Sensitivity analysis of permeability parameters of bovine nucleus pulposus obtained through inverse fitting of the nonlinear biphasic equation : effect of sampling strategy

Permeability controls the fluid flow into and out of soft tissue, and plays an important role in maintaining the health status of such tissue. Accurate determination of the parameters that define permeability is important for the interpretation of models that incorporate such processes. This paper describes the determination of strain-dependent permeability parameters from the nonlinear biphasic equation from experimental data of different sampling frequencies using the Nelder–Mead simplex method. The ability of this method to determine the global optimum was assessed by constructing the whole manifold arising from possible parameter combinations. Many parameter combinations yielded similar fits with the Nelder–Mead algorithm able to identify the global maximum within the resolution of the manifold. Furthermore, the sampling strategy affected the optimum values of the permeability parameters. Therefore, permeability parameter estimations arising from inverse methods should be utilised with the knowledge that they come with large confidence intervals

LRP1 Has a Predominant Role in Production over Clearance of Aβ in a Mouse Model of Alzheimer's Disease.

The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD

Geographical concentration of falciparum malaria treated in the UK and delay to treatment with artesunate in severe cases: an observational study.

OBJECTIVES: To quantify geographical concentration of falciparum malaria cases in the UK at a hospital level. To assess potential delay-to-treatment associated with hub-and-spoke distribution of artesunate in severe cases. DESIGN: Observational study using national and hospital data. SETTING AND PARTICIPANTS: 3520 patients notified to the Malaria Reference Laboratory 2008-2010, 34 patients treated with intravenous artesunate from a tropical diseases centre 2002-2010. MAIN OUTCOME MEASURES: Geographical location of falciparum cases notified in the UK. Diagnosis-to-treatment times for intravenous artesunate. RESULTS: Eight centres accounted for 43.9% of the UK's total cases; notifications from 107 centres accounted for 10.2% of cases; 51.5% of hospitals seeing malaria notified 5 or fewer cases in 3 years. Centres that saw <10 cases/year treat 26.3% of malaria cases; 6.1% of cases are treated in hospitals seeing <2 cases/year. Concentration of falciparum malaria was highest in Greater London (1925, 54.7%), South East (515, 14.6%), East of England (402, 11.4%) and North West (192, 5.4%). The North East and Northern Ireland each notified 5 or fewer cases per year. Median diagnosis-to-treatment time was 1 h (range 0.5-5) for patients receiving artesunate in the specialist centre; 7.5 h (range 4-26) for patients receiving it in referring hospitals via the hub-and-spoke system (p=0.02); 25 h (range 9-45) for patients receiving it on transfer to the regional centre from a referring hospital (p=0.002). CONCLUSIONS: Most UK hospitals see few cases of falciparum malaria and geographical distances are significant. Over 25% of cases are seen in hospitals where malaria is rare, although 60% are seen in hospitals seeing over 50 cases over 3 years. A hub-and-spoke system minimises drug wastage and ensures availability in centres seeing most cases but is associated with treatment delays elsewhere. As with all observational studies, there are limitations, which are discussed

Motility-induced phase separation mediated by bacterial quorum sensing

We study motility-induced phase separation (MIPS) in living active matter, in which cells interact through chemical signalling, or quorum sensing. In contrast to previous theories of MIPS, our multiscale continuum model accounts explicitly for genetic regulation of signal production and motility. Through analysis and simulations, we derive a new criterion for the onset of MIPS that depends on features of the genetic network. Furthermore, we identify and characterise a new type of oscillatory instability that occurs when gene regulation inside cells promotes motility in higher signal concentrations

Group 2 Innate Lymphoid Cells Are Redundant in Experimental Renal Ischemia-Reperfusion Injury.

Acute kidney injury (AKI) can be fatal and is a well-defined risk factor for the development of chronic kidney disease. Group 2 innate lymphoid cells (ILC2s) are innate producers of type-2 cytokines and are critical regulators of homeostasis in peripheral organs. However, our knowledge of their function in the kidney is relatively limited. Recent evidence suggests that increasing ILC2 numbers by systemic administration of recombinant interleukin (IL)-25 or IL-33 protects against renal injury. Whilst ILC2s can be induced to protect against ischemic- or chemical-induced AKI, the impact of ILC2 deficiency or depletion on the severity of renal injury is unknown. Firstly, the phenotype and location of ILC2s in the kidney was assessed under homeostatic conditions. Kidney ILC2s constitutively expressed high levels of IL-5 and were located in close proximity to the renal vasculature. To test the functional role of ILC2s in the kidney, an experimental model of renal ischemia-reperfusion injury (IRI) was used and the severity of injury was assessed in wild-type, ILC2-reduced, ILC2-deficient, and ILC2-depleted mice. Surprisingly, there were no differences in histopathology, collagen deposition or mRNA expression of injury-associated (Lcn2), inflammatory (Cxcl1, Cxcl2, and Tnf) or extracellular matrix (Col1a1, Fn1) factors following IRI in the absence of ILC2s. These data suggest the absence of ILC2s does not alter the severity of renal injury, suggesting possible redundancy. Therefore, other mechanisms of type 2-mediated immune cell activation likely compensate in the absence of ILC2s. Hence, a loss of ILC2s is unlikely to increase susceptibility to, or severity of AKI

Echocardiographic assessment and percutaneous closure of multiple atrial septal defects

Atrial septal defect closure is now routinely performed using a percutaneous approach under echocardiographic guidance. Centrally located, secundum defects are ideal for device closure but there is considerable morphological variation in size and location of the defects. A small proportion of atrial septal defects may have multiple fenestrations and these are often considered unsuitable for device closure. We report three cases of multiple atrial septal defects successfully closed with two Amplatzer septal occluders

Cranial nerve palsies in Nigerian children

Background: Cranial nerve palsies are common clinical problem routinely encountered in neurological practice; the dysfunction can occur at any point in the course of the nerve and may point to serious pathology. The aim of this study was to determine the pattern and underlying aetiology of cranial nerve palsies in Nigerian children.Method: Children in the Children’s Emergency Unit and the Children’s Ward of the University of Calabar Teaching Hospital, Calabar, Nigeria, with neurological problems over a 12-month period (January through December 2012), were recruited into the study. Each child was admitted and evaluated by the Paediatric Neurology Unit. Those with cranial nerve palsies were selected for detailed analysis. The biodata, clinical features and relevant laboratory results were documented.Results: Of the 285 with neurological problems 23 (8.1%) had cranial nerve palsies. Fifteen (65.2%) of the children had single cranial nerve palsies while eight (34.8%) had multiple cranial nerves involvement. Of the 43 nerves involved, the facial nerve was the commonest (38.3%) followed by the oculomotor (23.5%) and abducens (20.6%). Intracranial infections such as meningitis, viral encephalitis and brain abscess were incriminated in 60.8% of the patients and 70.6% of the nerves involved.Conclusion: Cranial nerve palsies cause handicap and cosmetic problems. It is recommended that every child with cranial neuropathy should be evaluated for intracranial infections among other differentials. Prompt diagnosis, treatment and immunisation against related infections is paramount

Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome

Background The introduction of molecular karyotyping technologies facilitated the identification of specific genetic disorders associated with imbalances of certain genomic regions. A detailed phenotypic delineation of interstitial 16p13.3 duplications is hampered by the scarcity of such patients. Objectives To delineate the phenotypic spectrum associated with interstitial 16p13.3 duplications, and perform a genotype-phenotype analysis. Results The present report describes the genotypic and phenotypic delineation of nine submicroscopic interstitial 16p13.3 duplications. The critically duplicated region encompasses a single gene, CREBBP, which is mutated or deleted in Rubinstein-Taybi syndrome. In 10 out of the 12 hitherto described probands, the duplication arose de novo. Conclusions Interstitial 16p13.3 duplications have a recognizable phenotype, characterized by normal to moderately retarded mental development, normal growth, mild arthrogryposis, frequently small and proximally implanted thumbs and characteristic facial features. Occasionally, developmental defects of the heart, genitalia, palate or the eyes are observed. The frequent de novo occurrence of 16p13.3 duplications demonstrates the reduced reproductive fitness associated with this genotype. Inheritance of the duplication from a clinically normal parent in two cases indicates that the associated phenotype is incompletely penetrant