Cerebral ischemic damage in diabetes: an inflammatory perspective

Stroke is one of the leading causes of death worldwide. A strong inflammatory response characterized by activation and release of cytokines, chemokines, adhesion molecules, and proteolytic enzymes contributes to brain damage following stroke. Stroke outcomes are worse among diabetics, resulting in increased mortality and disabilities. Diabetes involves chronic inflammation manifested by reactive oxygen species generation, expression of proinflammatory cytokines, and activation/expression of other inflammatory mediators. It appears that increased proinflammatory processes due to diabetes are further accelerated after cerebral ischemia, leading to increased ischemic damage. Hypoglycemia is an intrinsic side effect owing to glucose-lowering therapy in diabetics, and is known to induce proinflammatory changes as well as exacerbate cerebral damage in experimental stroke. Here, we present a review of available literature on the contribution of neuroinflammation to increased cerebral ischemic damage in diabetics. We also describe the role of hypoglycemia in neuroinflammation and cerebral ischemic damage in diabetics. Understanding the role of neuroinflammatory mechanisms in worsening stroke outcome in diabetics may help limit ischemic brain injury and improve clinical outcomes

Test-retest repeatability of ADC in prostate using the multi b-Value VERDICT acquisition

Purpose: VERDICT (Vascular, Extracellular, Restricted Diffusion for Cytometry in Tumours) MRI is a multi b-value, variable diffusion time DWI sequence that allows generation of ADC maps from different b-value and diffusion time combinations. The aim was to assess precision of prostate ADC measurements from varying b-value combinations using VERDICT and determine which protocol provides the most repeatable ADC. // Materials and Methods: Forty-one men (median age: 67.7 years) from a prior prospective VERDICT study (April 2016–October 2017) were analysed retrospectively. Men who were suspected of prostate cancer and scanned twice using VERDICT were included. ADC maps were formed using 5b-value combinations and the within-subject standard deviations (wSD) were calculated per ADC map. Three anatomical locations were analysed per subject: normal TZ (transition zone), normal PZ (peripheral zone), and index lesions. Repeated measures ANOVAs showed which b-value range had the lowest wSD, Spearman correlation and generalized linear model regression analysis determined whether wSD was related to ADC magnitude and ROI size. // Results: The mean lesion ADC for b0 b1500 had the lowest wSD in most zones (0.18–0.58x10-4 mm2/s). The wSD was unaffected by ADC magnitude (Lesion: p = 0.064, TZ: p = 0.368, PZ: p = 0.072) and lesion Likert score (p = 0.95). wSD showed a decrease with ROI size pooled over zones (p = 0.019, adjusted regression coefficient = -1.6x10-3, larger ROIs for TZ versus PZ versus lesions). ADC maps formed with a maximum b-value of 500 s/mm2 had the largest wSDs (1.90–10.24x10-4 mm2/s). // Conclusion: ADC maps generated from b0 b1500 have better repeatability in normal TZ, normal PZ, and index lesions

Effect of a Macrofilaricidal Agent on the Bioenergetics of Acanthocheilonema viteae as Studied by <31>^P-NMR and Biochemical Analysis

^P-NMR has been applied to the study on the energy metabolism of intact rodent filariids Acanthocheilonema viteae. Based on chemical shifts and analysis of worm extracts, the phosphorus components included sugar phosphates, inorganic phosphate, glycerophosphoryl choline (GPC) and -ethanolamine (GPE), phosphoenol pyruvate (PEP), nucleotide mono, -di and -tri phosphates, nicotinamide adenine dinucleotide and uridine diphosphate glucose. Effect of adulticidal candidate drug (C. D. R. I. Comp. 82/437, in its clinical phase I trial) on the bioenergetics of A. viteae adult filariids was assessed by ^P-NMR and revalidated by metabolic and enzymatic studies. Comp. 82/437 at the active dose of 50mg/kg, orally×5 days, showed maximum effect on day-16 post treatment. ^P-NMR data revealed significantly low amount of GPE (52.2%), GPC (43.5%), ATP (54.8%) and PEP (77.2%) in the treated worms. Biochemically also, ATP and PEP levels in these worms were found to be reduced by 30.9 and 44% respectively. Amongst enzymes the activity of hexokinase rose by 58%. By this enhancement, the enzyme may be able to effectively mediate the entry of extra glucose (48%), into glycolysis. On the other hand, a substantial (30%) decrease in activity seems to make phosphofructokinase a real rate limiting step in the glycolysis. This would ultimately lead to the lower production of ATP. In the energy deprived worm all the metabolic activities will gradually decline and may result in the penultimate death due to drug action. NMR observations and conventional biochemical methods substantiate the findings of one another and direct towards the hitting of bioenergetic machinery of A. viteae by macrofilaricidal agent (Comp. 82/437)

Prospective Evaluation of In Vivo and Phantom Repeatability and Reproducibility of Diffusion-Weighted MRI Sequences on 1.5 T MRI-Linear Accelerator (MR-Linac) and MR Simulator Devices for Head and Neck Cancers

INTRODUCTION: Diffusion-weighted imaging (DWI) on MRI-linear accelerator (MR-linac) systems can potentially be used for monitoring treatment response and adaptive radiotherapy in head and neck cancers (HNC) but requires extensive validation. We performed technical validation to compare six total DWI sequences on an MR-linac and MR simulator (MR sim) in patients, volunteers, and phantoms. METHODS: Ten human papillomavirus-positive oropharyngeal cancer patients and ten healthy volunteers underwent DWI on a 1.5 T MR-linac with three DWI sequences: echo planar imaging (EPI), split acquisition of fast spin echo signals (SPLICE), and turbo spin echo (TSE). Volunteers were also imaged on a 1.5 T MR sim with three sequences: EPI, BLADE (vendor tradename), and readout segmentation of long variable echo trains (RESOLVE). Participants underwent two scan sessions per device and two repeats of each sequence per session. Repeatability and reproducibility within-subject coefficient of variation (wCV) of mean ADC were calculated for tumors and lymph nodes (patients) and parotid glands (volunteers). ADC bias, repeatability/reproducibility metrics, SNR, and geometric distortion were quantified using a phantom. RESULTS: In vivo repeatability/reproducibility wCV for parotids were 5.41%/6.72%, 3.83%/8.80%, 5.66%/10.03%, 3.44%/5.70%, 5.04%/5.66%, 4.23%/7.36% for EPI CONCLUSION: MR-linac DWI sequences demonstrated near-comparable performance to MR sim sequences and warrant further clinical validation for treatment response assessment in HNC

Physical Passaging of Embryoid Bodies Generated from Human Pluripotent Stem Cells

Spherical three-dimensional cell aggregates called embryoid bodies (EBs), have been widely used in in vitro differentiation protocols for human pluripotent stem cells including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Recent studies highlight the new devices and techniques for hEB formation and expansion, but are not involved in the passaging or subculture process. Here, we provide evidence that a simple periodic passaging markedly improved hEB culture condition and thus allowed the size-controlled, mass production of human embryoid bodies (hEBs) derived from both hESCs and hiPSCs. hEBs maintained in prolonged suspension culture without passaging (>2 weeks) showed a progressive decrease in the cell growth and proliferation and increase in the apoptosis compared to 7-day-old hEBs. However, when serially passaged in suspension, hEB cell populations were significantly increased in number while maintaining the normal rates of cell proliferation and apoptosis and the differentiation potential. Uniform-sized hEBs produced by manual passaging using a 1∶4 split ratio have been successfully maintained for over 20 continuous passages. The passaging culture method of hEBs, which is simple, readily expandable, and reproducible, could be a powerful tool for improving a robust and scalable in vitro differentiation system of human pluripotent stem cells

Neoadjuvant chemotherapy in breast cancer: early response prediction with quantitative MR imaging and spectroscopy.

A prospective study was undertaken in women undergoing neoadjuvant chemotherapy for locally advanced breast cancer in order to determine the ability of quantitative magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to predict ultimate tumour response (percentage decrease in volume) or to detect early response. Magnetic resonance imaging and MRS were carried out before treatment and after the second of six treatment cycles. Pharmacokinetic parameters were derived from T1-weighted dynamic contrast-enhanced MRI, water apparent diffusion coefficient (ADC) was measured, and tissue water:fat peak area ratios and water T2 were measured using unsuppressed one-dimensional proton spectroscopic imaging (30 and 135 ms echo times). Pharmacokinetic parameters and ADC did not detect early response; however, early changes in water:fat ratios and water T2 (after cycle two) demonstrated substantial prognostic efficacy. Larger decreases in water T2 accurately predicted final volume response in 69% of cases (11/16) while maintaining 100% specificity and positive predictive value. Small/absent decreases in water:fat ratios accurately predicted final volume non-response in 50% of cases (3/6) while maintaining 100% sensitivity and negative predictive value. This level of accuracy might permit clinical application where early, accurate prediction of non-response would permit an early change to second-line treatment, thus sparing patients unnecessary toxicity, psychological morbidity and delay of initiation of effective treatment

ADC measurements on the Unity MR-linac - A recommendation on behalf of the Elekta Unity MR-linac consortium

Background and purpose: Diffusion-weighted imaging (DWI) for treatment response monitoring is feasibleon hybrid magnetic resonance linear accelerator (MR-linac) systems. The MRI scanner of the ElektaUnity system has an adjusted design compared to diagnostic scanners. We investigated its impact onmeasuring the DWI-derived apparent diffusion coefficient (ADC) regarding three aspects: the choice ofb-values, the spatial variation of the ADC, and scanning during radiation treatment. The aim of this studyis to give recommendations for accurate ADC measurements on Unity systems.Materials and methods: Signal-to-noise ratio (SNR) measurements with increasing b-values were done todetermine the highest bvalue that can be measured reliably. The spatial variation of the ADC wasassessed on six Unity systems with a cylindrical phantom of 40 cm diameter. The influence of gantry rotationand irradiation was investigated by acquiring DWI images before and during treatment of 11 prostatecancer patients.Results: On the Unity system, a maximum b-value of 500 s/mm2 should be used for ADC quantification, asa trade-off between SNR and diffusion weighting. Accurate ADC values were obtained within 7 cm fromthe iso-center, while outside this region ADC values deviated more than 5%. The ADC was not influencedby the rotating linac or irradiation during treatment.Conclusion: We provide Unity system specific recommendations for measuring the ADC. This willincrease the consistency of ADC values acquired in different centers on the Unity system, enabling largecohort studies for biomarker discovery and treatment response monitoring.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Does humeral fixation technique affect long-term outcomes of total shoulder arthroplasty?

Background For anatomic total arthroscopic repair, cementless humeral fixation has recently gained popularity. However, few studies have compared clinical, radiographic, and patient-reported outcomes between cemented and press-fit humeral fixation, and none have performed follow-up for longer than 5 years. In this study, we compared long-term postoperative outcomes in patients receiving a cemented versus press-fit humeral stem anatomic arthroscopic repair. Methods This study retrospectively analyzed 169 shoulders that required primary anatomic total shoulder arthroplasty (aTSA). Shoulders were stratified by humeral stem fixation technique: cementation or press-fit. Data were collected pre- and postoperatively. Primary outcome measures included range of motion, patient reported outcomes, and radiographic measures. Results One hundred thirty-eight cemented humeral stems and 31 press-fit stems were included. Significant improvements in range of motion were seen in all aTSA patients with no significant differences between final cemented and press-fit stems (forward elevation: P=0.12, external rotation: P=0.60, and internal rotation: P=0.77). Patient reported outcome metrics also exhibited sustained improvement through final follow-up. However, at final follow-up, the press-fit stem cohort had significantly better overall scores when compared to the cemented cohort (visual analog score: P=0.04, American Shoulder and Elbow Surgeon Score: P<0.01, Simple Shoulder Test score: P=0.03). Humeral radiolucency was noted in two cemented implants and one press-fit implant. No significant differences in implant survival were observed between the two cohorts (P=0.75). Conclusions In this series, we found that irrespective of humeral fixation technique, aTSA significantly improves shoulder function. However, within this cohort, press-fit stems provided significantly better outcomes than cemented stems in terms of patient reported outcome scores. Level of evidenceIII

The Wolbachia Genome of Brugia malayi: Endosymbiont Evolution within a Human Pathogenic Nematode

Complete genome DNA sequence and analysis is presented for Wolbachia, the obligate alpha-proteobacterial endosymbiont required for fertility and survival of the human filarial parasitic nematode Brugia malayi. Although, quantitatively, the genome is even more degraded than those of closely related Rickettsia species, Wolbachia has retained more intact metabolic pathways. The ability to provide riboflavin, flavin adenine dinucleotide, heme, and nucleotides is likely to be Wolbachia's principal contribution to the mutualistic relationship, whereas the host nematode likely supplies amino acids required for Wolbachia growth. Genome comparison of the Wolbachia endosymbiont of B. malayi (wBm) with the Wolbachia endosymbiont of Drosophila melanogaster (wMel) shows that they share similar metabolic trends, although their genomes show a high degree of genome shuffling. In contrast to wMel, wBm contains no prophage and has a reduced level of repeated DNA. Both Wolbachia have lost a considerable number of membrane biogenesis genes that apparently make them unable to synthesize lipid A, the usual component of proteobacterial membranes. However, differences in their peptidoglycan structures may reflect the mutualistic lifestyle of wBm in contrast to the parasitic lifestyle of wMel. The smaller genome size of wBm, relative to wMel, may reflect the loss of genes required for infecting host cells and avoiding host defense systems. Analysis of this first sequenced endosymbiont genome from a filarial nematode provides insight into endosymbiont evolution and additionally provides new potential targets for elimination of cutaneous and lymphatic human filarial disease