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Hemophilic arthropathy (HA) is characterized by joint damage following recurrent joint bleeds frequently observed in patients affected by the clotting disorder hemophilia. Joint bleeds or hemarthroses trigger inflammation in the synovial tissue, which promotes damage to the articular cartilage. The plasminogen activation system is integral to fibrinolysis, and the urokinase plasminogen activator, or uPA in particular, is strongly upregulated following hemarthroses. uPA is a serine protease that catalyzes the production of plasmin, a broad-spectrum protease that can degrade fibrin as well as proteins of the joint extracellular matrix and cartilage. Both uPA and plasmin are able to proteolytically generate active forms of matrix metalloproteinases (MMPs). The MMPs are a family of >20 proteases that are secreted as inactive proenzymes and are activated extracellularly. MMPs are involved in the degradation of all types of collagen and proteoglycans that constitute the extracellular matrix, which provides structural support to articular cartilage. The MMPs have an established role in joint destruction following rheumatoid arthritis (RA). They degrade cartilage and bone, indirectly promoting angiogenesis. MMPs are also implicated in the pathology of osteoarthritis (OA), characterized by degradation of the cartilage matrix that precipitates joint damage and deformity. HA shares a number of overlapping pathological characteristics with RA and OA. Here we discuss how the plasminogen activation system and MMPs might exacerbate joint damage in HA, lending insight into novel possible therapeutic targets to reduce the comorbidity of hemophilia.

Funding Acknowledgements Type of funding sources: None. Background/Introduction 24-hour Holter monitors have been used widely to assess patients with suspected and known arrhythmias. Recent studies have shown increased yield of arrhythmia detection with longer durations of Holter monitoring. Purpose The aim of the study was to evaluate the incremental yield in significant arrhythmias detected using a 7-day continuous Holter monitor, as compared to what can be achieved within a 24-hour and 48 to 72 hours study. Methods A retrospective study of patients from 72 sites in two geographical locations, A and B, who completed a continuous 7-days patch monitor study was performed. 801 of these studies detected significant arrhythmias; pauses 3 seconds or more (PA), ventricular tachycardia of 6 beats or more (VT), and paroxysmal atrial fibrillation (PAF). The day of the first occurrence of a significant arrhythmia was noted and tallied to determine the incremental yield of a multiday Holter monitoring. Results Of 801 total cases detected with significant arrhythmia, only 278 (35%) were detected in the first 24hours, while 523 (65%) cases were detected after Day 1. 331 (41%) had first significant arrhythmia detected after the 3rd day of monitoring, with 68 (44%) being PA, 125 (40%) PAF, and 138 (41%) VT. Notably, in Group A, 31 (72%) of total VT detected and 35 (72%) of total PAF detected were first picked up after Day 1, 21 (49%) of total VT were first detected only after the 3rd day of monitoring. Conclusions 1-day (24-hour) monitoring period fails to detect a significant number of potentially serious cardiac arrhythmias. Extended continuous Holter monitoring increases the yield of detection, with a substantial fraction (40-49%) detected after the 3rd day of monitoring. No difference in results obtained between two geographical locations demonstrates strong evidence that findings are consistent across different sites. Review of current practice and guidelines is necessary to further expand usage of multiday Holter monitoring, thus increasing benefits to patients.

Aims: G protein-coupled receptor (GPCR) transactivation of kinase receptors greatly expands the actions attributable to GPCRs. Thrombin, via its cognate GPCR, protease-activated receptor (PAR)-1, transactivates tyrosine and serine/threonine kinase receptors, specifically the epidermal growth factor receptor and transforming growth factor-β receptor, respectively. PAR-1 transactivation-dependent signalling leads to the modification of lipid-binding proteoglycans involved in the retention of lipids and the development of atherosclerosis. The mechanisms of GPCR transactivation of kinase receptors are distinct. We aimed to investigate the role of proximal G proteins in transactivation-dependent signalling. Main Methods: Using pharmacological and molecular approaches, we studied the role of the G⍺ subunits, G⍺q and G⍺11, in the context of PAR-1 transactivation-dependent signalling leading to proteoglycan modifications. Key Findings: Pan G⍺q subunit inhibitor UBO-QIC/FR900359 inhibited PAR-1 transactivation of kinase receptors and proteoglycans modification. The G⍺q/11 inhibitor YM254890 did not affect PAR-1 transactivation pathways. Molecular approaches revealed that of the two highly homogenous G⍺q members, G⍺q and G⍺11, only the G⍺q was involved in regulating PAR-1 mediated proteoglycan modification. Although G⍺q and G⍺11 share approximately 90% homology at the protein level, we show that the two isoforms exhibit different functional roles. Significance: Our findings may be extrapolated to other GPCRs involved in vascular pathology and highlight the need for novel pharmacological tools to assess the role of G proteins in GPCR signalling to expand the preeminent position of GPCRs in human therapeutics.

Introduction: Foreign workers (FWs) on work permit face unique health challenges and potential barriers to healthcare. We aimed to examine the epidemiology, attendance patterns, disposition, and adherence to follow-up, by FWs on work permit to two emergency departments (EDs) in Singapore. Methods: In this retrospective observational study, we included consecutive FWs on work permit who registered at the EDs of two public restructured hospitals from 1 May 2016 to 31 October 2016. Data obtained from electronic medical records included patient demographics, triage acuity, disposition, ED diagnoses and bill information. Results: There were 6,429 individual FWs on work permit who contributed to 7,157 ED visits over the 6-month study period, with male predominance (72.7%, 4672/6429), and median age of 31 (interquartile range 26 to 38) years. A high proportion of these FWs were triaged to low-acuity status compared to the general ED population (66.9% versus 45.9%, P

Stroke is caused by obstructed blood flow (ischaemia) or unrestricted bleeding in the brain (haemorrhage). Global brain ischaemia occurs after restricted cerebral blood flow e.g. during cardiac arrest. Following ischaemic injury, restoration of blood flow causes ischaemia–reperfusion (I/R) injury which worsens outcome. Secondary injury mechanisms after any stroke are similar, and encompass inflammation, endothelial dysfunction, blood–brain barrier (BBB) damage and apoptosis. We developed a new model of transient global forebrain I/R injury (dual carotid artery ligation; DCAL) and compared the manifestations of this injury with those in a conventional I/R injury model (middle-cerebral artery occlusion; MCAo) and with intracerebral haemorrhage (ICH; collagenase model). MRI revealed that DCAL produced smaller bilateral lesions predominantly localised to the striatum, whereas MCAo produced larger focal corticostriatal lesions. After global forebrain ischaemia mice had worse overall neurological scores, although quantitative locomotor assessment showed MCAo and ICH had significantly worsened mobility. BBB breakdown was highest in the DCAL model while apoptotic activity was highest after ICH. VCAM-1 upregulation was specific to ischaemic models only. Differential transcriptional upregulation of pro-inflammatory chemokines and cytokines and TLRs was seen in the three models. Our findings offer a unique insight into the similarities and differences in how biological processes are regulated after different types of stroke. They also establish a platform for analysis of therapies such as endothelial protective and anti-inflammatory agents that can be applied to all types of stroke.

Background frailty has been shown to be a better predictor of clinical outcomes than age alone across many diseases. Few studies have examined the relationship between frailty, stroke and stroke interventions such as endovascular thrombectomy (EVT). Objective we aimed to investigate the impact of frailty measured by clinical frailty scale (CFS) on clinical outcomes after EVT for acute ischemic stroke (AIS) in older patients ≥70 years. Methods in this retrospective cohort study, we included all consecutive AIS patients age ≥ 70 years receiving EVT at a single comprehensive stroke centre. Patients with CFS of 1–3 were defined as not frail, and CFS > 3 was defined as frail. The primary outcome was modified Rankin Score (mRS) at 90 days. The secondary outcomes included duration of hospitalisation, in-hospital mortality, carer requirement, successful reperfusion, symptomatic intracranial haemorrhage and haemorrhagic transformation. Results a total of 198 patients were included. The mean age was 78.1 years and 52.0% were female. Frail patients were older, more likely to be female, had more co-morbidities. CFS was significantly associated with poor functional outcome after adjustment for age, NIHSS and time to intervention (adjusted odds ratio [aOR] 1.54, 95% confidence interval [CI] 1.04–2.28, P = 0.032). There was trend towards higher mortality rate in frail patients (frail: 18.3%; non-frail: 9.6%; P = 0.080). There were no significant differences in other secondary outcomes except increased carer requirement post discharge in frail patients (frail: 91.6%; non-frail: 72.8%; P = 0.002). Conclusions frailty was associated with poorer functional outcome at 90 days post-EVT in patients ≥ 70 years.

A structured oral exam (SOE) can be utilized as a formative assessment to provide high-quality formative feedback to trainees, but has not been adequately studied in graduate medical education. We obtained fellow and faculty perspectives on: 1) educational effectiveness, 2) feasibility/acceptability, and 3) time/cost of a SOE for formative feedback.Four pediatric endocrinology cases were developed and peer-reviewed to generate a SOE. The exam was administered by faculty to pediatric endocrinology fellows individually, with feedback after each case. Fellow/faculty perspectives of the SOE were obtained through a questionnaire. Qualitative thematic analysis was utilized to analyze written comments generated by faculty and fellows.Seven of 10 pediatric endocrinology fellowship programs and all 18 fellows within those programs agreed to participate. Thematic analysis of fellow and faculty comments resulted in 5 perceived advantages of the SOE: 1) improved identification of clinically relevant knowledge deficits, 2) improved assessment of clinical reasoning, 3) immediate feedback/teaching, 4) assurance of adequate teaching/assessment of uncommon cases, and 5) more clinically relevant assessment. Mean time to administer one case was 15.8 minutes (2.0) and was mentioned as a potential barrier to implementation. Almost all fellows (17/18, 94%) and faculty (6/7, 86%) would recommend or would most likely recommend implementation of the SOE into their curriculum.The SOE utilized for formative feedback was perceived by fellows and faculty to have several educational advantages over current assessments and high acceptability. Objective educational advantages should be assessed on future studies of the SOE.

Background/Aims: Studies are lacking regarding the timing of peak growth hormone (PGH) response. We aim to elucidate the timing of PGH response to arginine and levodopa (A-LD) and evaluate the influence of body mass index (BMI) and other metabolic parameters on PGH. Methods: During growth hormone (GH) stimulation testing (ST) with A-LD, serum GH was measured at baseline and every 30 min up to 180 min. The PGH cut-off was defined as Results: In the 315 tested children, stimulated PGH levels occurred at or before 120 min in 97.8% and at 180 min in 2.2%. GH area under the curve (AUC) positively correlated with PGH in all patients and with IGF-1 in pubertal males and females. BMI negatively correlated with PGH in all subjects. GH AUC negatively correlated with HOMA-IR and total cholesterol. Conclusion: We propose termination of the GH ST with A-LD at 120 min since omission of GH measurement at 180 min did not alter the diagnosis of GH deficiency based on a cut-off of < 10 ng/mL. BMI should be considered in the interpretation of GH ST with A-LD. The relationships between GH AUC and metabolic parameters need further study.

The Coronavirus disease 2019 (COVID-19) pandemic is rapidly evolving and affecting healthcare systems across the world. Singapore has escalated its alert level to Disease Outbreak Response System Condition (DORSCON) Orange, signifying severe disease with community spread. We aimed to study the overall volume of AIS cases and the delivery of hyperacute stroke services during DORSCON Orange. This was a single-centre, observational cohort study performed at a comprehensive stroke centre responsible for AIS cases in the western region of Singapore, as well as providing care for COVID-19 patients. All AIS patients reviewed as an acute stroke activation in the Emergency Department (ED) from November 2019 to April 2020 were included. System processes timings, treatment and clinical outcome variables were collected. We studied 350 AIS activation patients admitted through the ED, 206 (58.9%) pre- and 144 during DORSCON Orange. Across the study period, number of stroke activations showed significant decline (p = 0.004, 95% CI 6.513 to − 2.287), as the number of COVID-19 cases increased exponentially, whilst proportion of activations receiving acute recanalization therapy remained stable (p = 0.519, 95% CI − 1.605 to 2.702). Amongst AIS patients that received acute recanalization therapy, early neurological outcomes in terms of change in median NIHSS at 24 h (-4 versus -4, p = 0.685) were largely similar between the pre- and during DORSCON orange periods. The number of stroke activations decreased while the proportion receiving acute recanalization therapy remained stable in the current COVID-19 pandemic in Singapore. Electronic supplementary material The online version of this article (10.1007/s11239-020-02225-1) contains supplementary material, which is available to authorized users.

The aim of this study was to quantify and describe a population of patients in rural Cameroon who present with a surgically treatable illness but ultimately decline surgery, and to understand the patient decision-making process and identify key socioeconomic factors that result in barriers to care.An estimated 5 billion people lack access to safe, affordable surgical care and anesthesia when needed, and this unmet need resides disproportionally in low-income countries (LICs). An understanding of the socioeconomic factors underlying decision-making is key to future efforts to expand surgical care delivery in this population. We assessed patient decision-making in a LIC with a cash-based health care economy.Standardized interviews were conducted of a random sample of adult patients with treatable surgical conditions over a 7-week period in a tertiary referral hospital in rural Cameroon. Main outcome measures included participant's decision to accept or decline surgery, source of funding, and the relative importance of various factors in the decision-making process.Thirty-four of 175 participants (19.4%) declined surgery recommended by their physician. Twenty-six of 34 participants declining surgery (76.4%) cited procedure cost, which on average equaled 6.4 months' income, as their primary decision factor. Multivariate analysis revealed female gender [odds ratio (OR) 3.35, 95% confidence interval (95% CI) 2.14-5.25], monthly earnings (OR 0.83, 95% CI, 0.77-0.89), supporting children in school (OR 1.22, 95% CI 1.13-1.31), and inability to borrow funds from family or the community (OR 6.49, 95% CI 4.10-10.28) as factors associated with declining surgery.Nearly one-fifth of patients presenting to a surgical clinic with a treatable condition did not ultimately receive needed surgery. Both financial and sociocultural factors contribute to the decision to decline care.

Calculus migration is a common problem during ureteroscopic laser lithotripsy procedure to treat urolithiasis. A conventional experimental method to characterize calculus migration utilized a hosting container (e.g., a “V” grove or a test tube). These methods, however, demonstrated large variation and poor detectability, possibly attributed to the friction between the calculus and the container on which the calculus was situated. In this study, calculus migration was investigated using a pendulum model suspended underwater to eliminate the aforementioned friction. A high-speed camera was used to study the movement of the calculus which covered zero order (displacement), first order (speed), and second order (acceleration). A commercialized, pulsed Ho:YAG laser at 2.1 μm, a 365-μm core diameter fiber, and a calculus phantom (Plaster of Paris, 10 × 10 × 10 mm3) was utilized to mimic laser lithotripsy procedure. The phantom was hung on a stainless steel bar and irradiated by the laser at 0.5, 1.0, and 1.5 J energy per pulse at 10 Hz for 1 s (i.e., 5, 10, and 15 W). Movement of the phantom was recorded by a high-speed camera with a frame rate of 10,000 FPS. The video data files are analyzed by MATLAB program by processing each image frame and obtaining position data of the calculus. With a sample size of 10, the maximum displacement was 1.25 ± 0.10, 3.01 ± 0.52, and 4.37 ± 0.58 mm for 0.5, 1, and 1.5 J energy per pulse, respectively. Using the same laser power, the conventional method showed

Summary Hydraulic-fracturing technology is widely used to facilitate and enhance the recovery process from oil and gas reservoirs. Much worldwide experience has been gained in stimulating conventional and shale oil reservoirs; however, achieving good stimulation results in mature (depleted) oil fields with moderate permeability can be challenging and results can easily fall below expectations for a variety of reasons. To narrow the gap between expected results and actual well performance after a successful fracturing treatment, it is very important to understand the reservoir characteristics and the actual reservoir potential. Despite the common opinion that stimulating mature, depleted wells is unprofitable, experience shows that stimulating such wells can still result in substantial and profitable production increases. Twenty hydraulic-fracturing treatments were performed on wells in a mature onshore oil field in Myanmar, in Southeast Asia. These wells had never been fracture stimulated in the past, because of the moderate-to-high permeability of the reservoir. The stimulated wells have shown significant increases in initial incremental oil-production rate—on average, by a factor of two, which was still below the expectations. The treatments have effectively increased cumulative production and added to reserves. At the time of writing, the daily production rate from the 20 wells is actually increasing, rather than declining. This is likely caused by some kind of cleanup effect related to fracture stimulation in this highly depleted reservoir. This paper discusses the challenges seen and the results obtained using hydraulic-fracture stimulation in a mature oil field. This case shows the importance of a proper candidate-selection method, which has contributed to successful stimulation and has improved oil recovery in this case.

Scleroderma is a group of skin-fibrosing diseases for which there are no effective treatments. A feature of the skin fibrosis typical of scleroderma is atrophy of the dermal white adipose tissue (DWAT). Adipose tissue contains adipose-derived mesenchymal stromal cells (ADSCs) that have regenerative and reparative functions; however, whether DWAT atrophy in fibrosis is accompanied by ADSC loss is poorly understood, as are the mechanisms that might maintain ADSC survival in fibrotic skin. Here, we have shown that DWAT ADSC numbers were reduced, likely because of cell death, in 2 murine models of scleroderma skin fibrosis. The remaining ADSCs showed a partial dependence on dendritic cells (DCs) for survival. Lymphotoxin β (LTβ) expression in DCs maintained ADSC survival in fibrotic skin by activating an LTβ receptor/β1 integrin (LTβR/β1 integrin) pathway on ADSCs. Stimulation of LTβR augmented the engraftment of therapeutically injected ADSCs, which was associated with reductions in skin fibrosis and improved skin function. These findings provide insight into the effects of skin fibrosis on DWAT ADSCs, identify a DC-ADSC survival axis in fibrotic skin, and suggest an approach for improving mesenchymal stromal cell therapy in scleroderma and other diseases.

Laser-tissue vaporization through a fiber catheter is evolving into a major category of surgical operations to remove diseased tissue. Currently, during a surgery, the surgeon still relies on personal experience to optimize surgical techniques. Monitoring tissue temperature during laser-tissue vaporization would provide important feedback to the surgeon; however, simple and low-cost temperature sensing technology, which can be seamlessly integrated with a fiber catheter, is not available. We propose to monitor tissue temperature during laser-tissue vaporization by detecting blackbody radiation (BBR) between 1.6 µm-1.8 µm, a relatively transparent window for both water and silica fiber. We could detect BBR after passing through a 2-meter silica fiber down to ∼70°C using lock-in detection. We further proved the feasibility of the technology through ex vivo tissue studies. We found that the BBR can be correlated to different tissue vaporization levels. The results suggest that this simple and low-cost technology could be used to provide objective feedback for surgeons to maximize laser-tissue vaporization efficiency and ensure the best clinical outcomes.

Perpendicular Spin-Transfer Torque (STT) MRAM is a promising technology in terms of read/write speed, low power consumption and non-volatility, but there has not been a demonstration of high density manufacturability at small geometries. In this paper we present an unprecedented demonstration of a robust STT-MRAM technology designed in a 2x nm CMOS-embedded 40 Mb array. Key features are full array functionality with low BER (bit error rate), process uniformity and reliability, 10 years data retention at 125C with extended endurance to ∼ 107 cycles. All achieved with standard BEOL process temperatures. Data retention post 260°C solder reflow temperature cycle is demonstrated.

First-generation MRAM, based on a field switching innovation called “Savtchenko switching,” is mass produced by Everspin in densities up to 16Mb.

GH exerts a diverse array of physiological actions that include prominent roles in growth and metabolism, with a major contribution via stimulating IGF-1 synthesis. GH achieves its effects by influencing gene expression profiles, and Igf1 is a key transcriptional target of GH signaling in liver and other tissues. This review examines the mechanisms of GH-mediated gene regulation that begin with signal transduction pathways activated downstream of the GH receptor and continue with chromatin events at target genes and additionally encompasses the topics of negative regulation and cross talk with other cellular inputs. The transcription factor, signal transducer and activator of transcription 5b, is regarded as the major signaling pathway by which GH achieves its physiological effects, including in stimulating Igf1 gene transcription in liver. Recent studies exploring the mechanisms of how activated signal transducer and activator of transcription 5b accomplishes this are highlighted, which begin to characterize epigenetic features at regulatory domains of the Igf1 locus. Further research in this field offers promise to better understand the GH-IGF-1 axis in normal physiology and disease and to identify strategies to manipulate the axis to improve human health.

In this paper we present an overview of important features for reliable and manufacturable ST-MRAM as well as new results in two areas: pMTJ arrays with data retention sufficient for programming before 260°C wave solder, and performance of a 256Mb, DDR3 ST-MRAM product chip.

The diverse roles of IGF-1 in physiology include acting as the endocrine intermediate to elicit the anabolic actions of GH. The majority of serum IGF-1 is synthesized in liver, where GH stimulates Igf1 gene transcription via the transcription factor, signal transducer and activator of transcription (Stat)5b. We and others have identified multiple Stat5-binding domains at the Igf1 locus that function in gene regulation, but it remains unclear whether the roles of these domains are tissue specific. Survey of the chromatin landscape of regulatory domains can provide insight about mechanisms of gene regulation, with chromatin accessibility regarded as a hallmark feature of regulatory domains. We prepared chromatin from liver, kidney, and spleen of C57BL/6 mice, and used formaldehyde-associated isolation of regulatory elements to assess chromatin accessibility at the major Igf1 promoter and 7 -binding enhancers. Whereas the promoters of other prototypical tissue-specific genes are open in a tissue-specific way, the major Igf1 promoter is open in all 3 tissues, albeit moderately more so in liver. In contrast, chromatin accessibility at Igf1 Stat5-binding domains is essentially restricted to liver, indicating that the enhancers are driving extensive differences in tissue expression. Furthermore, studies with Ghrhrlit/lit mice reveal that prior GH exposure is not necessary to establish open chromatin at these domains. Lastly, formaldehyde-associated isolation of regulatory elements of human liver samples confirms open chromatin at IGF1 Promoter 1, but unexpectedly, homologous Stat5-binding motifs are not accessible. We conclude that robust GH-stimulated hepatic Igf1 gene transcription utilizes tissue-specific mechanisms of epigenetic regulation that are established independent of GH signaling.

A spin torque magnetoresistive random access memory (ST-MRAM) holds great promise to be a fast, high density, nonvolatile memory that can enhance the performance of a variety of applications, particularly when used as a non-volatile buffer in data storage devices and systems. Towards that end, we have developed a fully functional 64 Mb DDR3 ST-MRAM built on 90 nm CMOS technology. The memory is organized in an 8-bank configuration that can sustain 1.6 GigaTransfers/s (DDR3-1600). We have run standard memory tests, such as a March6N pattern, on the full 64 Mb at 800 MHz with 0 fails for greater than 10 5 cycles. Full functionality was also verified from 0°C to 70°C with no significant change in performance. The bits are magnetic tunnel junctions (MTJs) having an MgO tunnel barrier and a magnetic free layer made of a CoFeB-based alloy with an in-plane magnetization, but with an out-of-plane anisotropy reduced by more than 50% due to an enhanced perpendicular surface anisotropy. To enable the 64 Mb performance, we developed an MTJ stack that has low switching voltage (Vsw), high breakdown voltage (Vbd), and excellent switching reliability with tight distributions. The ST switching distribution has σ ≈ 10%, and we found excellent agreement with a single Gaussian distribution down to an error rate . For our optimized material, the Vsw/Vbd ≈ 0.3, and the separation between Vsw and Vbd is ≈ 25σ. The energy barrier to magnetization reversal (Eb) was characterized using both time-dependent coercivity and higher temperature to accelerate reversal. We found the average Eb ≈ 70kbT.

Hydraulic fracturing technology is widely used to facilitate and enhance the recovery process from oil and gas reservoirs. Much worldwide experience has been gained in stimulating conventional and shale oil reservoirs; however achieving good stimulation results in mature (depleted) oilfields with moderate permeability can be challenging and can easily fall below expectations for a variety of reasons. To narrow the gap between expected results and actual well performance after a successful fracturing treatment it is very important to understand the reservoir characteristics and the actual reservoir potential. Despite the common opinion that stimulating mature, depleted wells is unprofitable, experience shows that stimulating such wells can still result in substantial and profitable production increases. Twenty hydraulic fracturing treatments performed on wells in a mature onshore oil field wells in Myanmar, in south-east Asia have shown significant increases in initial incremental oil production rate—on average by a factor of two, which was still below the expectations. The treatments have effectively increased cumulative production and arrested exponential decline by +62% per annum. The result is a flatter production profile and has higher sustained oil production rates. This paper discusses the challenges seen and the results obtained utilizing hydraulic fracture stimulation in a mature oilfield. This case shows the importance of a proper candidate selection method, which has contributed to successful stimulation and improved oil recovery in this case.

During normal and pathologic immune responses, lymph nodes can swell considerably. The lymph node vascular–stromal compartment supports and regulates the developing immune responses and undergoes dynamic expansion and remodeling. Recent studies have shown that dendritic cells (DCs), best known for their antigen presentation roles, can directly regulate the vascular–stromal compartment, pointing to a new perspective on DCs as facilitators of lymphoid tissue function. Here, we review the phases of lymph node vascular–stromal growth and remodeling during immune responses, discuss the roles of DCs, and discuss how this understanding can potentially be used for developing novel therapeutic approaches.

Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Murovska M, Pall ML, Stevens S (Independent, Vancouver, BC, Canada; Independent, Calgary, AB, Canada; Department of Physiology and Medicine, Vrije University of Brussels, Himmunitas Foundation, Brussels, Belgium; Department of Medicine,University of Miami Miller School of Medicine and Miami Veterans Affairs Medical Center, Miami, FL, USA; Department of Medicine, University of Alberta, Edmonton, AB, Canada; Honorary Consultant for NHS at Peterborough/Cambridge, Lowestoft, Suffolk, UK; Gold Coast Public Health Unit, Southport, Queensland; Health Sciences and Medicine, Bond University, Robina, Queensland, Australia; Faculty of Health Sciences, McMaster University and St Joseph’s Healthcare Hamilton, Hamilton, ON, Canada; Independent, Durham, UK; Howick Health and Medical Centre, Howick, New Zealand; Fatigue Consultation Clinic, Salt Lake Regional Medical Center; Internal Medicine, Family Practice, University of Utah, Salt Lake City, UT, USA; ME/CFS Center, Oslo University Hospital HF, Norway; Department of Paediatrics, State University of New York, Buffalo, NY; Independent, Pavia, Italy; Harbor-UCLA Medical Center, University of California, Los Angeles, CA; EV Med Research, Lomita, CA, USA; University of Limerick, Limerick, Ireland; Pain Clinic, Konyang University Hospital, Daejeon, Korea; Donvale Specialist Medical Centre, Donvale, Victoria, Australia; Departments or Anesthesiology, Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah, USA; Health Sciences and Medicine, Bond University, Robina, Queensland, Australia; Department of Medicina Nuclear, Clinica Las Condes, Santiago, Chile; Whittemore Peterson Institute, University of Nevada, Reno, NV, USA; Miwa Naika Clinic, Toyama, Japan; A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia; Department of Biochemistry & Basic Medical Sciences, Washington State University, Portland, OR; Department of Sports Sciences, University of the Pacific, Stockton, CA USA). Myalgic encephalomyelitis: International Consensus Criteria (Review). J Intern Med 2011; 270: 327–338. The label ‘chronic fatigue syndrome’ (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term ‘myalgic encephalomyelitis’ (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3). Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.

Many of the long-term physiological effects of GH require hormone-mediated changes in gene expression. The transcription factor signal transducer and activator of transcription 5b (Stat5b) plays a critical role in the actions of GH on growth and metabolism by regulating a large number of GH-dependent genes by incompletely understood mechanisms. Here we have assessed the impact of GH-initiated and Stat5b-mediated signaling on the chromatin landscape of hormone-regulated genes in the liver of pituitary-deficient young adult male rats. In the absence of GH there was minimal ongoing transcription at the Socs2, Cish, Igfals, and Spi 2.1 promoters, minimal occupancy of Stat5b at proximal promoter sites, and relatively closed chromatin, as evidenced by low levels of core histone acetylation. In contrast, transcriptionally silent Igf1 promoter 1 appeared poised to be activated, based on binding of coactivators p300 and Med1/Trap220, high levels of histone acetylation, and the presence of RNA polymerase II. GH treatment led to a 8- to 20-fold rise in transcriptional activity of all five genes within 30–60 min and was accompanied by binding of Stat5b to the proximal Socs2, Cish, Igfals, and Spi 2.1 promoters and to seven distal Igf1 Stat5b elements, by enhanced histone acetylation at all five promoters, by recruitment of RNA polymerase II to the Socs2, Cish, Igfals, and Spi 2.1 promoters, and by loss of the transcriptional repressor Bcl6 from Socs2, Cish, and Igfals Stat5b sites, but not from two Igf1 Stat5b domains. We conclude that GH actions induce rapid and dramatic changes in hepatic chromatin at target promoters and propose that the chromatin signature of Igf1 differs from other GH-and Stat5b-dependent genes.

The growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis regulates somatic growth during childhood and orchestrates tissue repair throughout the life span. Recently described inactivating mutations in Stat5b in humans with impaired growth have focused attention on this transcription factor as a key agent linking GH-stimulated signals to IGF-I gene expression, and several putative Stat5b sites have been identified in the IGF-I gene. Here, we define and characterize potential GH- and Stat5b-activated chromosomal enhancers that can regulate IGF-I gene transcription. Of 89 recognizable Stat5 sequences in 200 kb centering on the rat IGF-I gene, 22 resided within conserved regions and/or were identical among different species. Only 15 of these sites, organized into 7 distinct domains, were found to bind Stat5b by quantitative chromatin immunoprecipitation assays in liver chromatin of rats, but only after acute GH treatment. These sites could bind Stat5b in vitro, and individual domains could mediate GH- and Stat5b-stimulated IGF-I promoter activity in cultured cells. Further analyses revealed that four Stat5b domains possessed chromatin signatures of enhancers, including binding of co-activators p300 and Med1, and RNA polymerase II. These modifications preceded GH-stimulated recruitment of Stat5b, as did lysine 4 monomethylation of histone H3, which was enriched in 6/7 Stat5b-binding elements. In contrast, histone acetylation was induced by GH but was limited to Stat5b binding domains found within the IGF-I transcription unit. We conclude that GH stimulates recruitment of Stat5b to multiple dispersed regions within the igf1 locus, including several with properties consistent with long range transcriptional enhancers that collectively regulate GH-activated IGF-I gene transcription.

The extent to which skin surface bioheat perfusion predicts penile physiological response such as an erection has not been extensively investigated. A biomechanical engineering study was performed to compare bioheat distribution on penile skin surface resulting from an induced erection at steady state to examine the efficacy of such method as an adjunct tool for the diagnosis and classification of erectile dysfunction (ED) due to different etiology. We based our arguments on the principle that blood vessel activity and perfusion to corpus cavernosa at the erect state are almost always higher than that in the flaccid state. Our results showed that a difference of 0.1-0.3 degrees C can be observed and hence used to develop database of 'smart diagnosis' for ED using the machine artificial intelligence. It is anticipated that such basic research into blood flow is critical, as blood perfusion into corpus cavernosa is the most influential factor determining functional erectile quality contributing to successful coitus. Increased understanding of the hemodynamic response profile contributes toward optimal treatment and thus enables clinicians to adopt an appropriate management scheme for ED.

The GH-activated signal transducer and activator of transcription 5b (STAT5b) is an essential regulator of somatic growth. The transcriptional response to STAT5b in liver is poorly understood. We have combined microarray-based expression profiling and phylogenetic analysis of gene regulatory regions to study the interplay between STAT5b and GH in the regulation of hepatic gene expression. The acute transcriptional response to GH in vivo after a single pulse of GH was studied in the liver of hypophysectomized rats in the presence of either constitutively active or a dominant-negative STAT5b delivered by adenoviral gene transfer. Genes showing differential expression in these two situations were analyzed for the presence of STAT5b binding sites in promoter and intronic regions that are phylogenetically conserved between rats and humans. Using this approach, we showed that most rapid transcriptional effects of GH in the liver are not results of direct actions of STAT5b. In addition, we identified novel STAT5b cis regulatory elements in genes such as Frizzled-4, epithelial membrane protein-1, and the suppressor of cytokine signaling 2 (SOCS2). Detailed analysis of SOCS2 promoter demonstrated its direct transcriptional regulation by STAT5b upon GH stimulation. A novel response element was identified within the first intron of the human SOCS2 gene composed of an E-box followed by tandem STAT5b binding sites, both of which are required for full GH responsiveness. In summary, we demonstrate the power of combining transcript profiling with phylogenetic sequence analysis to define novel regulatory paradigms.

Purpose of review In this review of the literature from 2014 through mid-2015, we examine new data that shed light on how macrophages and other innate immune cells and signals contribute to inflammation, vascular dysfunction, and fibrosis in scleroderma. Recent findings Recent human studies have focused on changes early in scleroderma, and linked macrophages to inflammation in skin and progression of lung disease. Plasmacytoid dendritic cells have been implicated in vascular dysfunction. In mice, several factors have been identified that influence macrophage activation and experimental fibrosis. However, emerging data also suggest that myeloid cells can have differential effects in fibrosis. Sustained signaling through different toll-like receptors can lead to inflammation or fibrosis, and these signals can influence both immune and nonimmune cells. Summary There are many types of innate immune cells that can potentially contribute to scleroderma and will be worth exploring in detail. Experimentally dissecting the roles of macrophages based on ontogeny and activation state, and the innate signaling pathways in the tissue microenvironment, may also lead to better understanding of scleroderma pathogenesis.

Older persons have unique health needs and treatment preferences that require geriatric care for comprehensive evaluation and management. Telegeriatrics was implemented in December 2010 by an acute hospital in Singapore with the aim to provide timely specialist input to nursing home residents. This preliminary study explores the perspectives of users from the NHs and the acute hospital on two aspects of Telegeriatrics – the telemedicine consultation and the nurse training programme. Seven focus group discussions and three semi-structured moderate interviews were conducted with a total of 25 participants. To identify important themes and new themes that emerged during the coding process, thematic content analysis was applied. The most commonly cited benefits were increased access to specialist care, reduced need for hospitalizations, improved quality of care, and enhanced nursing skills and knowledge. However, common perceived barriers were the lack of personal touch, technical issues, and medico-legal issues. This mode of delivering specialist care was generally acceptable to the users. To the users, Telegeriatrics showed feasibility in providing consultation, delivering education, and enhancing nursing competence.

Due to the lack of expert clinical involvement in the nursing homes of Singapore, frail and older nursing home residents become frequent unnecessary users of acute care services. Telegeriatrics, a pilot programme implemented by an acute hospital in Singapore used videoconferencing to provide timelier geriatric care, which could reduce transfers to the acute hospital. We assess the impact of the level of engagement with Telegeriatrics has on nursing home to hospital transfer rates. From December 2010 to March 2015, a total of 579 telemedicine consultation episodes were conducted in two nursing homes. Hospital admission rates were monitored over a 2-year period and compared against the nursing home’s level of engagement with Telegeriatrics. The findings show a reduction in hospital admission rate for both nursing homes. There was a significant decrease of 33 % in hospital admission rates in the more-engaged nursing home while the less-engaged nursing home reported a 2 % increase. The results show that, by improving the availability of specialist support and with increased engagement in Telegeriatrics, unnecessary hospitalizations could be reduced. This leads to elimination of stress and disruption for the resident, as well as reduced costs and quicker medical care.

A predicted alanine to proline substitution in Stat5b that results in profound short stature, growth hormone insensitivity, and immunodeficiency represents the first natural mutation of this transcription factor in a human. To understand the mechanisms responsible for these pathophysiological abnormalities, we have studied the biochemical and biophysical properties of the mutant Stat5b molecule. In a cellular reconstitution model growth hormone robustly stimulated tyrosine phosphorylation and transcriptional activity of wild-type Stat5b while Stat5bA630P was minimally modified and did not promote reporter gene expression. Steady state levels of Stat5bWT were approximately 3-fold higher than Stat5bA630P in cell extracts prepared with nonionic detergents. Although initial rates of biosynthesis of both proteins were similar, pulse-chase experiments established that the apparent half-life of newly synthesized soluble Stat5bA630P was15% of Stat5bWT (3.5 h versus24 h). Stat5bA630P accumulated in cells primarily in cytoplasmic inclusion bodies. Structural analysis of the isolated SH2 domain containing the A630P mutation showed that it resembled the wild-type SH2 segment but that it exhibited reduced thermodynamic stability and slower folding kinetics, displayed an increased hydrophobic surface, and was prone to aggregation in solution. Our results are compatible with a model in which Stat5bA630P is an inactive transcription factor by virtue of its aberrant folding and diminished solubility triggered by a misfolded SH2 domain. The potential for aggregation and formation of cytoplasmic inclusions raises the possibility that Stat5bA630P could produce additional defects through inhibition of proteasome function.

A key agent in the anabolic actions of growth hormone (GH) is insulin-like growth factor-I (IGF-I), a 70-amino acid secreted protein with direct effects on somatic growth and tissue maintenance and repair. GH rapidly and potently stimulates IGF-I gene transcription by mechanisms independent of new protein synthesis, and recent studies have linked the transcription factor Stat5b to a regulatory network connecting the activated GH receptor on the cell membrane to the IGF-I gene in the nucleus. Here we analyze two distinct conserved GH response elements in the rat IGF-I locus that contain paired Stat5b sites. Each response element binds Stat5b in vivo in a GH-dependent way, as assessed by chromatin immunoprecipitation assays, and consists of one high affinity and one lower affinity Stat5b site, as determined by both qualitative and quantitative protein-DNA binding studies. In biochemical reconstitution experiments, both response elements are able to mediate GH-stimulated and Stat5b-dependent transcription when fused to a reporter gene containing either the major IGF-I promoter or a minimal neutral promoter, although the paired Stat5b sites located in the second IGF-I intron were more than twice as effective as the response element that mapped approximately 73 kb 5' to the IGF-I exon 1. Taken together, our results define the initial molecular architecture of a complicated GH-regulated transcriptional pathway, and suggest that apparently redundant hormone response elements provide a mechanism for amplifying GH action at a physiologically important target gene.