Protein Modification by Dicarbonyl Molecular Species in Neurodegenerative Diseases

Neurodegeneration results from abnormalities in cerebral metabolism and energy balance within neurons, astrocytes, microglia, or microvascular endothelial cells of the blood-brain barrier. In Alzheimer's disease, β-amyloid is considered the primary contributor to neuropathology and neurodegeneration. It now is believed that certain systemic diseases, such as diabetes mellitus, can contribute to neurodegeneration through the effects of chronic hyperglycemia/insulin resistance resulting in protein glycation, oxidative stress and inflammation within susceptible brain regions. Here, we present an overview of research focusing on the role of protein glycation, oxidative stress, and inflammation in the neurodegenerative process. Of special interest in this paper is the effect of methylglyoxal (MGO), a cytotoxic byproduct of glucose metabolism, elevated in neurodegenerative disease, and diabetes mellitus, on cerebral protein function and oxidative stress. How MGO interacts with amino acid residues within β-amyloid, and small peptides within the brain, is also discussed in terms of the affect on protein function

Do β-Defensins and Other Antimicrobial Peptides Play a Role in Neuroimmune Function and Neurodegeneration?

It is widely accepted that the brain responds to mechanical trauma and development of most neurodegenerative diseases with an inflammatory sequelae that was once thought exclusive to systemic immunity. Mostly cationic peptides, such as the β-defensins, originally assigned an antimicrobial function are now recognized as mediators of both innate and adaptive immunity. Herein supporting evidence is presented for the hypothesis that neuropathological changes associated with chronic disease conditions of the CNS involve abnormal expression and regulatory function of specific antimicrobial peptides. It is also proposed that these alterations exacerbate proinflammatory conditions within the brain that ultimately potentiate the neurodegenerative process

Limonite – a weathered residual soil heterogeneous at all scales

Limonite is a residual soil produced by the decomposition of magnesium silicate (olivine) rocks in tropical environments. During weathering most of the original rock is leached away leaving only its iron content, which is precipitated out in the form of iron sesqui-oxides to create a soft and highly porous soil. The predominant mineral present in limonite is goethite, which forms acicular nanoparticles that agglomerate to produce a silty sand with porous particles. The void ratio varies from 2 to 6, with higher values being a consequence of structure-supported voids. An extensive set of laboratory tests have been performed on a limonite soil profile which extends 50 m to rock. These data show that there is no pattern to shear strength with depth, with the shear strength equally likely to be 50 or 200 kPa through much of the profile. It is argued that the shear strength parameters for failure mechanisms, having any significant length, should be based on average values. The letter presents scanning electron microscopy photographs showing the fundamental particles, the results of triaxial tests comparing natural and reconstituted behaviour which show the effects of microstructure on the meso-scale response, and field data to show site variability

Toxicity and Cosmesis Outcomes for Single Fraction Intra-Operative Electron Radiotherapy (IOERT) for Breast Cancer

Background: Adjuvant radiation therapy is proven to reduce local recurrence in patients with early stage breast cancer. To reduce toxicity, improve geographic accuracy, and reduce treatment time, IOERT can be utilized as an alternative to external beam radiation therapy. The study’s objective was to determine the short term toxicity and cosmesis profile of single fraction IOERT given as definitive treatment in a community setting. Materials and Methods: From Mar 2012 to Jul 2014, 84 patients (3 bilateral), ages 45-91 y.o. with stage 0-II were treated with IOERT (Mobetron, IntraOp Medical, Sunnyvale, CA). A single 21 Gy fraction was administered to the tumor bed after resection. IOERT was delivered using 4.5 – 6 cm applicators with electron energies from 6-12 MeV. At 2w, 6mo and 12mo, toxicity was assessed according to CTCAE Version 4.0 (range 0-4) and cosmesis based on a scale derived for national trials. Results: The median pathologic tumor size was 13 mm (4 tumors \u3e 25mm) with 34 tumors being IDC, 4 ILC, 20 DCIS, and 29 mixed histologies. After the initial resection with IOERT, 85 breasts had a negative margin. Two required re-excision due to positive margins. 65 SLN biopsies were completed, 61 were negative, 4 positive (1 completion ALND). Median follow up was 57.1 weeks. Toxicity (Grade at 2 weeks, 6 months, and 12 months in %): 0: 49, 69, 62 1: 44, 29, 35 2: 7, 2, 3 Cosmesis(Appearance at 2 weeks, 6 months, 12 months in %): Excellent: 71, 86, 79 Good: 28, 14, 21 Fair: 1, 0, 0 *No patients had a toxicity of 3 or 4; or a cosmesis of poor. Conclusion: Single fraction IOERT was well tolerated by all patients with no grade 3+ toxicity up to 12 months. At one year, 97% of patients had 0-1 grade toxicity and 100% of patients had excellent or good cosmesis. This treatment, consistent with current reports, meets critical criteria for incorporation into practice and reduces treatment by 3-6 weeks

Late Status of Fontan Patients With Persistent Surgical Fenestration

ObjectivesThis study was undertaken to determine the effects of creating a systemic-to-pulmonary venous atrial-level communication (fenestration) at the time of the Fontan procedure on late outcomes.BackgroundFenestrations are frequently performed during Fontan procedures, but late consequences are not well described.MethodsPatient characteristics were compared between those with and without surgical fenestration among 536 subjects (mean age 11.9 years) enrolled in the Pediatric Heart Network Fontan Cross-Sectional Study. The status of the fenestration and the association of a currently patent fenestration with health status and measures of ventricular performance were investigated.ResultsFenestration was performed in 361 patients (67%), and frequency differed by year and center (p < 0.001 for each). After adjustment for center, age at Fontan, year of Fontan, and prior superior cavopulmonary surgery, the fenestrated group had shorter length of Fontan hospital stay. At the time of cross-sectional testing 8 ± 3 years after Fontan, the fenestration remained open in 19% of subjects. Among those with confirmed fenestration closure, 59% were by catheter intervention and 1% by surgical intervention, and 40% had apparent spontaneous closure. Compared with those without evidence of a fenestration, subjects with a current fenestration were taking more medications (p = 0.02) and had lower resting oxygen saturation (median 89% vs. 95%, p < 0.001). Functional health status, exercise performance, echocardiographic variables, prevalence of post-Fontan stroke or thrombosis, and growth did not differ by current fenestration status.ConclusionsSurgical fenestration is associated with well-demonstrated early post-operative benefits. This cross-sectional study found few associations between a persistent fenestration and deleterious later outcomes

Monoamine Oxidase is a Major Determinant of Redox Balance in Human Atrial Myocardium and is Associated With Postoperative Atrial Fibrillation

BACKGROUND: Onset of postoperative atrial fibrillation (POAF) is a common and costly complication of heart surgery despite major improvements in surgical technique and quality of patient care. The etiology of POAF, and the ability of clinicians to identify and therapeutically target high-risk patients, remains elusive. METHODS AND RESULTS: Myocardial tissue dissected from right atrial appendage (RAA) was obtained from 244 patients undergoing cardiac surgery. Reactive oxygen species (ROS) generation from multiple sources was assessed in this tissue, along with total glutathione (GSHt) and its related enzymes GSH-peroxidase (GPx) and GSH-reductase (GR). Monoamine oxidase (MAO) and NADPH oxidase were observed to generate ROS at rates 10-fold greater than intact, coupled mitochondria. POAF risk was significantly associated with MAO activity (Quartile 1 [Q1]: adjusted relative risk [ARR]=1.0; Q2: ARR=1.8, 95% confidence interval [CI]=0.84 to 4.0; Q3: ARR=2.1, 95% CI=0.99 to 4.3; Q4: ARR=3.8, 95% CI=1.9 to 7.5; adjusted Ptrend=0.009). In contrast, myocardial GSHt was inversely associated with POAF (Quartile 1 [Q1]: adjusted relative risk [ARR]=1.0; Q2: ARR=0.93, 95% confidence interval [CI]=0.60 to 1.4; Q3: ARR=0.62, 95% CI=0.36 to 1.1; Q4: ARR=0.56, 95% CI=0.34 to 0.93; adjusted Ptrend=0.014). GPx also was significantly associated with POAF; however, a linear trend for risk was not observed across increasing levels of the enzyme. GR was not associated with POAF risk. CONCLUSIONS: Our results show that MAO is an important determinant of redox balance in human atrial myocardium, and that this enzyme, in addition to GSHt and GPx, is associated with an increased risk for POAF. Further investigation is needed to validate MAO as a predictive biomarker for POAF, and to explore this enzyme's potential role in arrhythmogenesis

Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-Regulated Pathway

The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient’s life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn’s disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFb1 reduces production of proinflammatory cytokines, including TNFa, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses

'A good fit?' Bringing the Sociology of Footwear to the Clinical Encounter in Podiatry Services : A Narrative Review

Background: This narrative review explores the ways in which drawing on theories and methods used in sociological work on footwear and identity can contribute to healthcare research with podiatrists and their patients, highlighting recent research in this field, implications for practice and potential areas for future development. Traditionally, research within Podiatry Services has tended to adopt a quantitative, positivist focus, developing separately from a growing body of sociological work exploring the importance of shoes in constructing identity and self-image. Bringing qualitative research drawing on sociological theory and methods to the clinical encounter has real potential to increase our understanding of patient values, motivations and – crucially – any barriers to adopting ‘healthier’ footwear that they may encounter. Such work can help practitioners to understand why patients may resist making changes to their footwear practices, and help us to devise new ways for practitioners to explore and ultimately break down individual barriers to change (including their own preconceptions as practitioners). This, in turn, may lead to long-term, sustainable changes to footwear practices and improvements in foot health for those with complex health conditions and the wider population. Conclusion: A recognition of the complex links between shoes and identity is opening up space for discussion of patient resistance to footwear changes, and paving the way for future research in this field beyond the temporary ‘moment’ of the clinical encounter

Increase in invasive Streptococcus pyogenes M1 infections with close evolutionary genetic relationship, Iceland and Scotland, 2022 to 2023

Group A Streptococcus isolates of the recently described M1UK clade have emerged to cause human infections in several European countries and elsewhere. Full-genome sequence analysis of M1 isolates discovered a close genomic relationship between some isolates from Scotland and the majority of isolates from Iceland causing serious infections in 2022 and 2023. Phylogenetic analysis strongly suggests that an isolate from or related to Scotland was the precursor to an M1UK variant responsible for almost all recent M1 infections in Iceland