Intermittent systemic exposure to lipopolysaccharide-induced inflammation disrupts hippocampal long-term potentiation and impairs cognition in aging male mice.

Age-related cognitive decline, a common component of the brain aging process, is associated with significant impairment in daily functioning and quality of life among geriatric adults. While the complexity of mechanisms underlying cognitive aging are still being elucidated, microbial exposure and the multifactorial inflammatory cascades associated with systemic infections are emerging as potential drivers of neurological senescence. The negative cognitive and neurobiological consequences of a single pathogen-associated inflammatory experience, such as that modeled through treatment with lipopolysaccharide (LPS), are well documented. Yet, the brain aging impacts of repeated, intermittent inflammatory challenges are less well studied. To extend the emerging literature assessing the impact of infection burden on cognitive function among normally aging mice, here, we repeatedly exposed adult mice to intermittent LPS challenges during the aging period. Male 10-month-old C57BL6 mice were systemically administered escalating doses of LPS once every two weeks for 2.5 months. We evaluated cognitive consequences using the non-spatial step-through inhibitory avoidance task, and both spatial working and reference memory versions of the Morris water maze. We also probed several potential mechanisms, including cortical and hippocampal cytokine/chemokine gene expression, as well as hippocampal neuronal function via extracellular field potential recordings. Though there was limited evidence for an ongoing inflammatory state in cortex and hippocampus, we observed impaired learning and memory and a disruption of hippocampal long-term potentiation. These data suggest that a history of intermittent exposure to LPS-induced inflammation is associated with subtle but significantly impaired cognition among normally aging mice. The broader impact of these findings may have important implications for standard of care involving infections in aging individuals or populations at-risk for dementia.

Theoretical design of an absorption hologram-based sensor for dose quantification in daylight photodynamic therapy.

Daylight photodynamic therapy (D-PDT) is an effective and almost painless treatment for many skin conditions, where successful treatment relies on daylight activation of a topical photosensitizer. Optimization of D-PDT requires accurate assessment of light dose received. There is a requirement for a small-area sensor that can be placed adjacent to the treatment site to facilitate accurate dose quantification. Here, a novel, to the best of our knowledge, configuration for a D-PDT dose sensor, consisting of a holographic absorption grating fabricated in a photosensitive film, is presented. Theoretical modeling of the sensor's response (i.e., change in grating diffraction efficiency due to change in grating absorption modulation, α1, on exposure to daylight) was conducted using Kogelnik's coupled-wave theory. The influence of the different grating parameters (initial film absorption, thickness, spatial frequency, and reconstruction wavelength) on the sensor response was examined and revealed that the initial absorption and grating thickness values have a large impact on both the magnitude and rate of the D-PDT sensor response. The optimum design for an absorption grating-based D-PDT sensor is described.

Re-assessing microbiomes in the low-biomass reproductive niche.

The female reproductive tract represents a continuum between the vagina and the upper genital tract. New evidence from cultivation-independent studies suggests that the female upper genital tract is not sterile; however, the significance of this for reproductive health and disease remains to be elucidated fully. Further, diagnosis and treatment of infectious reproductive tract pathologies using cultivation-independent technologies represents a largely unchartered area of modern medical science. The challenge now is to design well-controlled experiments to account for the ease of contamination known to confound molecular-based studies of low-biomass niches, including the uterus and placenta. This will support robust assessment of the potential function of microorganisms, microbial metabolites, and cell-free bacterial DNA on reproductive function in health and disease. TWEETABLE ABSTRACT: Molecular microbial studies of low-biomass niches require stringent experimental controls to reveal causal relations in reproductive health and disease.

Integrated demultiplexing and amplification of coherent optical combs.

The explosive growth of the internet during the last few decades has been enabled by two complementary innovations in optical communications: the use of multiple optical channels within a single optical fibre, and the increase in the bandwidth of individual channels to hundreds of Gbps. Further increases in overall bandwidth look to be provided by more spectrally efficient optical superchannels that use coherent sub-carriers generated using optical orthogonal frequency division multiplexing (OFDM). Yet, a cost effective way of generating these signals has not been demonstrated. One crucial, but missing piece is an effective means to separate the closely frequency spaced optical sub-carriers from the coherent optical comb before placing information on each sub-carrier, and thus creating the OFDM signal. Here, we demonstrate a flexible strategy implemented in a compact photonic integrated circuit (PIC) that is used to separate and amplify these sub-carriers using on-chip injection locking.

Regulation of biosimilar medicines and current perspectives on interchangeability and policy.

Competition arising from the increasing availability of biosimilar medicines has resulted in healthcare savings and has provided greater patient access to high cost therapeutics in Europe. The biosimilar market in the USA is relatively new so the full impact of biosimilar availability remains to be seen. Educational initiatives relating to the use of biosimilar medicines are currently being undertaken by regulators, policy makers and industry. The debate on biosimilars has moved on from the appropriateness of the regulatory framework which governs their approval, to the practice of interchangeability. Interchangeability is an important issue for healthcare professionals but different definitions and regulatory frameworks exist in the USA and Europe. In the USA, an interchangeable biological product is a biosimilar which may be substituted by a pharmacist, subject to local State policies. The interchangeability of a biosimilar with its reference medicine will be evaluated by the United States Food and Drug Administration (FDA) in cases where approval as an 'interchangeable product' is sought. In contrast, the European Medicines Agency (EMA) does not assess or make recommendations on interchangeability, therefore, in Europe, interchangeability does not mean substitution but is generally physician-led or driven by national policy. This paper provides an overview of the regulation of biosimilar medicines. Challenges associated with the demonstration of interchangeability and practical considerations relating to switching are also discussed. Finally, we present policies that have been adopted to date in several European countries, the USA and Australia, which aim to promote the use of biosimilar medicines.

Key enabling technologies for optical communications at 2000 nm.

This paper discusses the potential for opening a new wavelength window at the 2 µm waveband for optical communications, showing current limitations of the system's performance. It focuses on novel results for key enabling technologies, including the analysis of laser injection locking at this waveband, an improved responsivity for bulk and strained InGaAs edge-couple detectors, and also an increased gain profile for thulium-doped fiber amplifiers.

Bovine glycomacropeptide promotes the growth of Bifidobacterium longum ssp. infantis and modulates its gene expression.

Bovine milk glycomacropeptide (GMP) is derived from κ-casein, with exclusively o-linked glycosylation. Glycomacropeptide promoted the growth of Bifidobacterium longum ssp. infantis in a concentration-dependent manner, and this activity was lost following periodate treatment of the GMP (GMP-P), which disables biological recognition of the conjugated oligosaccharides. Transcriptional analysis of B. longum ssp. infantis following exposure to GMP revealed a substantial response to GMP relative to bacteria treated with GMP-P, with a greater number of differentially expressed transcripts and larger fold changes versus the control. Therefore, stimulation of B. longum ssp. infantis growth by GMP is intrinsically linked to the peptide's O-linked glycosylation. The pool of differentially expressed transcripts included 2 glycoside hydrolase (family 25) genes, which were substantially upregulated following exposure to GMP, but not GMP-P. These GH25 genes were present in duplicated genomic islands that also contained genes encoding fibronectin type III binding domain proteins and numerous phage-related proteins, all of which were also upregulated. Homologs of this genomic arrangement were present in other Bifidobacterium species, which suggest it may be a conserved domain for the utilization of glycosylated peptides. This study provides insights into the molecular basis for the prebiotic effect of bovine milk GMP on B. longum ssp. infantis.

Tissue magnetic susceptibility mapping as a marker of tau pathology in Alzheimer's disease.

Alzheimer's disease is connected to a number of other neurodegenerative conditions, known collectively as 'tauopathies', by the presence of aggregated tau protein in the brain. Neuroinflammation and oxidative stress in AD are associated with tau pathology and both the breakdown of axonal sheaths in white matter tracts and excess iron accumulation grey matter brain regions. Despite the identification of myelin and iron concentration as major sources of contrast in quantitative susceptibility maps of the brain, the sensitivity of this technique to tau pathology has yet to be explored. In this study, we perform Quantitative Susceptibility Mapping (QSM) and T2* mapping in the rTg4510, a mouse model of tauopathy, both in vivo and ex vivo. Significant correlations were observed between histological measures of myelin content and both mean regional magnetic susceptibility and T2* values. These results suggest that magnetic susceptibility is sensitive to tissue myelin concentrations across different regions of the brain. Differences in magnetic susceptibility were detected in the corpus callosum, striatum, hippocampus and thalamus of the rTg4510 mice relative to wild type controls. The concentration of neurofibrillary tangles was found to be low to intermediate in these brain regions indicating that QSM may be a useful biomarker for early stage detection of tau pathology in neurodegenerative diseases.

Application of neurite orientation dispersion and density imaging (NODDI) to a tau pathology model of Alzheimer's disease.

Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease.

Past, Present, and Future of Dynamic Kidney and Liver Preservation and Resuscitation.

The increased demand for organs has led to the increased usage of "higher risk" kidney and liver grafts. These grafts from donation after circulatory death or expanded criteria donors are more susceptible to preservation injury and have a higher risk of unfavorable outcomes. Dynamic, instead of static, preservation could allow for organ optimization, offering a platform for viability assessment, active organ repair and resuscitation. Ex situ machine perfusion and in situ regional perfusion in the donor are emerging as potential tools to preserve and resuscitate vulnerable grafts. Preclinical findings have ignited clinical organ preservation research that investigates dynamic preservation, its various modes (continuous, preimplantation) and temperatures (hypo-, sub, or normothermic). This review outlines the current status of dynamic preservation of kidney and liver grafts and describes ongoing research and emerging clinical trials.

In vivo imaging of tau pathology using multi-parametric quantitative MRI.

As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention.

10 Gb/s InP-based Mach-Zehnder modulator for operation at 2 µm wavelengths.

We report on the first InP-based Mach-Zehnder modulator (MZM) employing quantum-confined Stark effect (QCSE) for operation around 2000 nm. The polarization sensitive device is based on 15 compressively strained quantum wells and achieves an electro-optic (EO) bandwidth of at least 9 GHz, with a DC extinction ratio of ~9 dB, and a V(π)L ~9.6 V.mm. We demonstrate back-to-back communication with a 10 Gb/s pseudo-random bit sequence (PRBS) of length 2(7)-1 at a wavelength around 2000 nm.

First demonstration of a 2µm few-mode TDFA for mode division multiplexing.

We report the first demonstration of an inline few-mode thulium doped fiber amplifier (TDFA) operating at 2µm for mode division multiplexed transmission. Similar gain and noise figure performance for both the LP(01) and LP(11) modes are obtained in a cladding pumped 2-mode group TDFA. A maximum gain of 18.3dB was measured at 1970nm with a 3dB gain bandwidth of 75nm while the average noise figure was measured to be between 7 and 8dB for wavelengths longer than 1970nm.

Clinical pregnancy following pre-implantation genetic diagnosis for cystic fibrosis.

Pre-implantation genetic diagnosis (PGD) is an established alternative to prenatal testing for couples at risk of transmitting genetic disorders such as cystic fibrosis (CF).PGD screens pre-implantation embryos, allowing the safe transfer of those identified as unaffected. Awareness of CF carrier status in Ireland is increasing following the introduction of neonatal screening in 2011. PGD is the most acceptable reproductive strategy for many at risk Irish couples but until now the treatment necessitated travelling abroad. In 2012, the Irish Medicines Board licenced two Irish fertility clinics to carry out embryo biopsy for PGD. This is the first reported clinical pregnancy following PGD carried out in Ireland.

On-chip optical phase locking of single growth monolithically integrated Slotted Fabry Perot lasers.

This work investigates the optical phase locking performance of Slotted Fabry Perot (SFP) lasers and develops an integrated variable phase locked system on chip for the first time to our knowledge using these lasers. Stable phase locking is demonstrated between two SFP lasers coupled on chip via a variable gain waveguide section. The two lasers are biased differently, one just above the threshold current of the device with the other at three times this value. The coupling between the lasers can be controlled using the variable gain section which can act as a variable optical attenuator or amplifier depending on bias. Using this, the width of the stable phase locking region on chip is shown to be variable.

Systematic review and meta-analysis of hypothermic machine perfusion versus static cold storage of kidney allografts on transplant outcomes.

BACKGROUND: Adequate preservation of renal allografts for transplantation is important for maintaining and improving transplant outcomes. There are two prevalent methods: hypothermic machine perfusion and static cold storage. The preferred method of storage, however, remains controversial. The objective was to review systematically the evidence comparing outcomes from these two modalities. METHODS: A literature search was performed using MEDLINE, Embase, the Cochrane Library, the Transplant Library and the International Clinical Trials Registry Platform. The final date for searches was 30 November 2012. Studies were assessed for methodological quality. Summary effects were calculated as relative risk (RR) with 95 per cent confidence interval (c.i.). Randomized clinical trials (RCTs) and non-RCTs were included, but evaluated separately. Results from RCTs alone were used for meta-analysis. RESULTS: Eighteen studies met the inclusion criteria, including seven RCTs (1475 kidneys) and 11 non-RCTs (728 kidneys). The overall risk of delayed graft function was lower with hypothermic machine perfusion than static cold storage (RR 0·81, 95 per cent c.i. 0·71 to 0·92; P = 0·002). There was no difference in the rate of primary non-function (RR 1·15, 0·46 to 2·90; P = 0·767). There was a faster initial fall in the level of serum creatinine with hypothermic machine perfusion in two RCTs, but not in another. There was no relationship between rates of acute rejection or patient survival and the method of preservation. CONCLUSION: Data from the included studies suggest that hypothermic machine perfusion reduces delayed graft function compared with static cold storage. There was no difference in primary non-function, acute rejection, long-term renal function or patient survival. A difference in renal graft survival is uncertain.

Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis.

Static cold storage is the most prevalent method for renal allograft preservation. Several solutions have been designed to counteract the detrimental effects of cold ischemia and reperfusion. The aim of this study was to appraise the evidence for the currently available preservation solutions. We performed a systematic literature search using MEDLINE, EMBASE, the Cochrane Library, the Transplant Library and trial registries. Inclusion criteria specified any comparative, prospective study for deceased donor renal allografts. Studies were assessed for methodological quality. The primary outcome was delayed graft function (DGF). Fifteen trials with a total of 3584 kidneys were included. Eurocollins was associated with a higher risk of DGF than University of Wisconsin solution (UW) in two randomized controlled trials (RCTs) and histidine-tryptophan-ketoglutarate (HTK) in two RCTs. UW was associated with an equal risk of DGF compared with Celsior in three RCTs and HTK in two RCTs. There was limited data regarding other comparisons and outcomes. The choice of preservation solution has an effect on the incidence of DGF, which might, in turn, affect long-term outcomes. Both UW and HTK have lower rates of DGF than Eurocollins. There is no difference in the incidence of DGF with the use of Celsior, HTK and UW. These findings are supported by registry data.

Boston biorepository, recruitment and integrative network (BBRAIN): A resource for the Gulf War Illness scientific community.

AIMS: Gulf War Illness (GWI), a chronic debilitating disorder characterized by fatigue, joint pain, cognitive, gastrointestinal, respiratory, and skin problems, is currently diagnosed by self-reported symptoms. The Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) is the collaborative effort of expert Gulf War Illness (GWI) researchers who are creating objective diagnostic and pathobiological markers and recommend common data elements for GWI research. MAIN METHODS: BBRAIN is recruiting 300 GWI cases and 200 GW veteran controls for the prospective study. Key data and biological samples from prior GWI studies are being merged and combined into retrospective datasets. They will be made available for data mining by the BBRAIN network and the GWI research community. Prospective questionnaire data include general health and chronic symptoms, demographics, measures of pain, fatigue, medical conditions, deployment and exposure histories. Available repository biospecimens include blood, plasma, serum, saliva, stool, urine, human induced pluripotent stem cells and cerebrospinal fluid. KEY FINDINGS: To date, multiple datasets have been merged and combined from 15 participating study sites. These data and samples have been collated and an online request form for repository requests as well as recommended common data elements have been created. Data and biospecimen sample requests are reviewed by the BBRAIN steering committee members for approval as they are received. SIGNIFICANCE: The BBRAIN repository network serves as a much needed resource for GWI researchers to utilize for identification and validation of objective diagnostic and pathobiological markers of the illness.

Invited review: Lactobacillus helveticus--a thermophilic dairy starter related to gut bacteria.

The strain Lactobacillus helveticus DPC4571 has emerged as a promising flavor adjunct culture for Cheddar cheese given that it is consistently associated with improved flavor. The availability of the complete genome sequence of Lb. helveticus DPC4571 has enabled the search for the presence or absence of specific genes on the genome, in particular those of technological interest. Indeed, this analysis has facilitated a greater understanding into the functioning of lactic acid bacteria as a whole. The biochemical pathways of Lb. helveticus responsible for producing flavor compounds during cheese ripening are poorly understood but now with the availability of a complete genomic sequence are ripe for exploitation. Bioinformatic analysis of the genome of Lb. helveticus DPC4571 has revealed a plethora of genes with industrial potential including those responsible for key metabolic functions that contribute to cheese flavor development such as proteolysis, lipolysis, and cell lysis. In addition, it has been demonstrated that Lb. helveticus has the potential to produce bioactive peptides such as angiotensin converting enzyme inhibitory activity in fermented dairy products, demonstrating the therapeutic value of this species. A most intriguing feature of the genome of Lb. helveticus DPC4571 is the remarkable similarity in gene content with many intestinal lactobacilli, although originating from considerably different environments. Bioinformatic analysis demonstrated that 65 to 75% of genes were conserved between the commensal and dairy lactobacilli, which allowed key niche-specific gene sets to be described. This review focuses on the isolation, characterization, and exploitation of the Lb. helveticus species with particular emphesis on taking into consideration recent genome sequence data for Lb. helveticus and other Lactobacillus species.