of SC-236 and neutralising antibody to amphiregulin (AR), a soluble EGFR ligand. Concordance in COX-2 and AR localisation in human colorectal tumours was noted.</p> <p>Conclusion</p> <p>COX-2 regulates cell cycle transition via EP4 receptor and altered p21^WAF1/CIP1expression. EGFR pathways appear important. Specific targeting of the EP4 receptor or downstream targets may offer a safer alternative to COX-2 inhibition in the chemoprevention of CRC.</p

A Single-Step Sequencing Method for the Identification of Mycobacterium tuberculosis Complex Species

The Mycobacterium tuberculosis complex (MTC) comprises several closely related species responsible for strictly human and zoonotic tuberculosis. Some of the species are restricted to Africa and were responsible for the high prevalence of tuberculosis. However, their identification at species level is difficult and expansive. Accurate species identification of all members is warranted in order to distinguish between strict human and zoonotic tuberculosis, to trace source exposure during epidemiological studies, and for the appropriate treatment of patients. In this paper, the Exact Tandem Repeat D (ETR-D) intergenic region was investigated in order to distinguish MTC species. The ETR-D sequencing unambiguously identified MTC species type strain except M. pinnipedii and M. microti, and the results agreed with phenotypic and molecular identification. This finding offers a new tool for the rapid and accurate identification of MTC species in a single sequencing reaction, replacing the current time-consuming polyphasic approach. Its use could assist public health interventions and aid in the control of zoonotic transmission in African countries, and could be of particular interest with the current emergence of multidrug-resistant and extended-resistance isolates

Magnetic resonance enterography, small bowel ultrasound and colonoscopy to diagnose and stage Crohn’s disease; patient acceptability, and perceived burden

Objectives: To compare patient acceptability and burden of magnetic resonance enterography (MRE) and ultrasound (US) to each other, and to other enteric investigations, particularly colonoscopy. Methods: 159 patients (mean age 38, 94 female) with newly diagnosed or relapsing Crohn’s disease, prospectively recruited to a multicentre diagnostic accuracy study comparing MRE and US, completed an experience questionnaire on the burden and acceptability of small bowel investigations between December 2013 and September 2016. Acceptability, recovery time, scan burden and willingness to repeat the test were analysed using the Wilcoxon signed rank and McNemar tests; and group differences in scan burden with Mann-Whitney U and Kruskal-Wallis tests. Results: Overall, 128 (88%) patients rated MRE as very or fairly acceptable, lower than US (144, 99%; p<0.001), but greater than colonoscopy (60, 60%; p<0.001). MRE recovery time was longer than US (p<0.001), but shorter than colonoscopy (p<0.001). Patients were less willing to undergo MRE again than US (127 vs 133, 91% vs. 99%; p=0.012), but more willing than for colonoscopy (68, 75%; p=0.017). MRE generated greater burden than US (p<0.001), although burden scores were low. Younger age and emotional distress were associated with greater MRE and US burden. Higher MRE discomfort was associated with patient preference for US (p=0.053). Patients rated test accuracy as more important than scan discomfort. Conclusions.: MRE and US are well tolerated. Although MRE generates greater burden, longer recovery, and is less preferred than US, it is more acceptable than colonoscopy. Patients however place greater emphasis on diagnostic accuracy than burden

The Genome of a Pathogenic Rhodococcus: Cooptive Virulence Underpinned by Key Gene Acquisitions

We report the genome of the facultative intracellular parasite Rhodococcus equi, the only animal pathogen within the biotechnologically important actinobacterial genus Rhodococcus. The 5.0-Mb R. equi 103S genome is significantly smaller than those of environmental rhodococci. This is due to genome expansion in nonpathogenic species, via a linear gain of paralogous genes and an accelerated genetic flux, rather than reductive evolution in R. equi. The 103S genome lacks the extensive catabolic and secondary metabolic complement of environmental rhodococci, and it displays unique adaptations for host colonization and competition in the short-chain fatty acid–rich intestine and manure of herbivores—two main R. equi reservoirs. Except for a few horizontally acquired (HGT) pathogenicity loci, including a cytoadhesive pilus determinant (rpl) and the virulence plasmid vap pathogenicity island (PAI) required for intramacrophage survival, most of the potential virulence-associated genes identified in R. equi are conserved in environmental rhodococci or have homologs in nonpathogenic Actinobacteria. This suggests a mechanism of virulence evolution based on the cooption of existing core actinobacterial traits, triggered by key host niche–adaptive HGT events. We tested this hypothesis by investigating R. equi virulence plasmid-chromosome crosstalk, by global transcription profiling and expression network analysis. Two chromosomal genes conserved in environmental rhodococci, encoding putative chorismate mutase and anthranilate synthase enzymes involved in aromatic amino acid biosynthesis, were strongly coregulated with vap PAI virulence genes and required for optimal proliferation in macrophages. The regulatory integration of chromosomal metabolic genes under the control of the HGT–acquired plasmid PAI is thus an important element in the cooptive virulence of R. equi