Chronic Mineral Dysregulation Promotes Vascular Smooth Muscle Cell Adaptation and Extracellular Matrix Calcification

In chronic kidney disease (CKD) vascular calcification occurs in response to deranged calcium and phosphate metabolism and is characterized by vascular smooth muscle cell (VSMC) damage and attrition. To gain mechanistic insights into how calcium and phosphate mediate calcification, we used an ex vivo model of human vessel culture. Vessel rings from healthy control subjects did not accumulate calcium with long-term exposure to elevated calcium and/or phosphate. In contrast, vessel rings from patients with CKD accumulated calcium; calcium induced calcification more potently than phosphate (at equivalent calcium-phosphate product). Elevated phosphate increased alkaline phosphatase activity in CKD vessels, but inhibition of alkaline phosphatase with levamisole did not block calcification. Instead, calcification in CKD vessels most strongly associated with VSMC death resulting from calcium- and phosphate-induced apoptosis; treatment with a pan-caspase inhibitor ZVAD ameliorated calcification. Calcification in CKD vessels was also associated with increased deposition of VSMC-derived vesicles. Electron microscopy confirmed increased deposition of vesicles containing crystalline calcium and phosphate in the extracellular matrix of dialysis vessel rings. In contrast, vesicle deposition and calcification did not occur in normal vessel rings, but we observed extensive intracellular mitochondrial damage. Taken together, these data provide evidence that VSMCs undergo adaptive changes, including vesicle release, in response to dysregulated mineral metabolism. These adaptations may initially promote survival but ultimately culminate in VSMC apoptosis and overt calcification, especially with continued exposure to elevated calcium

Does a SLAP lesion affect shoulder muscle recruitment as measured by EMG activity during a rugby tackle?

Background: The study objective was to assess the influence of a SLAP lesion on onset of EMG activity in shoulder muscles during a front on rugby football tackle within professional rugby players. Methods: Mixed cross-sectional study evaluating between and within group differences in EMG onset times. Testing was carried out within the physiotherapy department of a university sports medicine clinic. The test group consisted of 7 players with clinically diagnosed SLAP lesions, later verified on arthroscopy. The reference group consisted of 15 uninjured and full time professional rugby players from within the same playing squad. Controlled tackles were performed against a tackle dummy. Onset of EMG activity was assessed from surface EMG of Pectorialis Major, Biceps Brachii, Latissimus Dorsi, Serratus Anterior and Infraspinatus muscles relative to time of impact. Analysis of differences in activation timing between muscles and limbs (injured versus non-injured side and non injured side versus matched reference group). Results: Serratus Anterior was activated prior to all other muscles in all (P = 0.001-0.03) subjects. In the SLAP injured shoulder Biceps was activated later than in the non-injured side. Onset times of all muscles of the noninjured shoulder in the injured player were consistently earlier compared with the reference group. Whereas, within the injured shoulder, all muscle activation timings were later than in the reference group. Conclusions: This study shows that in shoulders with a SLAP lesion there is a trend towards delay in activation time of Biceps and other muscles with the exception of an associated earlier onset of activation of Serratus anterior, possibly due to a coping strategy to protect glenohumeral stability and thoraco-scapular stability. This trend was not statistically significant in all cases

Synaptic tagging and capture in the living rat

In isolated hippocampal slices, decaying long-term potentiation can be stabilized and converted to late long-term potentiation lasting many hours, by prior or subsequent strong high-frequency tetanization of an independent input to a common population of neurons—a phenomenon known as ‘synaptic tagging and capture’. Here we show that the same phenomenon occurs in the intact rat. Late long-term potentiation can be induced in CA1 during the inhibition of protein synthesis if an independent input is strongly tetanized beforehand. Conversely, declining early long-term potentiation induced by weak tetanization can be converted into lasting late long-term potentiation by subsequent strong tetanization of a separate input. These findings indicate that synaptic tagging and capture is not limited to in vitro preparations; the past and future activity of neurons has a critical role in determining the persistence of synaptic changes in the living animal, thus providing a bridge between cellular studies of protein synthesis-dependent synaptic potentiation and behavioural studies of memory persistence

Development of a cDNA microarray for the measurement of gene expression in the sheep scab mite Psoroptes ovis

Background: Sheep scab is caused by the ectoparasitic mite Psoroptes ovis which initiates a profound cutaneous inflammatory response, leading to the development of the skin lesions which are characteristic of the disease. Existing control strategies rely upon injectable endectocides and acaricidal dips but concerns over residues, eco-toxicity and the development of acaricide resistance limit the sustainability of this approach. In order to identify alternative means of disease control, a deeper understanding of both the parasite and its interaction with the host are required. Methods: Herein we describe the development and utilisation of an annotated P. ovis cDNA microarray containing 3,456 elements for the measurement of gene expression in this economically important ectoparasite. The array consists of 981 P. ovis EST sequences printed in triplicate along with 513 control elements. Array performance was validated through the analysis of gene expression differences between fed and starved P. ovis mites. Results: Sequences represented on the array include homologues of major house dust mite allergens and tick salivary proteins, along with factors potentially involved in mite reproduction and xenobiotic metabolism. In order to validate the performance of this unique resource under biological conditions we used the array to analyse gene expression differences between fed and starved P. ovis mites. These analyses identified a number of house dust mite allergen homologues up-regulated in fed mites and P. ovis transcripts involved in stress responses, autophagy and chemosensory perception up-regulated in starved mites. Conclusion: The P. ovis cDNA microarray described here has been shown to be both robust and reproducible and will enable future studies to analyse gene expression in this important ectoparasite

Diagnostic reliability of magnetic resonance imaging for central nervous system syndromes in systemic lupus erythematosus: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Previous studies of magnetic resonance imaging (MRI) as a diagnostic tool for central nervous system (CNS) syndromes in systemic lupus erythematosus (SLE) contained several limitations such as study design, number of enrolled patients, and definition of CNS syndromes. We overcame these problems and statistically evaluated the diagnostic values of abnormal MRI signals and their chronological changes in CNS syndromes of SLE.</p> <p>Methods</p> <p>We prospectively studied 191 patients with SLE, comparing those with (n = 57) and without (n = 134) CNS syndrome. CNS syndromes were characterized using the American College of Rheumatology case definitions.</p> <p>Results</p> <p>Any abnormal MRI signals were more frequently observed in subjects in the CNS group (n = 25) than in the non-CNS group (n = 32) [relative risk (RR), 1.7; 95% confidence interval (CI), 1.1-2.7; <it>p </it>= 0.016] and the positive and negative predictive values for the diagnosis of CNS syndrome were 42% and 76%, respectively. Large abnormal MRI signals (ø ≥ 10 mm) were seen only in the CNS group (n = 7; RR, 3.7; CI, 2.9-4.7; <it>p </it>= 0.0002), whereas small abnormal MRI signals (ø < 10 mm) were seen in both groups with no statistical difference. Large signals always paralleled clinical outcome (<it>p </it>= 0.029), whereas small signals did not (<it>p </it>= 1.000).</p> <p>Conclusions</p> <p>Abnormal MRI signals, which showed statistical associations with CNS syndrome, had insufficient diagnostic values. A large MRI signal was, however, useful as a diagnostic and surrogate marker for CNS syndrome of SLE, although it was less common.</p

The role of micro-organisms (Staphylococcus aureus and Candida albicans) in the pathogenesis of breast pain and infection in lactating women: study protocol

Background: The CASTLE (Candida and Staphylococcus Transmission: Longitudinal Evaluation) study will investigate the micro-organisms involved in the development of mastitis and &ldquo;breast thrush&rdquo; among breastfeeding women. To date, the organism(s) associated with the development of breast thrush have not been identified. The CASTLE study will also investigate the impact of physical health problems and breastfeeding problems on maternal psychological health in the early postpartum period.Methods/Design: The CASTLE study is a longitudinal descriptive study designed to investigate the role of Staphylococcus spp (species) and Candida spp in breast pain and infection among lactating women, and to describe the transmission dynamics of S. aureus and Candida spp between mother and infant. The relationship between breastfeeding and postpartum health problems as well as maternal psychological well-being is also being investigated. A prospective cohort of four hundred nulliparous women who are at least thirty six weeks gestation pregnant are being recruited from two hospitals in Melbourne, Australia (November 2009 to June 2011). At recruitment, nasal, nipple (both breasts) and vaginal swabs are taken and participants complete a questionnaire asking about previous known staphylococcal and candidal infections. Following the birth, participants are followed-up six times: in hospital and then at home weekly until four weeks postpartum. Participants complete a questionnaire at each time points to collect information about breastfeeding problems and postpartum health problems. Nasal and nipple swabs and breast milk samples are collected from the mother. Oral and nasal swabs are collected from the baby. A telephone interview is conducted at eight weeks postpartum to collect information about postpartum health problems and breastfeeding problems, such as mastitis and nipple and breast pain.Discussion: This study is the first longitudinal study of the role of both staphylococcal and candidal colonisation in breast infections and will help to resolve the current controversy about which is the primary organism in the condition known as breast thrush. This study will also document transmission dynamics of S. aureus and Candida spp between mother and infant. In addition, CASTLE will investigate the impact of common maternal physical health symptoms and the effect of breastfeeding problems on maternal psychological well-being.<br /

A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer

Published first January 24, 2022.Purpose: DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes. Experimental Design: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE). Results: Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucosederived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease. Conclusions: Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK–mediated aggressive disease phenotypes.Emanuela Dylgjeri, Vishal Kothari, Ayesha A. Shafi, Galina Semenova, Peter T. Gallagher, Yi F. Guan, Angel Pang, Jonathan F. Goodwin, Swati Irani, Jennifer J. McCann, Amy C. Mandigo, Saswati Chand, Christopher M. McNair, Irina Vasilevskaya, MatthewJ. Schiewer, Costas D. Lallas, Peter A. McCue, Leonard G. Gomella, Erin L. Seifert, Jason S. Carroll, Lisa M. Butler, Jeff Holst, William K. Kelly, and Karen E. Knudse

How and why do nectar-foraging bumblebees initiate movements between inflorescences of wild bergamot Monarda fistulosa (Lamiaceae)?

By experimental manipulation of the nectar in flowers, I characterized the decision-making process used by nectar-gathering bumblebees for initiating movements between inflorescences of wild bergamot. The decision-making process has these characteristics: departure from an inflorescence is less likely as nectar rewards increase; departure decisions are based on the amount of nectar in the last flower probed and are not influenced by the nectar rewards in either the previously probed flower or the previously visited inflorescence; the number of flowers already probed at an inflorescence influences departure decisions weakly; a bees' response (to stay or to depart) to a given size of nectar reward is variable. Since previously proposed foraging rules do not accord with this description, I propose a new rule. I show by experiment that the movements made by bumblebees enhance foraging success.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47784/1/442_2004_Article_BF00319785.pd

Psychosocial interventions for patients with advanced cancer – a systematic review of the literature

Advanced cancer is associated with emotional distress, especially depression and feelings of sadness. To date, it is unclear which is the most effective way to address these problems. This review focuses on the effects of psychosocial interventions on the quality of life (QoL) of patients with advanced cancer. It was hypothesised that patients will benefit from psychosocial interventions by improving QoL, especially in the domain of emotional functioning. The review was conducted using systematic review methodology involving a systematic search of the literature published between 1990 and 2002, quality assessment of included studies, systematic data extraction and narrative data synthesis. In all, 10 randomised controlled studies involving 13 trials were included. Overall interventions and outcome measures across studies were heterogeneous. Outcome measures, pertaining to the QoL dimension of emotional functioning, were most frequently measured. A total of 12 trials evaluating behaviour therapy found positive effects on one or more indicators of QoL, for example, depression. The results of the review support recommendation of behaviour therapy in the care of patients with advanced cancer

Psychosocial interventions for patients with advanced cancer – a systematic review of the literature

Advanced cancer is associated with emotional distress, especially depression and feelings of sadness. To date, it is unclear which is the most effective way to address these problems. This review focuses on the effects of psychosocial interventions on the quality of life (QoL) of patients with advanced cancer. It was hypothesised that patients will benefit from psychosocial interventions by improving QoL, especially in the domain of emotional functioning. The review was conducted using systematic review methodology involving a systematic search of the literature published between 1990 and 2002, quality assessment of included studies, systematic data extraction and narrative data synthesis. In all, 10 randomised controlled studies involving 13 trials were included. Overall interventions and outcome measures across studies were heterogeneous. Outcome measures, pertaining to the QoL dimension of emotional functioning, were most frequently measured. A total of 12 trials evaluating behaviour therapy found positive effects on one or more indicators of QoL, for example, depression. The results of the review support recommendation of behaviour therapy in the care of patients with advanced cancer