52 research outputs found
Impaired IGF1-GH axis and new therapeutic options in AlstrΓΆm Syndrome patients: a case series
AΞ²42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila
Aggregation of the amyloid-Ξ²-42 (AΞ²42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of AΞ² aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that AΞ² can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of AΞ²42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human AΞ²42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (AΞ²42Arc) and an artificial mutation (AΞ²42art) that is known to suppress aggregation and toxicity of AΞ²42 in vitro. In the Drosophila brain, AΞ²42Arc formed more oligomers and deposits than did wild type AΞ²42, while AΞ²42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of AΞ² peptides. Surprisingly, however, AΞ²42art caused earlier onset of memory defects than AΞ²42. More remarkably, each AΞ² induced qualitatively different pathologies. AΞ²42Arc caused greater neuron loss than did AΞ²42, while AΞ²42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin S-stained AΞ² aggregates: AΞ²42Arc formed large deposits in the cell body, AΞ²42art accumulated preferentially in the neurites, while AΞ²42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of AΞ²42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo
Multi-centred mixed-methods PEPFAR HIV care & support public health evaluation: study protocol
BACKGROUND: A public health response is essential to meet the multidimensional needs of patients and families affected by HIV disease in sub-Saharan Africa. In order to appraise current provision of HIV care and support in East Africa, and to provide evidence-based direction to future care programming, and Public Health Evaluation was commissioned by the PEPFAR programme of the US Government. METHODS/DESIGN: This paper described the 2-Phase international mixed methods study protocol utilising longitudinal outcome measurement, surveys, patient and family qualitative interviews and focus groups, staff qualitative interviews, health economics and document analysis. Aim 1) To describe the nature and scope of HIV care and support in two African countries, including the types of facilities available, clients seen, and availability of specific components of care [Study Phase 1]. Aim 2) To determine patient health outcomes over time and principle cost drivers [Study Phase 2]. The study objectives are as follows. 1) To undertake a cross-sectional survey of service configuration and activity by sampling 10% of the facilities being funded by PEPFAR to provide HIV care and support in Kenya and Uganda (Phase 1) in order to describe care currently provided, including pharmacy drug reviews to determine availability and supply of essential drugs in HIV management. 2) To conduct patient focus group discussions at each of these (Phase 1) to determine care received. 3) To undertake a longitudinal prospective study of 1200 patients who are newly diagnosed with HIV or patients with HIV who present with a new problem attending PEPFAR care and support services. Data collection includes self-reported quality of life, core palliative outcomes and components of care received (Phase 2). 4) To conduct qualitative interviews with staff, patients and carers in order to explore and understand service issues and care provision in more depth (Phase 2). 5) To undertake document analysis to appraise the clinical care procedures at each facility (Phase 2). 6) To determine principle cost drivers including staff, overhead and laboratory costs (Phase 2). DISCUSSION: This novel mixed methods protocol will permit transparent presentation of subsequent dataset results publication, and offers a substantive model of protocol design to measure and integrate key activities and outcomes that underpin a public health approach to disease management in a low-income setting
Pushing Lines Helps: Efficient Universal Centralised Transformations for Programmable Matter
In this paper, we study a discrete system of entities residing on a
two-dimensional square grid. Each entity is modelled as a node occupying a
distinct cell of the grid. The set of all nodes forms initially a connected
shape . Entities are equipped with a linear-strength pushing mechanism that
can push a whole line of entities, from 1 to , in parallel in a single
time-step. A target connected shape is also provided and the goal is to
\emph{transform} into via a sequence of line movements. Existing models
based on local movement of individual nodes, such as rotating or sliding a
single node, can be shown to be special cases of the present model, therefore
their (inefficient, ) \emph{universal transformations} carry over.
Our main goal is to investigate whether the parallelism inherent in this new
type of movement can be exploited for efficient, i.e., sub-quadratic
worst-case, transformations. As a first step towards this, we restrict
attention solely to centralised transformations and leave the distributed case
as a direction for future research. Our results are positive. By focusing on
the apparently hard instance of transforming a diagonal into a straight
line , we first obtain transformations of time without and
with preserving the connectivity of the shape throughout the transformation.
Then, we further improve by providing two -time transformations for
this problem. By building upon these ideas, we first manage to develop an
-time universal transformation. Our main result is then an -time universal transformation. We leave as an interesting open
problem a suspected -time lower bound.Comment: 40 pages, 27 figure
Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells
MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease
Sequestration and Tissue Accumulation of Human Malaria Parasites: Can We Learn Anything from Rodent Models of Malaria?
The sequestration of Plasmodium falciparumβinfected red blood cells (irbcs) in the microvasculature of organs is associated with severe disease; correspondingly, the molecular basis of irbc adherence is an active area of study. In contrast to P. falciparum, much less is known about sequestration in other Plasmodium parasites, including those species that are used as models to study severe malaria. Here, we review the cytoadherence properties of irbcs of the rodent parasite Plasmodium berghei ANKA, where schizonts demonstrate a clear sequestration phenotype. Real-time in vivo imaging of transgenic P. berghei parasites in rodents has revealed a CD36-dependent sequestration in lungs and adipose tissue. In the absence of direct orthologs of the P. falciparum proteins that mediate binding to human CD36, the P. berghei proteins and/or mechanisms of rodent CD36 binding are as yet unknown. In addition to CD36-dependent schizont sequestration, irbcs accumulate during severe disease in different tissues, including the brain. The role of sequestration is discussed in the context of disease as are the general (dis)similarities of P. berghei and P. falciparum sequestration
IpaD of Shigella flexneri is independently required for regulation of Ipa protein secretion and efficient insertion of IpaB and IpaC into host membranes
The Association Between Depressive Symptoms, Anger, and Perceived Support Resources Among Underserved Older HIV Positive Black/African American Adults
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