Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Correction: FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer.

In the published version of this article, the images for cytoplasmic and nuclear FGF7 in MDA-MB-231 cells were duplicated and mistaken for total FGF7 in SKBR-3 and MDA-MB-231 cells.

Radiological progression of end colostomy trephine diameter and area.

Background: Development of a parastomal hernia is common following abdominoperineal excision (APE). The true incidence is difficult to assess fully owing to differing lengths of follow-up and techniques used to assess herniation; radiological or clinical. The primary aim of this study was to evaluate colostomy diameter by studying the rate of change of axial and sagittal trephine diameters, trephine area, and the ratio of the trephine over time. A secondary aim was to investigate variation in trephine area and variables affecting parasternal hernia over time. Methods: Serial CT scans performed after APE from January 2006 to December 2014 were reviewed. Variables analysed included age, sex, trephine position relative to rectus abdominis muscle (RAM), type of incision for stoma creation, and axial and sagittal trephine diameters measured on follow-up CT. A Bayesian hierarchical modelling framework was used to examine the relationship of trephine diameters, area and ratio over time. Results: Of 112 patients undergoing APE, 103 were eligible for analysis; this included 91 colostomies (88·3 per cent) through the RAM and 12 (11·7 per cent) lateral to the RAM. Median age of the patients was 68 years. Sixty patients (58·3 per cent) had a circular and 43 (41·7 per cent) a cruciate incision for stoma creation. The sagittal trephine diameter increased by 0·22 (95 per cent credible interval 0·12 to 0·32) mm/month for both sexes. Women reported a significant increase in axial trephine diameters; the male : female ratio difference was -0·17 (-0·30 to -0·03) mm/month and for trephine areas -6·21 (0·96 to 13·7) mm2/month. Patient age, colostomy trephine location and shape of incision were not statistically significant variables for parasternal hernia. Conclusion: Female sex was the only variable affecting the rate of increase in axial trephine diameter and trephine area over time.

Sleep interventions for osteoarthritis and spinal pain: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To determine if sleep interventions improve pain and sleep in people with osteoarthritis (OA) and/or spinal pain compared to control/placebo. DESIGN: Medline, Embase, AMED, PsycINFO, CENTRAL, CINAHL and PEDro were searched from their inception date to July 2017. Keywords relating to "sleep", "OA", "spinal pain", and "randomized controlled trial (RCT)" were combined. Included RCTs investigated the use of sleep interventions for people with OA and/or spinal pain, and measured at least one sleep and health related outcome. Meta-analyses were performed to pool mean differences for pain and sleep quality. PROSPERO: CRD42016036315. RESULTS: Of 1445 unique records, 24 studies were included. Sixteen studies included participants with spinal pain, seven with OA, and one included a mixed population. Sleep interventions included established sleep interventions (ESI) [cognitive behavioural therapy (CBT) and pharmacological interventions], and a range of others. Intervention periods ranged from 4 to 10 weeks. Thirteen studies were of moderate to high quality (PEDro ≥ 6/10). Due to high heterogeneity between studies we also performed sub-group and sensitivity analyses. ESI decreased Insomnia Severity Index (ISI) for people with low back pain (LBP) (pooled mean difference: -6.78/28, 95% confidence interval (95% CI): [-9.47, -4.09], I2 = 40%) and OA (-2.41, [-4.19, -0.63], 0%). However ESI decreased pain for people with LBP (pooled mean difference: visual analogue scale (VAS) -12.77/100, 95% CI: [-17.57, -7.97], I2 = 0%), but not OA (-2.32, [-7.18, 2.54], 27%). CONCLUSION: ESI appeared to improve sleep and pain for people with LBP, and sleep for people with OA. However more vigorous studies need to be conducted.

Immediate and short-term effects of gait retraining on the knee joint moments and symptoms in patients with early tibiofemoral joint osteoarthritis: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of a knee adduction moment (KAM) gait retraining in patients with early knee osteoarthritis up to 6 months post-training. METHOD: We conducted a single blinded randomized controlled trial on a total of 23 patients with early knee osteoarthritis who were randomly allocated to the gait retraining group and walking exercise group. Twenty of them completed the corresponding training and the 6-month evaluation. We measured KAM, knee flexion moment (KFM) and western ontario and McMaster universities osteoarthritis index (WOMAC) osteoarthritis index before, immediate after, and 6 months after training. A repeated measures analysis of covariance (ANCOVA) was used to compare KAM, KFM and WOMAC osteoarthritis index scores across the three time points i.e., pre-training, post-training, and 6-month follow-up with gender, knee osteoarthritis severity, and pre-training KAM, KFM and WOMAC scores set as covariates. Post-hoc analyses were conducted when indicated. RESULTS: Significant time × group interactions were found for both KAM and WOMAC osteoarthritis index scores (P < 0.002). No interaction was found for KFM (P = 0.123). KAM after gait retraining was significantly lower than the pre-training value (P < 0.001) and such effect was maintained at 6-month follow-up (P = 0.01). There was no significant difference in the KAM across time in the walking exercise group (P > 0.208). WOMAC osteoarthritis index score after training and score at the 6-month follow-up were significantly improved in the gait retraining group (P = 0.001), while the WOMAC osteoarthritis index score remained similar. CONCLUSIONS: Gait retraining is an effective intervention to reduce KAM during walking and to improve the symptoms of patients with early knee osteoarthritis in short term.

High-functioning autism patients share similar but more severe impairments in verbal theory of mind than schizophrenia patients.

BACKGROUND: Evidence suggests that autism and schizophrenia share similarities in genetic, neuropsychological and behavioural aspects. Although both disorders are associated with theory of mind (ToM) impairments, a few studies have directly compared ToM between autism patients and schizophrenia patients. This study aimed to investigate to what extent high-functioning autism patients and schizophrenia patients share and differ in ToM performance. METHODS: Thirty high-functioning autism patients, 30 schizophrenia patients and 30 healthy individuals were recruited. Participants were matched in age, gender and estimated intelligence quotient. The verbal-based Faux Pas Task and the visual-based Yoni Task were utilised to examine first- and higher-order, affective and cognitive ToM. The task/item difficulty of two paradigms was examined using mixed model analyses of variance (ANOVAs). Multiple ANOVAs and mixed model ANOVAs were used to examine group differences in ToM. RESULTS: The Faux Pas Task was more difficult than the Yoni Task. High-functioning autism patients showed more severely impaired verbal-based ToM in the Faux Pas Task, but shared similar visual-based ToM impairments in the Yoni Task with schizophrenia patients. CONCLUSIONS: The findings that individuals with high-functioning autism shared similar but more severe impairments in verbal ToM than individuals with schizophrenia support the autism-schizophrenia continuum. The finding that verbal-based but not visual-based ToM was more impaired in high-functioning autism patients than schizophrenia patients could be attributable to the varied task/item difficulty between the two paradigms.

Stepwise preconditioning enhances mesenchymal stem cell-based cartilage regeneration through epigenetic modification.

OBJECTIVE: This study is to investigate the functions and underlying mechanisms of mesenchymal stem cells (MSCs) underwent stepwise preconditioning in chondrogenic medium before expansion, then further explore their therapeutic effects in a surgically induced osteoarthritis (OA) model. METHODS: MSCs isolated from the adult rats expressing Green Fluorescence Protein (GFP) were incubated in basal medium or primed in chondrogenic medium before expansion. The multipotency including cell proliferation, differentiation, and survivability was compared between chondrogenic manipulated MSCs (M-MSCs) and untreated MSCs. Methylation modification of Nanog and Oct4 were detected by bisulfite genomic sequencing. Loss-of-function phenotype in M-MSCs induced by shNanog was also observed. Then the therapeutic effect of the cells was evaluated in a surgically induced OA rat model by single intraarticular injection. The injected GFP-labeled cells in the joints were monitored in vivo. These rats were sacrificed and subjected to histological examinations and microstructural analysis after 4 weeks. RESULTS: We found that cell clonogenicity, proliferation, survivability, and chondrogenic property were enhanced after stepwise preconditioning. We then further found that the expression level of Nanog and Oct4 was temporarily increased in the M-MSCs. Results of epigenetic analysis revealed that demethylation happened in Nanog and Oct4 after the stepwise preconditioning. Results of in vivo imaging showed more GFP-labeled cells in the M-MSCs-injected group. And results of histology and micro-CT analysis also indicated a superior therapeutic effect of M-MSCs on the surgically induced-OA. CONCLUSION: These findings indicated a feasible method to obtain a cell population with high survivability and chondrogenic commitment for the treatment of OA.

Catalytic contribution of threonine 244 in human ALDH2.

Amongst the numerous conserved residues in the aldehyde dehydrogenase superfamily, the precise role of Thr-244 remains enigmatic. Crystal structures show that this residue lies at the interface between the coenzyme-binding and substrate-binding sites with the side chain methyl substituent oriented toward the B-face of the nicotinamide ring of the NAD(P)(+) coenzyme, when in position for hydride transfer. Site-directed mutagenesis in ALDH1A1 and GAPN has suggested a role for Thr-244 in stabilizing the nicotinamide ring for efficient hydride transfer. Additionally, these studies also revealed a negative effect on cofactor binding which is not fully explained by the interaction with the nicotinamide ring. However, it is suggestive that Thr-244 immediately precedes helix αG, which forms one-half of the primary binding interface for the coenzyme. Hence, in order to more fully investigate the role of this highly conserved residue, we generated valine, alanine, glycine and serine substitutions for Thr-244 in human ALDH2. All four substituted enzymes exhibited reduced catalytic efficiency toward substrate and coenzyme. We also determined the crystal structure of the T244A enzyme in the absence and presence of coenzyme. In the apo-enzyme, the alpha G helix, which is key to NAD binding, exhibits increased temperature factors accompanied by a small displacement toward the active site cysteine. This structural perturbation was reversed in the coenzyme-bound complex. Our studies confirm a role for the Thr-244 beta methyl in the accurate positioning of the nicotinamide ring for efficient catalysis. We also identify a new role for Thr-244 in the stabilization of the N-terminal end of helix αG. This suggests that Thr-244, although less critical than Glu-487, is also an important contributor toward coenzyme binding.

Formoterol, a highly ß2-selective agonist, increases energy expenditure and fat utilisation in men.

BACKGROUND: The sympathetic nervous system regulates energy metabolism via ß-adrenoreceptors. Therapeutic exploitation of previous ß2-adrenegic agonists for metabolic benefits has been hindered by cross stimulation of cardiac ß1-adrenoceptor, causing tachycardia. Formoterol is a novel highly ß2-selective adrenergic agonist and holds promise as a ß2-agonist that could impart selective beneficial metabolic effects. OBJECTIVE: To investigate the metabolic effects of formoterol on energy and substrate metabolism. PARTICIPANTS: Healthy volunteers. DESIGN: (1) Dose-finding study, step-wise incremental design of weekly administration of 80, 160 and 320 µg daily of formoterol in four subjects and, (2) metabolic study, an open-label metabolic evaluation of 1-week treatment in eight men using a dose determined from (1). MAIN OUTCOME: Resting energy expenditure (EE), diet-induced thermogenesis (DIT) and fat oxidation (Fox) using indirect calorimetry, heart rate and plasma non-esterified fatty acid (NEFA) levels. RESULTS: In the dose-finding study, all three doses increased resting EE and Fox with the 320 µg dose significantly increasing heart rate. In the metabolic study, the selected 160 µg daily dose increased resting EE by 13 ± 2% (P<0.001) and Fox by 23 ± 4% (P<0.01), but not DIT. Plasma NEFA levels rose by 16 ± 2% (P<0.01). Heart rate did not change significantly. Out of the eight subjects, six reported tremor and palpitation, two lost appetite and one suffered from insomnia. CONCLUSIONS: At a dose of 160 µg per day, formoterol increases resting EE and fat utilization without inducing tachycardia. From this first metabolic evaluation in humans, we conclude that formoterol imparts beneficial metabolic changes that may be exploited for therapy of obesity.

Associations of insulin-like growth factor-I and its binding proteins and testosterone with frailty in older men.

OBJECTIVE: Ageing is associated with frailty and decreased anabolic hormones, insulin-like growth factor-I (IGF-I) and testosterone. We hypothesized that components of the IGF-I system, in conjunction with testosterone, modulate frailty risk in the elderly. We examined associations between IGF-I, its binding proteins IGFBP1 and IGFBP3 and testosterone with frailty in men. DESIGN: Observational study of 3 447 community-dwelling men aged 70-89 years assessed in 2001-04, with 1 654 reassessed in 2008-09. METHODS: Baseline total IGF-I, IGFBP1, IGFBP3 and testosterone were assayed. Frailty was assessed using the FRAIL scale, comprising 5 domains: fatigue; difficulty climbing stairs; difficulty walking >100 m; >5 illnesses; weight loss >5%. Men with ≥ 3 domains were considered frail. RESULTS: At baseline, 527 men (15·3%) were frail. Frail men had lower IGFBP3 (3 630 ng/ml vs not frail: 3 800 ng/ml, P < 0·001) and comparable IGFBP1 (23·5 vs 21·5 ng/ml, P = 0·09). In multivariate analyses, higher IGFBP1 was associated with increased prevalence of frailty (highest vs lowest quartile Q4:Q1, adjusted odds ratio [OR] = 1·39, 95% CI = 1·03-1·88). New-onset frailty arose in 260 (17·5%) of 1 484 men. Lower baseline IGF-I predicted new-onset frailty (Q1:Q4 OR = 1·48, 95% CI = 1·00-2·20) as did higher IGFBP1 (Q4:Q1 OR = 1·59, 95% CI = 1·01-2·50). Men with both IGF-I and free testosterone in Q1 had greater odds of prevalent frailty (OR = 2·13, 95% CI = 1·54-2·95). CONCLUSIONS: Older men with higher IGFBP1 level, or both lower IGF-I and testosterone, are more likely to be frail, while those with lower IGF-I and higher IGFBP1 are more likely to become frail. Components of the IGF-I system may be biomarkers or independent predictors of frailty.

FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer.

Vascular endothelial growth factor (VEGF) has a central role in breast cancer development and progression, but the mechanisms that control its expression are poorly understood. Breast cancer tissue microarrays revealed an inverse correlation between the Forkhead transcription factor Forkhead box class O (FOXO)3a and VEGF expression. Using the lapatinib-sensitive breast cancer cell lines BT474 and SKBR3 as model systems, we tested the possibility that VEGF expression is negatively regulated by FOXO3a. Lapatinib treatment of BT474 or SKBR3 cells resulted in nuclear translocation and activation of FOXO3a, followed by a reduction in VEGF expression. Transient transfection and inducible expression experiments showed that FOXO3a represses the proximal VEGF promoter, whereas another Forkhead member, FOXM1, induces VEGF expression. Chromatin immunoprecipitation and oligonucleotide pull-down assays showed that both FOXO3a and FOXM1 bind a consensus Forkhead response element (FHRE) in the VEGF promoter. Upon lapatinib stimulation, activated FOXO3a displaces FOXM1 bound to the FHRE before recruiting histone deacetylase 2 (HDAC2) to the promoter, leading to decreased histones H3 and H4 acetylation, and concomitant transcriptional inhibition of VEGF. These results show that FOXO3a-dependent repression of target genes in breast cancer cells, such as VEGF, involves competitive displacement of DNA-bound FOXM1 and active recruitment of transcriptional repressor complexes.

Metabolic sequelae of ß-blocker therapy: weighing in on the obesity epidemic?

BACKGROUND: Sympathetic activation is an important metabolic adaptation limiting weight gain. Propensity of weight gain associated with ß-blocker therapy in the obese modern population is unknown. OBJECTIVE: To determine whether chronic ß-blocker therapy reduces energy expenditure (EE) and increases body weight. METHODS: We undertook (i) a mechanistic study comparing EE, diet-induced thermogenesis and habitual activity between healthy volunteers (n=11) with uncomplicated hypertension treated with a ß-blocker and anthropometrically matched controls (n=19) and (ii) three cross-sectional studies comparing body weight, body mass index (BMI) and waist circumference between ß-blocker treated and untreated patients from ambulatory patients attending (a) diabetes outpatient clinic (n=214), (b) hypertension outpatient (n=84) and (c) participants in a multi-centre type 2 diabetes trial (ADVANCE) (n=11140). RESULTS: Among weight-matched ß-blocker users, diet-induced thermogenesis, fat oxidation rate and weekly habitual activity were lower by 50% (P<0.01), 32% (P=0.04) and 30% (P<0.01), respectively, compared with controls. In ß-blocker treated patients, the adjusted mean body weight was 9.2 ± 1.2 kg (P=0.0002) higher among those attending the diabetes clinic, 17.2 ± 3.2 kg (P=0.004) higher among those attending the hypertension clinic and 5.2 ± 0.7 kg (P=0.0003) higher at baseline among participants in the ADVANCE trial compared with patients not treated with ß-blockers. BMI displayed a similar difference. CONCLUSIONS: EE is reduced and body weight increased in chronic ß-blocker users. We hypothesise that chronic ß-blockade causes obesity by blunting EE.

Current management practices for acromegaly: an international survey.

To determine whether peer-reviewed consensus statements have changed clinical practice, we surveyed acromegaly care in specialist centers across the globe, and determined the degree of adherence to published consensus guidelines on acromegaly management. Sixty-five acromegaly experts who participated in the 7th Acromegaly Consensus Workshop in March 2009 responded. Results indicated that the most common referring sources for acromegaly patients were other endocrinologists (in 26% of centers), neurosurgeons (25%) and primary care physicians (21%). In sixty-nine percent of patients, biochemical diagnoses were made by evaluating results of a combination of growth hormone (GH) nadir/basal GH and elevated insulin like growth factor-I (IGF-I) levels. In both Europe and the USA, neurosurgery was the treatment of choice for GH-secreting microadenomas and for macroadenomas with compromised visual function. The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-I and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly.

Pleuroscopy: our initial experience in Hong Kong.

OBJECTIVE: To report our preliminary experience using pleuroscopy for patients with pleural diseases. DESIGN: Prospective cohort study. SETTING: Tertiary referral hospital with service input from respiratory physicians and cardiothoracic surgeons in Hong Kong. PATIENTS: Between April and November 2007, patients with undiagnosed exudative pleural effusions and proven malignant pleural effusions were recruited for diagnostic evaluations and therapeutic interventions, respectively. INTERVENTION: Pleuroscopy with a semi-rigid thoracoscope performed under local anaesthesia and conscious sedation. RESULTS: A total of 20 patients (16 males and 4 females; mean age, 63 years) underwent the procedure and were followed up for a mean of 19 weeks. For the 14 patients having diagnostic pleuroscopy, the yield was 79% (11 patients). The 3-month success rate for the six patients undergoing pleurodesis was 83% (five patients). Complications were mild and included self-limiting fever (20%, four patients) and localised subcutaneous emphysema (20%, four patients). No major complications or mortality were noted. CONCLUSION: Pleuroscopy using a semi-rigid instrument is a safe and efficacious procedure for the management of pleural diseases in suitable patients.

Many forks in the path: cycling with FoxO.

FoxO transcription factors are an evolutionary conserved subfamily of the forkhead transcription factors, characterized by the forkhead DNA-binding domain. FoxO factors regulate a number of cellular processes involved in cell-fate decisions in a cell-type- and environment-specific manner, including metabolism, differentiation, apoptosis and proliferation. A key mechanism by which FoxO determines cell fate is through regulation of the cell cycle machinery, and as such the cellular consequence of FoxO deregulation is often manifested through perturbation of the cell cycle. Consequently, the deregulation of FoxO factors is implicated in the development of numerous proliferative diseases, in particular cancer.

The short-to-midterm results of endovascular stent grafting for acute thoracic aortic diseases in Chinese patients.

OBJECTIVE: To review the results of endovascular treatment of acute thoracic aortic diseases in a group of Chinese patients. DESIGN: Retrospective study. SETTING: A tertiary referral hospital with a cardiothoracic surgery service. PATIENTS: All 15 patients presenting with acute thoracic aortic diseases between September 2001 and October 2005 inclusive, of whom eight had traumatic rupture, four had complicated acute dissections, two had mycotic aneurysms, and one an aneurysm with an aortobronchial fistula. INTERVENTIONS: Thoracic aortic stent grafting. MAIN OUTCOME MEASURES: Immediate success, 6-month and 1-year survival rates. RESULTS: The median follow-up period was 20.6 months (range, 0-50.1 months). Stent grafts were deployed with immediate success in all patients. Two patients had ancillary bypass surgery for the supra-aortic branches. There were two in-hospital deaths. Four sustained access artery injury and needed graft repair. Computed tomography at 1 month showed complete thrombosis of the aneurysmal lumen or the thoracic aortic false lumen in 12 of 13 survivors. Computed tomography at 6 months showed complete thrombosis of the aneurysmal lumen or the false lumen in nine of 10 patients due for follow-up. Both 6-month and 1-year survival rates were 87%. CONCLUSIONS: Thoracic aortic stent grafting for acute thoracic aortic disease is feasible and has a high success rate, with good short-to-midterm results. However, the large size of the stent graft introducer set imposes a high risk of access artery injury, for which further improvements are necessary.

Influence of demographic factors and sport type on growth hormone-responsive markers in elite athletes.

CONTEXT: GH-responsive markers of the IGF system and of collagen turnover hold promise as the basis of a GH doping test. OBJECTIVE: The purpose of this study was to determine the influence of age, gender, body mass index (BMI), ethnicity, and sporting type on GH-responsive serum markers in a large cohort of elite athletes from different ethnic backgrounds. DESIGN: The study was designed as a cross-sectional study. PARTICIPANTS: A total of 1103 elite athletes (699 males, 404 females), aged 22.2 +/- 5.2 yr, from 12 countries and 10 major sporting categories participated in this study. MAIN OUTCOME MEASURES: Serum IGF-I, IGF binding protein-3 (IGFBP-3), acid labile subunit (ALS), and collagen markers [N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (ICTP), N-terminal propeptide of type III procollagen (PIIINP)] were measured. RESULTS: There was a significant negative correlation (r = -0.14 to -0.58, P < 0.0005) between age and each of the GH-responsive markers. Serum IGF-I, IGFBP-3, and ALS were all lower (P < 0.05), whereas the collagen markers PINP, ICTP, and PIIINP were higher (P < 0.05) in men than in women. Multiple regression analysis indicated that age, gender, BMI, and ethnicity accounted for 23-54% of total between-subject variability of the markers. Age and gender cumulatively accounted for 91% of the attributable variation of IGF-I and more than 80% for PINP, ICTP, and PIIINP. Gender exerted the greatest effect on ALS (48%), and BMI accounted for less than 12% attributable variation for all markers. The influence of ethnicity was greatest for IGFBP-3 and ALS; however, for the other markers, it accounted for less than 6% attributable variation. Analysis of 995 athletes indicated that sporting type contributed 5-19% of attributable variation. CONCLUSIONS: Age and gender were major determinants of variability of GH-responsive markers except for IGFBP-3 and ALS. Ethnicity is unlikely to confound the validity of a GH doping test based on IGF-I and these collagen markers.

Newer options in the management of acromegaly.

Paradigms for managing acromegaly have undergone major changes in the past two decades. This has been brought about by combining surgical, pharmacological and radiotherapeutic approaches that provide tight biochemical control to reduce mortality to that of the general population. The biochemical targets for treatment are a growth hormone of <2.5 ng/mL (approximately 7.5 mU/L) and a normal, age-adjusted insulin-like growth factor-1. Until 20 years ago, dopamine agonists were the only class of pharmaceutical agents available to control acromegaly. They have a limited adjunctive role, even with the development of second-generation selective agonists such as cabergoline. Surgery and radiotherapy were the mainstay of acromegaly management before the advent of the effective pharmacological therapies of the modern era: somatostatin analogues and pegvisomant, a growth hormone receptor antagonist. Somatostatin analogues achieve biochemical control in approximately 60% of patients. Pegvisomant, which is available in the USA and Europe and has just been registered in Australia, normalizes insulin-like growth factor-1 in nearly all patients but has no effect on tumour mass. Surgery is an appropriate first-line therapy for microadenomas as the chance of success is high. For large and/or invasive tumours where the prospect of surgical cure is remote, first-line therapy is somatostatin analogue treatment with debulking surgery having an adjunctive role to achieve tight control or to alleviate compression of the optic chiasm. Although acromegaly remains a challenging disease to manage, the expanding range of therapeutic options is likely to result in a better outcome for patients and offers the potential to tailor therapy based on a patient's individual requirements.

Characterization of MspA, an immunogenic autotransporter protein that mediates adhesion to epithelial and endothelial cells in Neisseria meningitidis.

A novel putative autotransporter protein (NMB1998) was identified in the available genomic sequence of meningococcal strain MC58 (ET-5; ST-32). The mspA gene is absent from the genomic sequences of meningococcal strain Z2491 (ET-IV; ST-4) and the gonococcal strain FA1090. An orthologue is present in the meningococcal strain FAM18 (ET-37; ST-11), but the sequence contains a premature stop codon, suggesting that the protein may not be expressed in this strain. MspA is predicted to be a 157-kDa protein with low cysteine content, and it exhibits 36 and 33% identity to the meningococcal autotransporter proteins immunoglobulin A1 (IgA1) protease and App, respectively. Search of the Pfam database predicts the presence of IgA1 protease and autotransporter beta-barrel domains. MspA was cloned, and a recombinant protein of the expected size was expressed and after being affinity purified was used to raise rabbit polyclonal monospecific antiserum. Immunoblot studies showed that ca. 125- and 95-kDa fragments of MspA are secreted in meningococcal strain MC58, which are absent from the isogenic mutant. Secretion of MspA was shown to be modified in an AspA isogenic mutant. A strain survey showed that MspA is expressed by all ST-32 and ST-41/44 (lineage 3) strains, but none of the ST-8 (A4) strains examined. Sera from patients convalescing from meningococcal disease were shown to contain MspA-specific antibodies. In bactericidal assays, anti-MspA serum was shown to kill the homologous strain (MC58) and another ST-32 strain. Escherichia coli-expressing recombinant MspA was shown to adhere to both human bronchial epithelial cells and brain microvascular endothelial cells.