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1.
Clin Exp Dermatol ; 43(3): 300-302, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29277927

ABSTRACT

We report a 23-year-old immunocompromised woman who, following cardiac transplantation, presented with an unusual cutaneous eruption. She developed a widespread pustular rash, systemic symptoms and a high temperature with raised inflammatory markers. The diagnosis was reached when a skin biopsy was cultured onto Legionella agar (buffered charcoal yeast extract) and Legionella feeleii was isolated. The patient was treated with 6 weeks of moxifloxacin and her cutaneous lesions gradually resolved. Cutaneous Legionella infections are uncommon and usually affect immunocompromised patients.


Subject(s)
Immunocompromised Host , Legionella/isolation & purification , Legionellosis/microbiology , Skin Diseases, Bacterial/microbiology , Biopsy , Diagnosis, Differential , Female , Heart Transplantation , Humans , Legionella/classification , Legionellosis/diagnosis , Skin/microbiology , Skin/pathology , Skin Diseases, Bacterial/diagnosis , Young Adult
2.
Am J Transplant ; 18(4): 916-926, 2018 04.
Article in English | MEDLINE | ID: mdl-28980446

ABSTRACT

The classical pathway (CP) of complement may contribute to the pathogenesis of antibody-mediated rejection (ABMR). Selective CP blockade may be a promising strategy to counteract rejection. The objective of this first-in-patient phase 1b trial was to evaluate the safety/tolerability and CP-blocking potential of 4 weekly doses (60 mg/kg) of the anti-C1s antibody BIVV009 in complement-mediated disorders. Here we describe the results in a cohort of 10 stable kidney transplant recipients (median of 4.3 years posttransplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement-fixing donor-specific antibodies (DSA). During 7 weeks follow-up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA-triggered CP activation in serum. Five of 8 C4d-positive recipients turned C4d-negative in 5-week follow-up biopsies, while another 2 recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody-triggered CP activation, even though short-course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials.gov NCT#02502903.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Complement C1s/immunology , Graft Rejection/drug therapy , Graft Survival/drug effects , Isoantibodies/adverse effects , Kidney Failure, Chronic/surgery , Kidney Transplantation/adverse effects , Adult , Aged , Allografts , Complement Activation/immunology , Female , Follow-Up Studies , Glomerular Filtration Rate , Graft Rejection/etiology , Graft Rejection/pathology , Graft Survival/immunology , HLA Antigens/immunology , Humans , Kidney Function Tests , Male , Middle Aged , Postoperative Complications , Prognosis , Prospective Studies , Risk Factors , Tissue Donors
3.
Nano Lett ; 17(11): 6696-6701, 2017 11 08.
Article in English | MEDLINE | ID: mdl-29052998

ABSTRACT

Structural quality and stability of nanocrystals are fundamental problems that bear important consequences for the performances of small-scale devices. Indeed, at the nanoscale, their functional properties are largely influenced by elastic strain and depend critically on the presence of crystal defects. It is thus of prime importance to be able to monitor, by noninvasive means, the stability of the microstructure of nano-objects against external stimuli such as mechanical load. Here we demonstrate the potential of Bragg coherent diffraction imaging for such measurements, by imaging in 3D the evolution of the microstructure of a nanocrystal exposed to in situ mechanical loading. Not only could we observe the evolution of the internal strain field after successive loadings, but we also evidenced a transient microstructure hosting a stable dislocation loop. The latter is fully characterized from its characteristic displacement field. The mechanical behavior of this small crystal is clearly at odds with what happens in bulk materials where many dislocations interact. Moreover, this original in situ experiment opens interesting possibilities for the investigation of plastic deformation at the nanoscale.

4.
Am J Transplant ; 17(9): 2300-2311, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28251805

ABSTRACT

The classic pathway (CP) of complement is believed to significantly contribute to alloantibody-mediated transplant injury, and targeted complement inhibition is currently considered to be a promising approach for preventing rejection. Here, we investigated the mode of action and efficacy of the humanized anti-C1s monoclonal antibody TNT009 and its parental mouse variant, TNT003, in preclinical in vitro models of HLA antibody-triggered CP activation. In flow cytometric assays, we measured the attachment of C1 subcomponents and C4/C3 split products (C4b/d, C3b/d) to HLA antigen-coated flow beads or HLA-mismatched aortic endothelial cells and splenic lymphocytes. Anti-C1s antibodies profoundly inhibited C3 activation at concentrations >20 µg/mL, in both solid phase and cellular assays. While C4 activation was also prevented, this was not the case for C1 subcomponent attachment. Analysis of serum samples obtained from 68 sensitized transplant candidates revealed that the potency of inhibition was related to the extent of baseline CP activation. This study demonstrates that anti-C1s antibodies TNT009 and TNT003 are highly effective in blocking HLA antibody-triggered complement activation downstream of C1. Our results provide the foundation for clinical studies designed to investigate the potential of TNT009 in the treatment or prevention of complement-mediated tissue injury in sensitized transplant recipients.


Subject(s)
Antibodies, Monoclonal/pharmacology , Complement Activation/immunology , Complement C1s/immunology , Graft Rejection/drug therapy , HLA Antigens/immunology , Isoantibodies/adverse effects , Kidney Transplantation/adverse effects , Animals , Follow-Up Studies , Glomerular Filtration Rate , Graft Rejection/etiology , Graft Survival , Humans , Kidney Failure, Chronic/immunology , Kidney Failure, Chronic/surgery , Kidney Function Tests , Mice , Prognosis
5.
Transplant Proc ; 48(10): 3387-3392, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27931586

ABSTRACT

BACKGROUND: Methotrexate (MTX) is potential change in immunosuppression after lung transplantation that may help to slow down the decline in lung function in bronchiolitis obliterans syndrome (BOS). METHODS: We sought to analyze the safety and efficacy of MTX in patients with BOS, by retrospective case review. RESULTS: Thirty lung allograft patients were treated with MTX for BOS after one bilateral lower lobe, nine single, 16 bilateral, and four heart-lung transplants. Twenty-one patients had MTX treatment for a minimum of 6 months, and their serial lung function was analyzed for efficacy. In these patients, there was a significant overall increase in mean forced expiratory volume in 1 second (FEV1) of 149 mL (P < .02) at 3 months, with an increase observed in 14 of 21 patients. At 6 months, there was a mean increase in FEV1 of 117 mL (P < .05). At 12 months, there was a mean non-significant increase of FEV1 of 60 mL (P = .19) observed in 18 patients who had MTX for this time period. The rate of decline in FEV1 before MTX was 118.5 mL/month and at 3 months after MTX increased to 49.5 mL/months (P < .0005) in the FEV1. Nine patients had been treated with MTX for less than 6 months; two died within 6 months of starting MTX, five tolerated the drug poorly with nausea and tiredness, and one developed leucopenia. One patient requested discontinuation of the medication after failing to halt the rapid progressive decline in lung function after 1 month. CONCLUSIONS: Methotrexate therapy provides a potential therapeutic strategy in managing the progressive decline in lung function observed in BOS. This is hampered by the observation of poor tolerability and side effects.


Subject(s)
Bronchiolitis Obliterans/drug therapy , Immunosuppression Therapy/methods , Immunosuppressive Agents/administration & dosage , Lung Transplantation/adverse effects , Methotrexate/administration & dosage , Adolescent , Adult , Bronchiolitis Obliterans/etiology , Bronchiolitis Obliterans/physiopathology , Female , Forced Expiratory Volume , Humans , Leukopenia/etiology , Lung/physiopathology , Male , Middle Aged , Respiratory Function Tests , Retrospective Studies , Treatment Outcome , Young Adult
6.
Philos Trans A Math Phys Eng Sci ; 374(2066)2016 Apr 28.
Article in English | MEDLINE | ID: mdl-27002070

ABSTRACT

I discuss various mathematical constructions that combine together to provide a natural setting for discrete and continuum geometric models of defective crystals. In particular, I provide a quite general list of 'plastic strain variables', which quantifies inelastic behaviour, and exhibit rigorous connections between discrete and continuous mathematical structures associated with crystalline materials that have a correspondingly general constitutive specification.

7.
BJOG ; 123(4): 588-97, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26542419

ABSTRACT

OBJECTIVE: To assess whether antenatal exercise in overweight/obese women would improve maternal and perinatal outcomes. DESIGN: Two-arm parallel randomised controlled trial. SETTING: Home-based intervention in Auckland, New Zealand. POPULATION AND SAMPLE: Pregnant women with body mass index ≥25 kg/m(2) . METHODS: Participants were randomised to a 16-week moderate-intensity stationary cycling programme from 20 weeks of gestation, or to a control group with no exercise intervention. MAIN OUTCOME MEASURES: Primary outcome was offspring birthweight. Perinatal and maternal outcomes were assessed, with the latter including weight gain, aerobic fitness, quality of life, pregnancy outcomes, and postnatal body composition. Exercise compliance was recorded with heart rate monitors. RESULTS: Seventy-five participants were randomised in the study (intervention 38, control 37). Offspring birthweight (adjusted mean difference 104 g; P = 0.35) and perinatal outcomes were similar between groups. Aerobic fitness improved in the intervention group compared with controls (48.0-second improvement in test time to target heart rate; P = 0.019). There was no difference in weight gain, quality of life, pregnancy outcomes or postnatal maternal body composition between groups. However, compliance with exercise protocol was poor, with an average of 33% of exercise sessions completed. Sensitivity analyses showed that greater compliance was associated with improved fitness (increased test time (P = 0.002), greater VO2 peak (P = 0.015), and lower resting heart rate (P = 0.014)), reduced postnatal adiposity (reduced fat mass (P = 0.007) and body mass index (P = 0.035)) and better physical quality of life (P = 0.034). CONCLUSIONS: Maternal non-weight-bearing moderate-intensity exercise in pregnancy improved fitness but did not affect birthweight or clinical outcomes. TWEETABLE ABSTRACT: Moderate-intensity exercise in overweight/obese pregnant women improved fitness but had no clinical effects.


Subject(s)
Exercise Therapy , Obesity/therapy , Overweight/therapy , Pregnant Women , Prenatal Care , Adult , Body Mass Index , Female , Humans , New Zealand/epidemiology , Obesity/epidemiology , Obesity/prevention & control , Overweight/epidemiology , Overweight/prevention & control , Patient Compliance , Pregnancy , Pregnancy Outcome , Pregnant Women/psychology , Quality of Life , Risk Reduction Behavior , Treatment Outcome , Weight Gain
8.
Am J Transplant ; 15(8): 2037-49, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25904443

ABSTRACT

Antibody-mediated rejection (AMR) of solid organ transplants (SOT) is characterized by damage triggered by donor-specific antibodies (DSA) binding donor Class I and II HLA (HLA-I and HLA-II) expressed on endothelial cells. While F(ab')2 portions of DSA cause cellular activation and proliferation, Fc regions activate the classical complement cascade, resulting in complement deposition and leukocyte recruitment, both hallmark features of AMR. We characterized the ability of an anti-C1s monoclonal antibody, TNT003, to inhibit HLA antibody (HLA-Ab)-induced complement activation. Complement deposition induced by HLA-Ab was evaluated using novel cell- and bead-based assays. Human aortic endothelial cells (HAEC) were cultured with HLA-Ab and human complement; production of activated complement proteins was measured by flow cytometry. Additionally, C3d deposition was measured on single antigen beads (SAB) mixed with HLA-Ab and human complement. TNT003 inhibited HLA-Ab mediated complement deposition on HAEC in a concentration-dependent manner; C3a, C4a and C5a anaphylatoxin production was also diminished by TNT003. Finally, TNT003 blocked C3d deposition induced by Class I (HLAI-Ab)- and Class II (HLAII-Ab)-specific antibodies on SAB. These data suggest TNT003 may be useful for modulating the effects of DSA, as TNT003 inhibits complement deposition and split product formation generated by HLA-I/II-Ab in vitro.


Subject(s)
Antibodies, Monoclonal/immunology , Complement Activation/immunology , Complement C1s/immunology , HLA Antigens/immunology , Cells, Cultured , Endothelium, Vascular/cytology , Endothelium, Vascular/immunology , Heart Transplantation , Humans
9.
Article in English | MEDLINE | ID: mdl-25679631

ABSTRACT

The formation of donut- and croissantlike buckles has been observed onto the free surface of gold thin films deposited on silicon substrates. Numerical simulations clearly evidence that the coupling effect between the atmospheric pressure acting on the free surface and the plastic folding of the ductile film is responsible for the circular blister destabilization and the formation of the donut- and croissantlike buckling patterns.

10.
J Mech Behav Biomed Mater ; 10: 183-96, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22520430

ABSTRACT

In this paper an analytical solution for the stress state in a coated stent is presented, with a particular focus on the interface stresses between the coating and stent. As a first step a simplified stent architecture consisting of a bi-layered composite elastic arch is considered. The variations of normal and shear stress at the interface as functions of the boundary conditions at the base of the arch are explored. Depending on applied displacement and rotation, very distinct distributions of stress occur along the interface: dominant shear or dominant normal stress, compressive or tensile normal stress. A bi-layered composite elastic strut is then added to the composite elastic arch in order to create a realistic coated stent geometry. A displacement is applied to the bottom of the strut to simulate stent deployment. The addition of the strut is found to increase the normal stress and decrease the shear stress at all points on the interface. The influence of the various geometrical and material parameters on interface stress is explored using the analytical procedure developed in the paper, providing practical insight for stent-coating design.


Subject(s)
Coated Materials, Biocompatible/chemistry , Stents , Stress, Mechanical , Elasticity , Equipment Design , Rotation , Shear Strength
11.
Health Technol Assess ; 14(44): 1-107, iii-iv, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20863477

ABSTRACT

BACKGROUND: Postnatal depression (PND) describes a wide range of distressing symptoms that can occur in women following childbirth. There is substantial evidence to support the use of cognitive behaviour therapy (CBT) in the treatment of depression, and psychological therapies are recommended by the National Institute for Health and Clinical Excellence as a first-line treatment for PND. However, access is limited owing to expense, waiting lists and availability of therapists. Group CBT may, therefore, offer a solution to these problems by reducing therapist time and increasing the number of available places for treatment. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of group CBT compared with currently used packages of care for women with PND. DATA SOURCES: Seventeen electronic bibliographic databases were searched (for example MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, etc.), covering biomedical, health-related, science, social science and grey literature (including current research). Databases were searched from 1950 to January 2008. In addition, the reference lists of relevant articles were checked and various health services' related resources were consulted via the internet. REVIEW METHODS: The study population included women in the postpartum period (up to 1 year), meeting the criteria of a standardised PND diagnosis using the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, or scoring above cut-off on the Edinburgh Postnatal Depression Scale (EPDS). No exclusion was made on the basis of the standardised depression screening/case finding instrument of standardised clinical assessment tool used to define PND. All full papers were read by two reviewers (AS and DS) who made independent decisions regarding inclusion or exclusion, and consensus, where possible, was obtained by meeting to compare decisions. In the event of disagreement, a third reviewer (EK) read the paper and made the decision. All data from included quantitative studies were extracted by one reviewer (AS) using a standardised data extraction form. All data from included qualitative studies were extracted by two reviewers (AS and AB) using a standardised data extraction form with disagreements resolved by discussion. Two different data extraction forms were used, one for the quantitative papers and a second for the qualitative papers. RESULTS: Six studies met the inclusion criteria for the quantitative review. Three were randomised controlled trials (RCTs) and three were non-randomised trials. Two studies met the inclusion criteria for the qualitative review. These were both treatment evaluations incorporating qualitative methods. Only one study was deemed appropriate for the decision problem; therefore a meta-analysis was not performed. This study indicated that the reduction in the EPDS score through group CBT compared with routine primary care (RPC) was 3.48 [95% confidence interval (CI) 0.23 to 6.73] at the end of the treatment period. At 6-month follow-up the relative reduction in EPDS score was 4.48 (95% CI 1.01 to 7.95). Three studies showed the treatment to be effective in reducing depression when compared to RPC, usual care or waiting list groups. There was no adequate evidence on which to assess group CBT compared with other treatments for PND. Two studies of group CBT for PND were included in the qualitative review. Both studies demonstrated patient acceptability of group CBT for PND, although negative feelings towards group CBT were also identified. A de novo economic model was constructed to assess the cost-effectiveness of group CBT. The base-case results indicated a cost per quality-adjusted life-year (QALY) of 46,462 pounds for group CBT compared with RPC. The 95% CI for this ratio ranged from 37,008 to 60,728 pounds. There was considerable uncertainty in the cost per woman of running a CBT course, of the appropriateness of efficacy data to the decision problem, and the residual length of benefit associated with group CBT. These were tested using univariate sensitivity analyses. Supplementary analyses that fitted distributions to the cost of treatment and the duration of comparative advantage reported a cost per QALY of 36,062 pounds (95% CI 20,464 to 59,262 pounds). LIMITATIONS: The cost per QALY ratio for group CBT in PND was uncertain because of gaps in the evidence base. There was little quantitative or qualitative RCT evidence to assess the effectiveness of group CBT for PND. The evidence that was available was of low quality in the main because of poor reporting of the results. Furthermore, little information was reported on concurrent treatment used in the studies, which was controlled for in only two of the studies. CONCLUSIONS: Evidence from the clinical effectiveness review provided inconsistent and low quality information on which to base any interpretations for service provision. Although three of the included studies provided some indication that group psycho-education incorporating CBT is effective compared with RPC, there is enough doubt in the quality of the study, the level of CBT implemented in the group programmes, and the applicability to a PND population to limit any interpretations significantly. It is also considered that the place of group CBT in a stepped care programme needs to be identified, as well as there being a need for a clearer referral process for group CBT.


Subject(s)
Cognitive Behavioral Therapy/economics , Cognitive Behavioral Therapy/methods , Depression, Postpartum/therapy , Psychotherapy, Group/economics , Psychotherapy, Group/methods , State Medicine/economics , Cost-Benefit Analysis , Depression, Postpartum/diagnosis , Depression, Postpartum/economics , Female , Humans , United Kingdom
12.
Arch Dis Child ; 95(11): 883-7, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20656734

ABSTRACT

BACKGROUND: Survival following cardiac transplantation in infancy has improved substantially. There is a growing shortage of donors, the impact of which may be offset by increase in ABO-incompatible transplants, size-mismatching and mechanical support. The authors reviewed their results and outcomes following infant listing for cardiac transplantation over 22 years. METHODS: Children <12 months at time of listing for cardiac transplant in 1987-2008 were identified using the departmental cardiopulmonary transplant database. Details were obtained from databases and hospital medical records and subdivided into two eras, 1987-1997 and 1998-2008. RESULTS: In 1987-2008, 49 infants were listed, and 28 (57%) underwent cardiac transplantation (12 in 1987-1997 and 16 in 1998-2008). 15 patients (31%) died on the waiting list, 6 patients were delisted (5 of these because of recovery of cardiac function). There was a decrease in suitable donor offers from a mean of 36 per year in 1996-2000 to 11 per year in 2001-2006 (p=0.008). In 1998-2008, nine listed infants were on mechanical support; there were seven ABO-incompatible transplants, and all transplants were size-mismatched with donors on average 2.7 times heavier than recipients. Waiting times decreased from median 83 to 47 days. Six (21%) of the transplanted patients died, the majority in 1987-1997 and perioperatively. CONCLUSIONS: There has been a fall in suitable donors for infant cardiac transplants over time despite increased demand. However, the introduction of size-mismatching, ABO-incompatible transplants and mechanical support has enabled an increase in the number of transplants to be carried out despite this fall in donor numbers. Outcomes following transplantation have improved over time.


Subject(s)
Heart Transplantation/methods , Tissue Donors/supply & distribution , ABO Blood-Group System , Blood Group Incompatibility , Body Weight , Cardiomyopathies/surgery , Epidemiologic Methods , Extracorporeal Membrane Oxygenation , Female , Heart Defects, Congenital/surgery , Heart-Assist Devices , Humans , Immunosuppression Therapy/methods , Infant , Infant, Newborn , Male , Treatment Outcome , United Kingdom , Waiting Lists
13.
Heart ; 96(15): 1217-22, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20639237

ABSTRACT

BACKGROUND: Due to increasing success with repair or palliation in childhood, there is a rapidly growing population of adult patients with complex congenital heart disease who may require transplantation. There remains little data on outcomes of cardiac transplantation in this group. METHODS: 38 orthotopic cardiac transplants were performed in 37 patients (18 men) > or =18 years of age with congenital heart disease (CHD) from 1988 to 2009 in our institution. Outcomes were reviewed using medical records and transplant databases. RESULTS: 15 patients (41%) had univentricular and 22 (59%) biventricular physiology. The biggest group was transposition of the great arteries following atrial switch in eight patients (22%). Six (16%) had no previous surgical intervention. Mean age at transplant was 33.5 years (range 19.1-59.9 years). 11 patients (30%) required additional surgical procedures at transplant. 16 (43%) died, 12 early and 4 late deaths (1.8, 2.4, 2.7 and 7 years). Survival was 70% at 30 days, 68% at 1 year, 58% at 5 years and 53% at 10 and 15 years. Outcome improved in later eras with reduction in 30-day mortality from 50% to 18% and increase in 5-year survival from 50% to 69%. Two patients developed post-transplant lymphoproliferative disease. None required long-term renal replacement therapy. One patient was re-transplanted for cardiac allograft vasculopathy. CONCLUSIONS: While operative mortality following cardiac transplantation for adult congenital heart disease is higher than for other diagnostic groups, long-term survival is good and comparable to patients without CHD. Disappointing early results are improved with increasing experience.


Subject(s)
Heart Defects, Congenital/surgery , Heart Transplantation , Adult , Cause of Death , Female , Heart Defects, Congenital/diagnosis , Humans , Immunosuppression Therapy/methods , Male , Middle Aged , Patient Selection , Postoperative Care/methods , Prognosis , Reoperation , Survival Analysis , Treatment Outcome , Young Adult
14.
Int J Clin Pract ; 64(7): 892-9, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20584222

ABSTRACT

AIMS: To determine which factors predict outcomes in a group of patients with advanced heart failure, and in particular if NT-proBNP provides additional clinical and prognostic information to other haemodynamic and biochemical data. METHODS AND RESULTS: Ninety-one patients were studied who were being evaluated for heart transplantation, with 166 assessments. The patients had advanced heart failure as determined by median cardiac index of 2.0 l/min/m(2), left ventricular end-diastolic diameter of 7.0 mm and levels of NT-proBNP of 2473 pg/ml. Median follow-up time was 359 days. Clinicians were blinded to NT-proBNP levels. NT-proBNP significantly correlated with cardiac index (R = -0.44, p < 0.001), right atrial pressure (R = 0.40, p < 0.001), pulmonary arterial wedge pressure (R = 0.38, p < 0.001) and albumin (R = -0.52, p < 0.001), and total bilirubin with right atrial pressure (R = 0.59, p < 0.001). Cardiac index was the most important independent predictor of outcome (p = 0.0001), although bilirubin (p = 0.001) and NT-proBNP (p < 0.05) were also significant. In patients with a 50% increase in NT-proBNP, 64% had adverse outcomes, whereas those in whom levels were stable, 22% had adverse outcomes (p < 0.05). CONCLUSION: Cardiac index is the primary independent predictor of outcome in advanced heart failure when haemodynamic deterioration is evident. In situations where invasive haemodynamics are not available, total bilirubin (reflecting hepatic congestion) and NT-proBNP (related to haemodynamics) also provide important prognostic information.


Subject(s)
Heart Failure/surgery , Natriuretic Peptide, Brain/metabolism , Peptide Fragments/metabolism , Biomarkers/metabolism , Female , Heart Failure/blood , Heart Transplantation , Hemodynamics/drug effects , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Treatment Outcome
15.
J Med Genet ; 47(9): 601-7, 2010 Sep.
Article in English | MEDLINE | ID: mdl-19939853

ABSTRACT

BACKGROUND: Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype. METHODS AND RESULTS: Based on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA. CONCLUSIONS: Together with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.


Subject(s)
Brachial Plexus Neuritis/enzymology , Brachial Plexus Neuritis/genetics , Chromosome Duplication/genetics , Septins/genetics , Base Pairing/genetics , Base Sequence , DNA Mutational Analysis , Exons/genetics , Female , Humans , Male , Molecular Sequence Data , Pedigree , Recurrence
16.
Qual Saf Health Care ; 18(6): 462-6, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19955458

ABSTRACT

OBJECTIVES: To measure the patient safety attitudes of trainee physicians at an academic paediatric hospital. DESIGN: Cross-sectional survey. SETTING: An academic paediatric hospital. PARTICIPANTS: 209 trainee physicians based at the academic paediatric hospital in January 2004. MAIN OUTCOME MEASURES: Patient safety attitudes of trainee physicians measured using the Safety Attitudes Questionnaire (Inpatient Version) and a specific trainee survey. RESULTS: In the Safety Attitudes Questionnaire, responses were most positive in areas associated with independent care: job satisfaction (mean factor score = 77.5) safety climate (76.1), working conditions (75.6), perception of management (70.4) and less positively in areas associated with interdependent care: teamwork climate (64.6) and stress recognition (59.1). In the trainee survey, following a principal component analysis to identify summary factors, responses were most positive in the independent areas of clinical supervision and support (75.0), communication with their immediate senior physician (65.5) and orientation of new personnel (63.9), and less positive in the interdependent areas of handoffs and multiple services, (58.1), role identification during codes (51.0) and support following an adverse event (42.8). The combined independent factor scores were higher than the interdependent (difference = 17.9, 95% CI 16.1 to 19.7, p<0.001). Fellows reported higher independent factor scores than residents (5.5, 95% CI 2.2 to 8.9, p = 0.001), but not for the interdependent scores (-0.5, 95% CI -3.6 to 2.7, p = 0.767). CONCLUSIONS: Trainees appear comfortable with caring independently for patients but less so caring interdependently. With experience, trainee physicians may experience improvement in their ability to act independently but not interdependently. Recently developed patient safety culture instruments may enable additional understanding of what could be implemented to make improvements.


Subject(s)
Attitude of Health Personnel , Internship and Residency , Pediatrics/education , Safety Management , Academic Medical Centers , Adult , Cross-Sectional Studies , Female , Hospitals, Pediatric , Humans , Job Satisfaction , Male , Organizational Culture , Professional-Patient Relations , Surveys and Questionnaires
17.
Proc Natl Acad Sci U S A ; 106(52): 22540-5, 2009 Dec 29.
Article in English | MEDLINE | ID: mdl-20018756

ABSTRACT

Auxin regulates most aspects of plant growth and development. The hormone is perceived by the TIR1/AFB family of F-box proteins acting in concert with the Aux/IAA transcriptional repressors. Arabidopsis plants that lack members of the TIR1/AFB family are auxin resistant and display a variety of growth defects. However, little is known about the functional differences between individual members of the family. Phylogenetic studies reveal that the TIR1/AFB proteins are conserved across land plant lineages and fall into four clades. Three of these subgroups emerged before separation of angiosperms and gymnosperms whereas the last emerged before the monocot-eudicot split. This evolutionary history suggests that the members of each clade have distinct functions. To explore this possibility in Arabidopsis, we have analyzed a range of mutant genotypes, generated promoter swap transgenic lines, and performed in vitro binding assays between individual TIR1/AFB and Aux/IAA proteins. Our results indicate that the TIR1/AFB proteins have distinct biochemical activities and that TIR1 and AFB2 are the dominant auxin receptors in the seedling root. Further, we demonstrate that TIR1, AFB2, and AFB3, but not AFB1 exhibit significant posttranscriptional regulation. The microRNA miR393 is expressed in a pattern complementary to that of the auxin receptors and appears to regulate TIR1/AFB expression. However our data suggest that this regulation is complex. Our results suggest that differences between members of the auxin receptor family may contribute to the complexity of auxin response.


Subject(s)
Arabidopsis Proteins/metabolism , Arabidopsis/growth & development , Arabidopsis/metabolism , F-Box Proteins/metabolism , Plant Proteins/metabolism , Receptors, Cell Surface/metabolism , Arabidopsis/genetics , Arabidopsis Proteins/genetics , F-Box Proteins/genetics , Gene Expression Regulation, Plant , Genes, Plant/drug effects , Indoleacetic Acids/metabolism , Indoleacetic Acids/pharmacology , MicroRNAs/genetics , Mutation , Plant Proteins/genetics , Plant Roots/growth & development , Plant Roots/metabolism , Plants, Genetically Modified , RNA, Plant/genetics , Receptors, Cell Surface/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism
18.
J Neurol Sci ; 277(1-2): 1-8, 2009 Feb 15.
Article in English | MEDLINE | ID: mdl-19091330

ABSTRACT

To develop diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), a retrospective series of patients' records diagnosed by sexpert consensus as CIDP or other chronic polyneuropathies were analyzed. Classification and regression tree analysis was applied to 150 patients to derive a classification rule. According to the rule, diagnosis of CIDP required that a patient have a chronic non-genetic polyneuropathy, progressive for at least eight weeks, without a serum paraprotein and either 1) recordable compound muscle action potentials in > or =75% of motor nerves and either abnormal distal latency in >50% of nerves or abnormal motor conduction velocity in >50% of nerves or abnormal F wave latency in >50% of nerves; or 2) symmetrical onset of motor symptoms, symmetrical weakness of four limbs, and proximal weakness in > or =1 limb. When validated in 117 patients, the rule had 83% sensitivity (95% confidence interval 69%-93%) and 97% specificity (95% confidence interval 89%-99%) and performed better than published criteria.


Subject(s)
Diagnostic Techniques, Neurological/standards , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Humans , Practice Guidelines as Topic , Reproducibility of Results , Sensitivity and Specificity
19.
Arch Dis Child ; 94(3): 210-5, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19106117

ABSTRACT

OBJECTIVE: The purpose of this work was to investigate the incidence rate for admission and mortality of children receiving paediatric intensive care in relation to socioeconomic status and ethnicity in England and Wales. DESIGN: National cohort of sequential hospital admissions. SETTING: Twenty nine paediatric intensive care units in England and Wales. PARTICIPANTS: All children aged under 16 years admitted to paediatric intensive care in the 4 years 2004-2007. MAIN OUTCOME MEASURES: Incidence rates for admission and odds ratios (OR) for risk-adjusted mortality by an area based measure of deprivation (Townsend score) and ethnic group (south Asian vs non-south Asian determined using two-name analysis algorithms). RESULTS: The incidence for south Asian children was higher than that of non-south Asian children (138 vs 95/100,000, incidence rate ratio 1.36, 95% CI 1.32 to 1.40). The age-sex standardised incidence for children admitted to paediatric intensive care ranged from 69/100,000 in the least deprived fifth of the population to 124/100,000 in the most deprived fifth. The risk-adjusted OR for mortality for south Asian children was 1.36 (95% CI 1.18 to 1.57) overall, rising to 2.40 (95% CI 1.40 to 4.10) in the least deprived fifth of the population when a statistical interaction term for deprivation was included. CONCLUSIONS: In England and Wales, the admission rate to paediatric intensive care is higher for children from more deprived areas and 36% higher for children from the south Asian population. Risk-adjusted mortality increases in south Asian children as deprivation decreases.


Subject(s)
Critical Illness/epidemiology , Adolescent , Age Distribution , Asian People/statistics & numerical data , Child , Child, Preschool , England/epidemiology , Epidemiologic Methods , Female , Hospitalization/statistics & numerical data , Humans , Infant , Infant, Newborn , Intensive Care Units/statistics & numerical data , Male , Poverty Areas , Sex Distribution , Socioeconomic Factors , Wales/epidemiology
20.
Atherosclerosis ; 202(2): 612-6, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18589426

ABSTRACT

INTRODUCTION: Increasing age is associated with reduced numbers of circulating endothelial progenitor cells (EPCs). It is unclear whether this relates to depletion or impairment of bone marrow progenitors, or to deficient mobilization signals from aging tissues. In cardiac transplant patients, one previous study has reported an association between circulating EPCs and the risk of cardiac allograft vasculopathy (CAV). We investigated whether increased donor heart age, a strong risk factor for CAV, was associated with reduced circulating EPC numbers in a group of cardiac transplant recipients matched for factors which influence EPC numbers, but with maximally discordant donor heart ages. METHODS: We identified 32 patient pairs, matched for factors known to influence EPC numbers, but who had discordant donor heart ages by at least 20 years. EPCs were quantified using flow cytometry for absolute counts of cells expressing all the combinations of CD45, CD34, CD133 and the kinase domain receptor (KDR). RESULTS: There were no significant differences in the numbers of circulating EPCs between patients with old or young donor heart age. There was no association between the presence of CAV and circulating EPC numbers. CONCLUSIONS: We suggest that the increased susceptibility to CAV of older donor hearts is not mediated via circulating EPCs. Our results are consistent with the theory that the normal age-related decline in EPC numbers relates to bone marrow aging rather than failure of target tissues to induce EPC mobilization.


Subject(s)
Endothelium, Vascular/cytology , Heart Transplantation/statistics & numerical data , Hematopoietic Stem Cells/cytology , Postoperative Complications/epidemiology , Vascular Diseases/epidemiology , Adult , Age Distribution , Aged , Cell Count , Cohort Studies , Female , Flow Cytometry , Humans , Male , Middle Aged , Risk Factors , Tissue Donors , Transplantation, Homologous
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