Widespread horse-based mobility arose around 2,200 BCE in Eurasia.

Horses revolutionized human history with fast mobility1. However, the timeline between their domestication and widespread integration as a means of transportation remains contentious2-4. Here we assemble a large collection of 475 ancient horse genomes to assess the period when these animals were first reshaped by human agency in Eurasia. We find that reproductive control of the modern domestic lineage emerged ~2,200 BCE (Before Common Era), through close kin mating and shortened generation times. Reproductive control emerged following a severe domestication bottleneck starting no earlier than ~2,700 BCE, and coincided with a sudden expansion across Eurasia that ultimately resulted in the replacement of nearly every local horse lineage. This expansion marked the rise of widespread horse-based mobility in human history, which refutes the commonly-held narrative of large horse herds accompanying the massive migration of steppe peoples across Europe ~3,000 BCE and earlier3,5. Finally, we detect significantly shortened generation times at Botai ~3,500 BCE, a settlement from Central Asia associated with corrals and a subsistence economy centered on horses6,7. This supports local horse husbandry before the rise of modern domestic bloodlines.

Peripheral blood immune markers in breast cancer: Differences in regulatory T cell abundance are related to clinical parameters.

BACKGROUND: Cancer development is among other factors driven by tumor immune escape and tumor-mediated changes in the immune response. Investigating systemic immune changes may provide important knowledge for the improvement of patient prognosis and treatment opportunities. METHODS: The systemic immune profile of patients with ER-positive breast cancer (n = 22) and healthy controls (n = 30) was investigated based on complete blood counts, flow cytometric analysis of T cell subsets including regulatory T cells (Tregs), and immune assays investigating soluble (s)HLA-G and the cytokine profile in plasma. We further examined the correlation between the immune markers and clinical parameters including tumor size, tumor grade and lymph node involvement. RESULTS: Results indicated that breast cancer patients possessed a higher amount of neutrophils and monocytes and fewer lymphocytes and eosinophils compared with healthy controls. Breast cancer patients had significantly more CD25+CD127low Tregs than controls, and both lymphocyte and Treg numbers were negatively correlated with tumor size. Furthermore, Treg numbers were elevated in grade I tumors compared with grade II tumors and with healthy controls. No difference in sHLA-G levels was observed between patients and controls. Higher levels of IL-6 and TNF-α were observed in breast cancer patients. Cytokine and sHLA-G levels were not associated with clinical parameters. CONCLUSION: The results of this exploratory study contribute to the elucidation of the systemic immune response in breast cancer indicating a potential use of peripheral immune cell counts and Tregs to distinguish patients from healthy controls and as potential diagnostic and prognostic biomarkers to be investigated in future studies.

Novel chicken two-dimensional intestinal model comprising all key epithelial cell types and a mesenchymal sub-layer.

The intestinal epithelium plays a variety of roles including providing an effective physical barrier and innate immune protection against infection. Two-dimensional models of the intestinal epithelium, 2D enteroids, are a valuable resource to investigate intestinal cell biology and innate immune functions and are suitable for high throughput studies of paracellular transport and epithelial integrity. We have developed a chicken 2D enteroid model that recapitulates all major differentiated cell lineages, including enterocytes, Paneth cells, Goblet cells, enteroendocrine cells and leukocytes, and self-organises into an epithelial and mesenchymal sub-layer. Functional studies demonstrated the 2D enteroids formed a tight cell layer with minimal paracellular flux and a robust epithelial integrity, which was maintained or rescued following damage. The 2D enteroids were also able to demonstrate appropriate innate immune responses following exposure to bacterial endotoxins, from Salmonella enterica serotype Typhimurium and Bacillus subtilis. Frozen 2D enteroids cells when thawed were comparable to freshly isolated cells. The chicken 2D enteroids provide a useful ex vivo model to study intestinal cell biology and innate immune function, and have potential uses in screening of nutritional supplements, pharmaceuticals, and bioactive compounds.

Cardiovascular adaptations after 10 months of intense school-based physical training for 8- to 10-year-old children.

This study examined cardiovascular adaptations in 8- to 10-year-old schoolchildren after 10 months (a full school year) of 3 × 40 minute per week of small-sided ball games (SSG, including football, basketball, and/or floorball) or circuit strength training (CST). The study involved 291 Danish schoolchildren, 8-10 years old, cluster-randomized to SSG (n = 93, 4 schools, 5 classes), CST (n = 83, 4 schools, 4 classes), or a control group (CON, n = 115, 2 schools, 5 classes). Before and after the 10-month intervention, resting heart rate and blood pressure measurements were performed as well as comprehensive transthoracic echocardiography and peripheral arterial tonometry (PAT). Analysis of baseline-to-10-months changes showed between-group differences (P < 0.05) after both training interventions in diastolic blood pressure (delta scores: SSG -2.1 ± 6.0 mm Hg; CST -3.0 ± 7.1 mm Hg; CON 0.2 ± 5.3 mm Hg). Moreover, there were between-group differences in delta scores (P < 0.05) in interventricular septum thickness (SSG 0.17 ± 0.87 mm; CST 0.30 ± 0.94 mm; CON -0.15 ± 0.68 mm), left-atrial volume index (SSG 0.32 ± 5.13 mL/m2 ; CON 2.60 ± 5.94 mL/m2 ), and tricuspid annular plane systolic excursion (SSG -0.4 ± 3.3 mm; CON: 0.1 ± 3.6 mm). No significant between-group differences were observed for the PAT-derived reactive hyperemia index. In conclusion, 10 months of 3 × 40 minutes per week of SSG and CST in 8- to 10-year-old children decreased diastolic blood pressure and elicited discrete cardiac adaptations, suggesting that intense physical exercise in school classes can have effects on cardiovascular health in children.

Positive effects on bone mineralisation and muscular fitness after 10†months of intense school-based physical training for children aged 8-10†years: the FIT FIRST randomised controlled trial.

OBJECTIVES: We investigated whether musculoskeletal fitness of school children aged 8-10 years was affected by frequent intense PE sessions. DESIGN AND PARTICIPANTS: 295 Danish school children aged 8-10 years were cluster randomised to a small-sided ball game group (SSG) (n=96, four schools, five classes), a circuit strength training group (CST) (n=83, four schools, four classes) or a control group (CON, n=116, two schools, five classes). INTERVENTION: SSG or CST was performed 3×40 min/week over 10 months. Whole-body dual-energy X-ray absorptiometry (DXA) scans were used to determine areal bone mineral density (aBMD), bone mineral content (BMC) and lean body mass (LBM). Flamingo balance, standing long jump and 20-m sprint tests were used to determine muscular fitness. RESULTS: Analysis of baseline-to-10 months change scores showed between-group differences in favour of the interventions in whole-body aBMD (SSG vs CON: 8 mg/cm2, 95% CI 3 to 13; CST vs CON: 7 mg/cm2, 95% CI 2 to 13, p<0.05) and leg BMC (SSG vs CON: 11 g, 95% CI 4 to 18; CST vs CON: 11 g, 95% CI 3 to 18, p<0.05). SSG had higher change scores in leg aBMD compared with CON and CST (SSG vs CON: 19 mg/cm2, 95% CI 11 to 39, p<0.05; SSG vs CST: 12 mg/cm2, 95% CI 3 to 21, p<0.05), and CST had higher change scores in whole-body BMC compared with CON (CST vs CON: 25 g, 95% CI 10 to 39, p<0.05). Both training types resulted in higher change scores in postural balance (SSG vs CON: 2.4 fewer falls/min, 95% CI 0.3 to 4.5, CST vs CON: 3.6 fewer falls/min, 95% CI 1.3 to 5.9, p<0.05) and jump length (SSG vs CON: 10%, 95% CI 5 to 16%; CST vs CON: 9%, 95% CI 3 to 15%, p<0.05). No between-group differences were observed for sprint performance or LBM (p>0.05). CONCLUSIONS: In conclusion, 3×40 min/week with SSG or CST over a full school year improves bone mineralisation and several aspects of muscular fitness of children aged 8-10 years, suggesting that well-organised intense physical education classes can contribute positively to develop musculoskeletal health in young children. TRIAL REGISTRATION NUMBER: NCT02000492, post results.

Physical Fitness and Body Composition in 8-10-Year-Old Danish Children Are Associated With Sports Club Participation.

Larsen, MN, Nielsen, CM, Ørntoft, CØ, Randers, M, Manniche, V, Hansen, L, Hansen, PR, Bangsbo, J, and Krustrup, P. Physical fitness and body composition in 8-10-year-old Danish children are associated with sports club participation. J Strength Cond Res 31(12): 3425-3434, 2017-We investigated whether physical fitness and body composition in 8-10-year-old Danish children are associated with sports club participation. The study included 423 schoolchildren, comprising 209 girls and 214 boys, of whom 67 and 74%, respectively, were active in sports clubs. Yo-Yo intermittent recovery level 1 for children (YYIR1C), balance, jump and coordination tests, together with dual-energy X-ray absorptiometry, were used to determine exercise capacity and body composition. Children active in sports clubs had better (p < 0.05) YYIR1C (33%, 767 ± 26 vs. 575 ± 29 m), 20-m sprint (3%, 4.33 ± 0.03 vs. 4.48 ± 0.04 seconds), coordination (6%, 68 ± 1 vs. 72 ± 1 second), and balance test performances (9%, 19.3 ± 0.5 vs. 21.2 ± 0.7 falls·min) and lower fat mass index (16%, 3.8 ± 0.1 vs. 4.5 ± 0.2 kg[fat]·m) than children not active in sports clubs. Ball game players had better (p < 0.05) YYIR1C (38%, 925 ± 39 vs. 671 ± 28 m), 20-m sprint (4%, 4.25 ± 0.03 vs. 4.42 ± 0.04 seconds), and coordination test performances (5%, 65 ± 1 vs. 69 ± 1 second), along with higher (p < 0.05) lean body mass (5%, 24.00 ± 0.22 vs. 22.83 ± 0.25 kg) and whole-body BMD (2%, 0.90 ± < 0.01 vs. 0.88 ± <0.01 g·cm) compared with children active in other sports. The study showed that 8[FIGURE DASH]10-year-old Danish children engaged in sports-club activity, especially ball game players, have better exercise capacity and superior body composition compared with children not active in sports clubs.

Interpretation of the skin cancer quality of life score: a validated quality of life questionnaire for non-melanoma skin cancer.

BACKGROUND: Health-related quality of life (HRQoL) instruments are used increasingly. In order to assign clinical meaning to HRQoL scores, the interpretation of instruments is essential but lagging in dermatology. OBJECTIVE: To establish a clinical interpretation of the Skin Cancer Quality of Life questionnaire (SCQoL), a newly validated HRQoL instrument for patients with non-melanoma skin cancer (NMSC), using an anchor-based method, and to test the responsiveness. METHODS: Receiver-operating characteristic analysis was used to propose clinically meaningful cut-off scores for SCQoL including 101 patients with NMSC. RESULTS: The following bands were established: score 0-3 corresponds to no impairment, 4-6 corresponds to mild impairment, 7-10 to moderate impairment and 11-27 to severe impairment of HRQoL. Testing the responsiveness shows a moderate effect size and significantly lower scores only for the domain emotion and the global item. CONCLUSION: Using proposed clinical cut-off scores for SCQoL may help clinicians in their decision-making, help monitoring clinical improvement and classify patients just as e.g. the Dermatology Life Quality Index can.

Insignificant influence of the intertransverse process block for major breast cancer surgery: a randomized, blinded, placebo-controlled, clinical trial.

INTRODUCTION: The intertransverse process (ITP) block mimics the thoracic paravertebral block and allegedly ameliorates hemithoracic postoperative pain. However, concerning major reconstructive breast cancer surgery the modality has never been tested against placebo in a randomized clinical trial. We aimed to assess the efficacy of the multiple-injection ITP block and hypothesized that the blockade would reduce postoperative opioid consumption. METHODS: We screened 58 patients with breast cancer scheduled for unilateral subpectoral implant-based primary breast reconstruction, involving mastectomy with complete fascial dissection of the major pectoral muscle. A randomization procedure allowed for the allocation of 36 patients to receive either unilateral multiple-injection active ITP block (0.5% ropivacaine 3×10 mL) or placebo ITP block (isotonic saline 3×10 mL) at T2, T4, T6 in a prospective, blinded, clinical trial. The primary outcome was total opioid consumption within the first 24 postoperative hours. Secondary outcomes included opioid consumption at 4-hour intervals, postoperative pain, patient satisfaction with block application, time to first opioid, ambulation and discharge, opioid-related side effects, and quality of recovery. RESULTS: Opioid consumption within the first 24 postoperative hours showed no significant reduction when comparing the active and placebo group median (IQR): 75.0 mg (45-135) vs 62.5 mg (30-115), p=0.5, respectively. We did not find any consequential clinically relevant results of the secondary outcomes. CONCLUSIONS: Following major reconstructive breast cancer surgery, a preoperative multiple-injection ITP block neither reduces 24-hour opioid consumption postoperatively nor promotes substantial clinical positive outcomes. TRIAL REGISTRATION NUMBER: EudraCT2019-001016-35.

Assessment of the effects of intramuscular administration of alfaxalone with and without medetomidine in Horsfield's tortoises (Agrionemys horsfieldii).

OBJECTIVE: To characterise four different intramuscular (IM) anaesthetic protocols, two with alfaxalone and two with alfaxalone in combination with medetomidine in terrestrial tortoises. STUDY DESIGN: Blinded, randomized, cross-over experimental study. ANIMALS: Nine healthy adult male Horsfield's tortoises (Agrionemys horsfieldii). METHODS: Each tortoise was randomly assigned to one of four different protocols: 1) 10 mg kg(-1) alfaxalone; 2) 10 mg kg(-1) alfaxalone + 0.10 mg kg(-1) medetomidine; 3) 20 mg kg(-1) alfaxalone; and 4) 20 mg kg(-1) alfaxalone + 0.05 mg kg(-1) medetomidine. During the experiment, the following variables were recorded: heart rate; respiratory rate; peripheral nociceptive responses; muscle strength; ability to intubate; palpebral, corneal and tap reflexes; and cloacal temperature. RESULTS: Protocols 1 and 2 resulted in moderate sedation with no analgesia, and moderate to deep sedation with minimal analgesia, respectively. Protocols 3 and 4 resulted in deep sedation or anaesthesia with variable analgesic effect; these two protocols had the longest total anaesthetic time and allowed intubation in 6/9 and 8/9 tortoises respectively. The total anaesthesia/sedation time produced by alfaxalone was significantly increased (p < 0.05) by the addition of medetomidine. There were no significant differences regarding time to plateau phase and duration of plateau phase. Baseline heart rate of 53 ± 6 beats minute(-1) decreased significantly (p < 0.05) with all protocols, and was lower (p < 0.05) in protocols 3 and 4. Heart rate increased after atipamezole administration, but the increase was transient. In two tortoises, extreme bradycardia with no cardiac activity for 10 minutes was observed with protocols 3 and 4. CONCLUSION AND CLINICAL RELEVANCE: Alfaxalone 10 and 20 mg kg(-1) IM can be used for sedation for non-painful procedures. Alfaxalone in combination with medetomidine can be used for deeper sedation or anaesthesia, but the observed respiratory and cardiovascular depression may limit its use.

Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.

We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.

Changed activation, oxygenation, and pain response of chronically painful muscles to repetitive work after training interventions: a randomized controlled trial.

The aim of this randomized controlled trial was to assess changes in myalgic trapezius activation, muscle oxygenation, and pain intensity during repetitive and stressful work tasks in response to 10 weeks of training. In total, 39 women with a clinical diagnosis of trapezius myalgia were randomly assigned to: (1) general fitness training performed as leg-bicycling (GFT); (2) specific strength training of the neck/shoulder muscles (SST) or (3) reference intervention without physical exercise. Electromyographic activity (EMG), tissue oxygenation (near infrared spectroscopy), and pain intensity were measured in trapezius during pegboard and stress tasks before and after the intervention period. During the pegboard task, GFT improved trapezius oxygenation from a relative decrease of -0.83 ± 1.48 µM to an increase of 0.05 ± 1.32 µM, and decreased pain development by 43%, but did not affect resting levels of pain. SST lowered the relative EMG amplitude by 36%, and decreased pain during resting and working conditions by 52 and 38%, respectively, without affecting trapezius oxygenation. In conclusion, GFT performed as leg-bicycling decreased pain development during repetitive work tasks, possibly due to improved oxygenation of the painful muscles. SST lowered the overall level of pain both during rest and work, possibly due to a lowered relative exposure as evidenced by a lowered relative EMG. The results demonstrate differential adaptive mechanisms of contrasting physical exercise interventions on chronic muscle pain at rest and during repetitive work tasks.

Electronic patient-reported outcome measures to enable systematic follow-up in treatment and care of women diagnosed with breast cancer: a feasibility study protocol.

INTRODUCTION: The use of patient-reported outcome measures (PROMs) in clinical practice has the potential to promote person-centred care and improve patients' health-related quality of life. We aimed to develop an intervention centred around electronic PROMs (ePROMs) for systematic follow-up in patients diagnosed with breast cancer and to evaluate its feasibility. METHODS AND ANALYSIS: We developed a nurse-oriented and surgeon-oriented intervention in PROMs, including (1) an education programme for nurses and surgeons; (2) administration of BREAST-Q as proactive ePROMs during follow-up in patients diagnosed with breast cancer and (3) feedback to nurses and surgeons on PROM scores and a guidance manual for healthcare practitioners. Subsequently, we designed a non-controlled feasibility evaluation on the outcomes acceptability, demand, implementation, practicality and integration. The feasibility evaluation includes qualitative ethnographic studies exploring the user perspectives of patients, nurses and surgeons and quantitative studies to explore the characteristics of the patient population regarding demographic background, response rates and response patterns. The feasibility study was initiated in September 2021, will continue until 2024 and will include approximately 900 patients. EPROMs are collected at the following assessment time points: baseline (after diagnosis, before surgery), 1-year follow-up and 3-year endpoint. ETHICS AND DISSEMINATION: The study will be conducted according to the General Data Protection Regulation and the fifth version of the Helsinki Declaration. The National Committee on Health Research Ethics approved the study according to the law of the Committee § 1, part 4. All data will be anonymised before its publication. The results of the feasibility study will be published in peer-reviewed, international journals.

Evolutionary conservation of heavy chain protein transfer between glycosaminoglycans.

The bikunin proteins are composed of heavy chains (HCs) covalently linked to a chondroitin sulfate chain originating from Ser-10 of bikunin. Tumor necrosis factor stimulated gene-6 protein (TSG-6)/heavy chain 2 (HC2) cleaves this unique cross-link and transfers the HCs to hyaluronan and other glycosaminoglycans via a covalent HC*TSG-6 intermediate. In the present study, we have investigated if this reaction is evolutionary conserved based on the hypothesis that it is of fundamental importance. The results revealed that plasma/serum samples from mammal, bird, and reptile were able to form TSG-6 complexes suggesting the presence of proteins with the same function as the human bikunin proteins. To substantiate this, the complex forming protein from Gallus gallus (Gg) plasma was purified and identified as a Gg homolog of human HC2*bikunin. In addition, Gg pre-alpha-inhibitor and smaller amount of high molecular weight forms composed of bikunin and two HCs were purified. Like the human bikunin proteins, the purified Gg proteins were all stabilized by a protein-glycosaminoglycan-protein cross-link, i.e. the HCs were covalently attached to a chondroitin sulfate originating from bikunin. Furthermore, the complex formed between Gg HC2*bikunin and human TSG-6 appeared to be identical to that of the human proteins. Akin to human, Gg HC2 was further transferred to hyaluronan when present, and when incubated in vitro, Gg pre-alpha-inhibitor and TSG-6, failed to form the intermediate covalent complex, essential for HC transfer. Significantly, Gg HC2, analogous to human HC2, promoted complex formation between human HC3 and human TSG-6, substantiating the evolutionary conservation of these interactions. The present study demonstrates that the unique interactions between bikunin proteins, glycosaminoglycans, and TSG-6 are evolutionary conserved, emphasizing the physiological importance of the TSG-6/HC2-mediated HC-transfer reaction. In addition, the data show that the evolution of HC transfer is likely to predate the role of HC.HA complexes in female fertility and thus has evolved in the context of inflammation rather than fertility.

COPE-ICD: a randomised clinical trial studying the effects and meaning of a comprehensive rehabilitation programme for ICD recipients -design, intervention and population.

BACKGROUND: Growing evidence exists that living with an ICD can lead to fear and avoidance behaviour including the avoidance of physical activity. It has been suggested that psychological stress can increase the risk of shock and predict death. Small studies have indicated a beneficial effect arising from exercise training and psychological intervention, therefore a large-scale rehabilitation programme was set up. METHODS/DESIGN: A mixed methods embedded experimental design was chosen to include both quantitative and qualitative measures. A randomised clinical trial is its primary component. 196 patients (power-calculated) were block randomised to either a control group or intervention group at a single centre. The intervention consists of a 1-year psycho-educational component provided by two nurses and a 12-week exercise training component provided by two physiotherapists. Our hypothesis is that the COPE-ICD programme will reduce avoidance behaviour, sexual dysfunction and increase quality of life, increase physical capability, reduce the number of treatment-demanding arrhythmias, reduce mortality and acute re-hospitalisation, reduce sickness leading to absence from work and be cost-effective. A blinded investigator will perform all physical tests and data collection. DISCUSSION: Most participants are men (79%) with a mean age of 58 (range 20-85). Most ICD implantations are on primary prophylactic indication (66%). 44% is NYHA II. Mean walk capacity (6MWT) is 417 m. Mean perception of General Health (SF-36) is PCS 42.6 and MCS 47.1.A large-scale ICD rehabilitation trial including psycho-educational intervention and exercise training has been initiated and will report findings starting in 2011. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00569478.

Immunogenicity of the Novel Glucagon Analogue Dasiglucagon: Results of a Dedicated Immunogenicity Trial in Type 1 Diabetes.

Dasiglucagon is a next-generation glucagon analogue that is stable in aqueous formulation. This dedicated immunogenicity trial to support use as rescue treatment for severe hypoglycemia was conducted to evaluate the immunogenicity of repeated subcutaneous doses of dasiglucagon in subjects with type 1 diabetes. A total of 112 subjects were randomized 1:1 to receive three subcutaneous weekly doses of either 0.6 mg dasiglucagon or 1.0 mg recombinant glucagon (GlucaGen®) according to a double-blind parallel-group trial design. Subjects were followed for 15 weeks, with a multitiered testing approach planned for assessment of antidrug antibody (ADA) formation. For the primary immunogenicity endpoint, the overall ADA incidence was zero, as no subject demonstrated any treatment-induced or treatment-boosted ADA response at any time point in this trial involving three consecutive weekly doses of trial drug. No injection site reactions were reported for subjects receiving dasiglucagon. There were no unexpected safety findings for the trial.

Effect of cycling on oxygenation of relaxed neck/shoulder muscles in women with and without chronic pain.

Work-related neck/shoulder muscle pain has been associated with increased anaerobic muscle metabolism. Thus, interventions to enhance oxygenation of painful muscles seem relevant. While cycling with relaxed shoulders has been shown to result in acute neck/shoulder muscle pain reduction, the effect on tissue oxygenation remains unknown. The aim of the present study was to investigate tissue oxygenation of the passive trapezius muscle during and after cycling in female workers with (MYA) and without (CON) trapezius myalgia. Eligible participants (n = 17 MYA, n = 8 CON) performed 20 min sub-maximal cycling in an upright position with relaxed shoulders. Near-infrared spectroscopy was used to measure trapezius muscle oxygenation during and 2 min after the cycling period. For both MYA and CON, oxygenation of the passive trapezius increased in a linear fashion over time, to values approximately 5 microM above baseline at the end of the cycling period, with no significant group difference (CON 5.2, MYA 4.9 microM). Two min after termination of exercise, oxygenation was increased further in both groups, but significantly more in CON (8.8 microM) than in MYA (7.0 microM) (P = 0.05). In conclusion, cycling increases oxygenation of resting neck/shoulder muscles in women with and without trapezius myalgia, indicating acute positive effects of either neural or humoral factors on vascular beds of distant relaxed muscles. Although this beneficial response was observed in both groups, the post-exercise response was lower in women with trapezius myalgia.

Cardiovascular adaptations after 10 months of daily 12-min bouts of intense school-based physical training for 8-10-year-old children.

The present study examined cardiovascular adaptations in 8-10-year-old schoolchildren after a full school year (10 months) of 5 × 12 min/wk. of intense physical training, including small-sided ball games (soccer, basketball and floorball) or interval running. The study involved 8-10-year-old healthy Danish schoolchildren (n = 232), who were cluster-randomized to a small-sided games group (SSG, n = 60), an interval running group (IR, n = 57) or a control group (CON, n = 115). Comprehensive transthoracic echocardiography, resting heart rate and blood pressure measurements were performed at baseline and post intervention. For interval running, analysis of baseline-to-10-months changes showed significant (P < 0.05) between-group differences in delta scores for diastolic blood pressure (BP) and mean arterial BP (IR -3.2 ±â€¯5.7 and - 2.2 ±â€¯6.5 mmHg vs. CON 0.2 ±â€¯5.3 and 0.4 ±â€¯6.4 mmHg, respectively). Delta scores also showed a trend for reduction of mean arterial BP in SSG compared to CON (-2.1 ±â€¯6.0 vs. 0.2 ±â€¯5.3 mmHg, P = 0.067). Moreover, there were between-group differences in delta scores (P < 0.05) for selected echocardiographic parameters, i.e. in SSG vs. CON for interventricular septum thickness and peak transmitral flow velocity in early diastole, and in IR vs. CON for left ventricular systolic diameter. In conclusion, 10 months of 5 × 12 min/wk. of IR in 8-10-year-old children decreased diastolic BP, while both IR and SSG elicited cardiac adaptations. The results suggest that frequent low volume, intense physical training can have effects on the cardiovascular health profile in healthy children.

A phenylalanine zipper mediates APS dimerization.

The APS, SH2-B and LNK proteins are adapters that activate and modulate receptor tyrosine kinase and JAK/STAT signaling. We now show that a conserved N-terminal domain mediates APS homodimerization. We determined the crystal structure of the dimerization domain at a resolution of 1.7 A using bromide ion MAD phasing. Each molecule contributes two helices to a compact four-helix bundle having a bisecting-U topology. Its most conspicuous feature is a stack of interdigitated phenylalanine side chains at the domain core. These residues create a new motif we refer to as a 'phenylalanine zipper,' which is critical to dimerization. A newly developed bridging yeast tri-hybrid assay showed that APS dimerizes JAK2, insulin receptor and IGF1 receptor kinases using its SH2 and dimerization domains. Dimerization via the phenylalanine zipper domain provides a mechanism for activating and modulating tyrosine kinase activity even in the absence of extracellular ligands.

[Mastitis].

Mastitis is defined as an inflammation of the breast and may or may not be accompanied by infection. It usually affects fertile women but can be seen at all ages and even in males. Mastitis is commonly divided into two groups: lactational mastitis which occurs in breastfeeding women, and non-lactational mastitis. A timely diagnosis and correct management is essential to avoid complications. In this review, we assess different types of inflammations of the breast and elucidate important differential diagnoses, such as inflammatory breast cancer.

Kinase activation through dimerization by human SH2-B.

The isoforms of SH2-B, APS, and Lnk form a family of signaling proteins that have been described as activators, mediators, or inhibitors of cytokine and growth factor signaling. We now show that the three alternatively spliced isoforms of human SH2-B readily homodimerize in yeast two-hybrid and cellular transfections assays, and this is mediated specifically by a unique domain in its amino terminus. Consistent with previous reports, we further show that the SH2 domains of SH2-B and APS bind JAK2 at Tyr813. These findings suggested a model in which two molecules of SH2-B or APS homodimerize with their SH2 domains bound to two JAK2 molecules, creating heterotetrameric JAK2-(SH2-B)2-JAK2 or JAK2-(APS)2-JAK2 complexes. We further show that APS and SH2-B isoforms heterodimerize. At lower levels of SH2-B or APS expression, dimerization approximates two JAK2 molecules to induce transactivation. At higher relative concentrations of SH2-B or APS, kinase activation is blocked. SH2-B or APS homodimerization and SH2-B/APS heterodimerization thus provide direct mechanisms for activating and inhibiting JAK2 and other kinases from the inside of the cell and for potentiating or attenuating cytokine and growth factor receptor signaling when ligands are present.