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Background X-linked hypophosphataemia (XLH) is a rare genetic condition passed on through the X chromosome which causes multiple symptoms including weakened teeth, bones, and muscles. Due to the rarity of the condition, little is known about the health outcomes as reported by people with the disease. The objectives of this study were threefold: to characterise key patient reported outcome measures (PROMs) in adults with XLH, to identify clusters of symptom-severity groups based on PROMs, and to analyse the longitudinal progression of available PROMs. Methods Data from 48 participants from the Rare and Undiagnosed Diseases cohort Study (RUDY) was used to analyse both cross-sectional and longitudinal patient-reported outcomes. We analysed data for health-related quality of life (HRQL): EuroQol 5 dimensions-5 levels (EQ-5D-5L), Short-form 36 (SF-36) Physical Component Score (PCS), and SF-36 Mental Component Score (MCS), sleep: Pittsburgh sleep quality index (PSQI) and Epworth Sleepiness scale (ESS), fatigue: Fatigue Severity Scale (FSS) and Functional assessment of chronic illness therapy-fatigue (FACIT-F), pain: Short form McGill pain questionnaire version 2 (SF-MPQ-2) and PainDETECT, and mental well-being: Hospital anxiety and depression scale (HADS) anxiety and depression. Summary statistics, tests of mean differences, mixed-effects models, and cluster analysis were used to describe and examine the various health dimensions of individuals with XLH. Results Overall mean scores were EQ-5D-5L = 0.65, SF-36-PCS = 32.7, and SF-36-MCS = 48.4 for HRQL, ESS = 5.9 and PSQI = 8.9 for sleep, FSS = 32.8 and FACIT-F = 104.4 for fatigue, SF-MPQ-2 = 1.9 for pain, and HADS-depression = 4.7 and HADS-anxiety = 6.2 for mental well-being. 7% reported neuropathic pain (PainDETECT). Whilst many adults with XLH reported good outcomes, extreme or severe problems were reported across all outcomes. Cluster analysis identified that adults with XLH could be divided into two distinct groups, one reporting worse (35.3%) and the other better outcomes (64.7%) (less pain, fatigue, depression, and higher levels of sleep). Longitudinal analysis showed that FACIT-F and HADS-anxiety scores worsened slightly over two years with statistically significant (p Conclusion Although about two thirds of adult participants of the RUDY cohort with XLH report good health outcomes, for a considerable third much worse outcomes are reported. More research is needed to examine why some experience good and others poor health outcomes and the characteristics which identify them.

Pseudomonas aeruginosa is one of the most common pathogens related to healthcare-associated infections. The Brazilian isolate, named CCBH4851, is a multidrug-resistant clone belonging to the sequence type 277. The antimicrobial resistance mechanisms of the CCBH4851 strain are associated with the presence of blaSPM-1 gene, encoding a metallo-beta-lactamase, in addition to other exogenously acquired genes. Whole-genome sequencing studies focusing on emerging pathogens are essential to identify physiological key aspects that may lead to the exposure of new targets for therapy. This study was designed to characterize the genome of Pseudomonas aeruginosa CCBH4851 through the detection of genomic features and genome comparison with other Pseudomonas aeruginosa strains. The CCBH4851 closed genome showed features that were consistent with data reported for the specie. However, comparative genomics revealed the absence of genes important for pathogenesis. On the other hand, CCBH4851 genome contained acquired genomic islands that carry additional virulence and antimicrobial resistance-related genes. The presence of single nucleotide polymorphisms in the core genome, mainly those located in resistance-associated genes, suggests that these mutations could influence the multidrug-resistant behavior of CCBH4851. Overall, the characterization of Pseudomonas aeruginosa CCBH4851 complete genome revealed several features that could directly impact the profile of virulence and antibiotic resistance of this pathogen in infectious outbreaks.

Objective Develop and internally validate risk models and a clinical risk score tool to predict incident radiographic knee osteoarthritis (RKOA) in middle-aged women. Methods We analysed 649 women in the Chingford 1000 Women study. The outcome was incident RKOA, defined as Kellgren/Lawrence grade 0-1 at baseline and ≥2 at year 5. We estimated predictors’ effects on the outcome using logistic regression models. Two models were generated. The clinical model considered patient characteristics, medication, biomarkers, and knee symptoms. The radiographic model considered the same factors, plus radiographic factors (e.g., angle between the acetabular roof and ilium’s vertical cortex (hip α-angle)). The models were internally validated. Model performance was assessed using calibration and discrimination (area under the receiver characteristic curve, AUC). Results The clinical model contained age, quadriceps circumference, and a cartilage degradation marker (CTX-II) as predictors (AUC = 0.692). The radiographic model contained older age, greater quadriceps circumference, knee pain, knee baseline Kellgren/Lawrence 1 (versus 0), greater hip α-angle, greater spinal bone mineral density, and contralateral RKOA at baseline as predictors (AUC = 0.797). Calibration tests showed good agreement between the observed and predicted incident RKOA. A clinical risk score tool was developed from the clinical model. Conclusion Two models predicting incident RKOA within 4 years were developed; including radiographic variables improved model performance. First-time predictor hip α-angle and contralateral RKOA suggest osteoarthritis origins beyond the knee. The clinical tool has the potential to help physicians identify patients at risk of RKOA in routine practice, but should be externally validated.

Background: Adhesion of braces to dental enamel is critical for orthodontic treatments, for that purpose, phosphoric acid has been used successfully to prepare dental enamel surface before bonding braces. ER:YAG laser has proved ability to do the same over buccal surfaces of dental enamel, but the increasing interest for lingual orthodontics leaded to the question whether ER:YAG laser can prepare equally palatal and buccal surfaces for bonding lingual braces. Material and methods: 15 teeth that were extracted for clinical purposes were microscopic electronic scanned (MES) before treatment, after phosphoric acid 37%, and after ER:YAG laser irradiated, images of buccal and palatal faces after each treatment were analyzed by image J software. Results: After all treatments enamel surfaces were mostly type 1, no statistically significant differences were found between groups. Conclusion: Phosphoric acid 37% and the used dose of Er:YAG laser can successfully prepare dental enamel surface before bonding braces over buccal and palatal faces of teeth.

Objectives: It has been suggested that metalloproteinase-9 (MMP-9) could predict the onset of cerebral vasospasm after subarachnoidal haemorrhage (SAH). The aim of this study was to analyse, in patients with SAH, the difference between patients with MRI ischaemic infarcts and patients without, and to investigate the role of metalloproteases as a prognostic factor for ischaemic infarcts. Methods: Sixty eight consecutive patients with SAH and diffusion-weighted magnetic resonance imaging (DWI-MRI) done 3 weeks after SAH. We define two groups, with and without DWI-MRI infarcts. Blood samples were taken at entry, 3 days and 1 week MMP-9 was determined through ELISA method. Results: Forty per cent were male, with a mean age of 54 +/- 14 years. Twenty five patients, 36.8%, had DWI-MRI infarcts; in patients with MRI infarcts, SAH was more severe (Fisher=4 52 vs 25.6%, P=0.037), with more morbi-mortality (Rankin>3 48 vs 18.6%, P=0.014), and more symptomatic vasospasm (28 vs 7%, P=0.031). Levels of MMP-9 were higher than controls, but there were no significant differences between patients with and without infarcts (first determination no infarcts 39.40 ng/ml +/- 35.40 vs infarcts 49.75 ng/ml +/- 34.54, P>0.005, 3 days no infarcts 72.10 ng/ml +/- 70.95 vs infarcts 62.28 +/- 33.84, P>0.005, 1 week no infarcts 148.48 ng/ml +/- 142.73 vs infarcts 91.51 ng/ml +/- 41.20, P>0.005). Conclusion: Thirty eight percent in a well-studied series of patients with SAH have DWI-MRI infarcts; the infarcts were associated to SAH severity, SAH outcome and symptomatic vasospasm. Metalloproteinase-9 was higher in SAH patients than in controls, but it could not discriminate the infarct patients.

Purpose of review In this article, we summarize the current knowledge on new roles played by platelets and their interactions with blood components, and their possible implications in malignant hematological disorders. Recent findings Recent reports in the literature are revealing that platelets are important partners in different aspects of physiology and pathophysiology beyond hemostasis and thrombosis, including but not restricted to inflammation, cancer or host defense. Moreover, several studies suggest that platelet interactions with other blood cells could regulate functional and biochemical responses of each other. Finally, platelet alterations in number as well as in function have been observed in different hematological disorders related with the action of treatments. Summary Common complications of leukemia are bleeding and thrombosis, in which the number and activity of platelets undoubtedly play an important role. Probably related with their apparent structural simplicity compared with other hematological cells, the interest in platelets in malignant hematological disorders has been mainly restricted to the determination of the number of circulating platelets. However, different studies have demonstrated that numbers of platelets between 6 and 80 x 10(9) platelets/l are a poor indicator of the risk of bleeding, as this number does not give any information on the functional activity of these platelets.

This paper establishes the methodology to numerically study the vertical axis wind turbine. This procedure is easily applied to water turbines to extract energy from water currents in rivers and seas. The interest of this kind of turbines is based on the low manufacture cost, easy maintenance and can operate with low fluid velocities. The only different between wind and water turbines are the solidity parameter. Computational Fluid Dynamics is an essential tool to model the performance of fluid systems in a previous step to the experimental study. The paper shows the numerical model, the post-process of results to obtain the characteristic curves of the performance of turbines as well as design tendencies when changing solidity. A collateral application could be the calibration of spinning anemometers to measure streams flows. The study of the follow patterns will gain an insight about the performance of the devices.

The optimal dose of aspirin for patients presenting with acute myocardial infarction (AMI) while receiving chronic aspirin therapy has not been clearly established. We evaluated whether continued treatment with 100 mg of aspirin or a loading dose (200-500 mg) influences thromboxane A(2) (TX) suppression or platelet reactivity. Sixty-four consecutive patients with AMI and 98 healthy subjects (82 aspirin-free and 16 receiving 100 mg daily for a week) were evaluated. Treatment was at the discretion of the attending physician. Collagen (1 mu g/ml)induced TX synthesis, C-14-serotonin-release, platelet aggregation, and the PFA-100 assay were evaluated. The platelet TX synthesis of patients receiving a loading dose of aspirin was sixfold lower than that of patients receiving 100 mg of aspirin (p= 95% inhibition vs. healthy aspirin-free subjects) revealed that 8% of the patients treated with loading doses had a poor response (

Background: Platelet inhibition measured by platelet function tests could be critical to understand the reasons for early recurrence and to guide therapeutic recommendations. We assess the platelet function during the acute phase of ischemic stroke in patients pretreated with aspirin who continue their treatment with aspirin only, are started on clopidogrel only, or add clopidogrel to aspirin. Methods: Sixty-four patients were taking aspirin before the stroke. Depending on the administered antiplatelet, 3 groups were defined: ASA: patients who continued on aspirin orally or intravenous acetylsalicylate of lysine, n = 30; CLO: patients who discontinued aspirin and were started on clopidogrel, n = 16; and ASA + CLO: patients who were prescribed both aspirin and clopidogrel, n = 10. Collagen-induced thromboxane A(2) (TXA(2)) synthesis, ADP (adenosine diphosphate)-induced aggregation, and occlusion time (PF-100) were measured. Results: CLO group only had a marked elevation of TXA(2) (17.44 +/- 15.62 ng/mL, P = .000) and a shortening of the platelet function analyzer (PFA)-100 closure time (157.13 +/- 88 seconds, P = .047) compared with the other 2 groups (ASA: TXA(2), .62 +/- 1.59 ng/mL; ASA + CLO: TXA(2) 1.79 +/- 4.59 ng/mL). They achieved a small (13%) but significant reduction of ADP-induced aggregation (87.00 +/- 23.06 mm, P = .008) compared with the ASA group (102.82 +/- 22.38 seconds). Conclusions: Stopping aspirin intake within the first 72 hours of the acute stroke drastically increases TXA(2) synthesis. During the same time window, the freshly prescribed clopidogrel manages to reduce the ADP-induced aggregation only slightly (13%). This study offers analytic proof that the common practice of replacing aspirin with clopidogrel does not leave stroke patients fully protected during the first days after an ischemic stroke. Possible solutions could be to preserve aspirin during a few days or to use loading doses of clopidogrel at hospital admission.

Statins have demonstrated effects beyond reducing cholesterol level that may contribute to their clinical benefit, including effects on platelet biochemistry and function.

The pharmacological target of aspirin is the inhibition of cyclooxygenase-1 (COX1) and thromboxane-A2 (TX) synthesis. Very few data are available on TX assessment in patients with stroke. We studied platelet TX synthesis, COX1-independent platelet reactivity, the influence of platelet-erythrocyte interactions and the potential association between platelet responses and the severity of stroke, evaluated with a clinical score (NIHSS).

We tested the hypothesis that the phytoestrogen genistein protects the brain against ischemic stroke by improving the circulatory function in terms of reduced production of thromboxane A2 and leukocyte-platelet aggregates, and of preserved vascular reactivity. Ischemia-reperfusion (90 min-3 days, intraluminal filament) was induced in male Wistar rats, and functional score and cerebral infarct volume were the end points examined. Genistein (10mg/kg/day) or vehicle (ß-cyclodextrin) was administered at 30 min after ischemia or sham-operation. Production of thromboxane A2 and leukocyte-platelet aggregates, as well as reactivity of carotid artery to U-46619 (thromboxane A2 analogue) and to platelet releasate was measured. At 3 days post-ischemia, both improvement in the functional examination and reduction in the total infarct volume were shown in the ischemic genistein-treated group. Genistein significantly reverted both the increased thromboxane A2 concentration and the increased leukocyte-platelet aggregates production found in samples from the ischemic vehicle-treated group. Both U-46619 and platelet releasate elicited contractions of the carotid artery, which were significantly lower in the ischemic vehicle-treated group. Genistein significantly restored both the decreased U-46619- and the decreased platelet releasate-elicited contractile responses. In conclusion, genistein protects the brain against an ischemia-reperfusion challenge, at least in part, by its beneficial effects on the circulatory function.

Platelets play an important role in both normal hemostasis and pathological thrombus formation. The key role of platelets in thrombosis is highlighted by the clinical benefit of treatment with antiplatelet drugs. Aspirin, either alone or in combination with clopidogrel in high-risk patients, is the most widely used antiplatelet agent. However, there is an individual response to these agents that may reduce the cardiovascular protection in patients who achieve a lower antiplatelet effect. Recently, P2Y12 receptor antagonists more potent than clopidogrel (e.g., prasugrel and ticagrelor) have been approved for patients with acute coronary syndromes and those undergoing percutaneous coronary interventions; these drugs provide greater platelet inhibition than clopidogrel. However, the increased effectiveness of these treatments has underscored the importance of carefully balancing the risks of ischemia and bleeding to achieve the best clinical outcomes. The increased knowledge of the molecular mechanisms of platelet activation has prompted a search for novel pharmacological targets for the inhibition of platelet reactivity. This article reviews the molecular mechanisms of action and limitations of use of current and emerging antiplatelet agents for treatment of cardiovascular disease.

Platelet function of patients with subarachnoid hemorrhage (SAH) may play an important part in both rebleeding and delayed cerebral ischemia, but little is known about aggregation pathways during the acute phase of stroke. Analgesics are used regularly in the first days after bleeding, and some can potentially inhibit the cyclooxygenase (COX) enzyme. We examined the platelet function of patients with SAH in order to describe their basal situation and determine whether the administration of intravenous nonsteroidal antiinflammatory drugs (NSAIDs) affected platelet aggregation.

Inhibition of platelet thromboxane A(2) (TXA(2)) by aspirin is critical in patients with acute myocardial infarction (AMI), but some patients have persistent platelet TXA(2) production within 48 hours of the onset of AMI. Statins are known to reduce TXA(2) in aspirin-free patients with hypercholesterolemia. We hypothesized that treatment with aspirin plus atorvastatin could reduce persistent TXA(2) synthesis and aspirin resistance in patients with AMI. We evaluated platelet function in 184 aspirin-treated patients within 48 hours of the onset of AMI. Patients were divided into group A (treated with aspirin alone, n = 139) and group B (treated with aspirin plus atorvastatin, n = 45). We studied collagen-induced platelet TXA(2) synthesis, serotonin ((14)C-5HT) release and recruitment, and adenosine diphosphate-, arachidonic acid-, and collagen-induced platelet aggregation. Persistent TXA(2) synthesis was detected in 25% and 9% of groups A and B, respectively (p = 0.03). TXA(2), arachidonic acid-aggregation, and collagen-induced responses were significantly reduced in patients receiving dual treatment compared to those receiving aspirin monotherapy. Atorvastatin did not modify platelet reactivity in patients with efficiently blocked TXA(2) synthesis. These results strongly suggest a direct effect of the statin on platelet eicosanoid synthesis. This was confirmed in vitro by incubating washed aspirin-free and aspirin (1 muM)-treated platelets from normal subjects with 1 to 20 microM atorvastatin. Atorvastatin in vitro significantly reduced platelet TXA(2) synthesis and collagen-induced aggregation. In conclusion, atorvastatin combined with aspirin early in the onset of the acute event significantly reduced persistent TXA(2) and TXA(2)-dependent aspirin resistance. This could contribute to the clinical benefit of atorvastatin in patients with AMI.

Heterogeneity in response to aspirin (ASA) treatment, or "aspirin resistance," could be of importance in patients with ST-segment elevation myocardial infarction (STEMI). Decreased effects of ASA in platelets could be due to partial inhibition of cyclo-oxygenase-1 (COX-1) or to COX-1-independent mechanisms. We evaluated the effect of ASA treatment in patients with STEMI for (1) platelet thromboxane A(2) (TXA(2)) synthesis, (2) platelet recruitment elicited by TXA(2)-dependent and -independent mechanisms, and (3) a possible association of these aspects of platelet reactivity with serum markers of myonecrosis. We studied 62 ASA-treated patients within 48 hours of onset of the acute event and 69 ASA-free and 10 ASA-treated controls. TXA(2) synthesis and platelet recruitment (fluid-phase proaggregate activity of cell-free releasate) were assessed after collagen stimulation (1 micro g/ml) of whole blood. Partial inhibition of TXA(2) by ASA was found in 21 patients (34%). This was associated with significant increases in troponin T, creatine kinase-MB mass, creatine kinase, and recruiting activity versus 41 patients with blocked TXA(2) production. This was independent of fibrinolysis, and platelet COX-2 expression was not augmented. TXA(2) blockade was achieved after subsequent daily treatments or platelet incubation with ASA in vitro, suggesting lower sensitivity of COX-1 to ASA. In addition, 28 patients (45%) had an abnormally increased recruiting activity despite TXA(2) blockade, which was also associated with increased myonecrosis. In conclusion, ASA resistance, elicited by TXA(2)-dependent and TXA(2)-independent mechanisms, was prevalent in patients with STEMI. This study describes, for the first time, the association of partial platelet TXA(2) inhibition with myonecrosis.

Activated platelets release biologically active compounds, which then recruit additional platelets into an evolving thrombus. We studied activation of alpha(IIb)beta(3) and exposure of P-selectin on platelets recruited by releasates obtained from collagen-treated platelets and evaluated modifications in prothrombotic effects of releasates induced by platelet-erythrocyte interactions and aspirin treatment. Releasates from collagen-stimulated platelets induced alpha(IIb)beta(3) activation and P-selectin exposure (monitored by flow cytometry using fluorescein isothiocyanate-PAC-1 and phycoerythrin-CD62 antibodies). These responses were markedly amplified by releasates from combined platelet-erythrocyte suspensions. This finding demonstrates a novel mechanism(s) by which erythrocytes intensify platelet aggregability and mediate increased platelet recruitment. Because P-selectin and alpha(IIb)beta(3) are potential sites for platelet-leukocyte interactions, erythrocytes may also modulate leukocyte recruitment. Following aspirin ingestion both the recruiting capacity of platelet releasates and erythrocyte-induced amplification of platelet recruitment were down-regulated. These events represent an additional antithrombotic property of aspirin. We also examined the possibility that arachidonic acid, or eicosanoids derived therefrom, can induce a prothrombotic activity of erythrocytes. The TXA(2)-analog U46 619 and free arachidonate, but not PGI(2) or 12-HETE, induced increases in cytosolic Ca(++) and promoted phosphatidylserine (PS) exposure on a subpopulation of erythrocytes. PS exposure and increases in erythrocyte [Ca(++)](i) are associated with enhanced procoagulant activity, increased endothelial adhesion, and reduced erythrocyte deformability. Our findings, therefore, suggest that TXA(2) and arachidonic acid, derived from activated platelets, induce a prothrombotic phenotype on erythrocytes in proximity. We conclude that by these mechanisms, erythrocytes can actively contribute to platelet-driven thrombogenesis and microvascular occlusion.

Red cell acid phosphatase (ACP1), adenylate kinase 1 (AK1), and aminolevulinate dehydratase (ALAD) polymorphisms were studied in a population sample from Northern Portugal. The gene frequency estimates found were: ACP1*A = 0.2825, ACP1*B = 0.6625, ACP1*C = 0.0547, ACP1*R = 0.0003 (N = 1517); AK1*1 = 0.9778, AK1*2 = 0.0213, AK1*3 = 0.0009 (N = 1081); ALAD*1 = 0.9094, ALAD*2 = 0.0906 (N = 1043).

OBJECTIVE: To determine whether visual evoked potentials (VEP) change, and to what degree, in different types of headache (migraine with or without aura, or tension headache). PATIENTS AND METHODS: We made a transversal study of 78 children (aged 3-14 years) studied between March 1997 and August 1998, classified into three groups according to HIS diagnostic criteria of 1988 and HIS-R 1997. A VEP of geometric pattern was done using the recording technique recommended by the International Society in their standards for VEP and the reference values were used for an amplitude of less than 5 microV and a latency of P100 +/- 15 ms. The qualitative variable was frequency, and the quantitative variables were the mean and the standard deviation. We studied the association between qualitative variables using the chi-squared test and the differences in means between the groups with ANOVA. All differences were considered to be statistically significant when p < 0.05. RESULTS: Girls made up 55%, with an average age of 8.84 years and a standard deviation of 3 years. There were no statistically significant differences in the mean of the VEP findings between the different types of headache with regard to amplitude (p = 0.975) and latency (p = 0.941). Neither were there any significant differences in the response to VEP in the different types of headache as far as sex and age were concerned, with p = 0.268 and p = 0.147 respectively. CONCLUSION: Our results show no statistically significant differences and do not support the idea of using VEP as a neurophysiological method for studying headaches and differentiating the various types.