The musculoskeletal manifestations of haemophilia: a review of the imaging findings.

Haemophilia is a common hereditary cause of bleeding diathesis and the musculoskeletal system is frequently affected. Repeated episodes of haemarthrosis initiate a cascade towards haemophilic arthropathy, a disabling and deforming joint disease with both degenerative and inflammatory features, which include articular cartilage loss, bone erosions, and synovitis. Haemophilic pseudotumour and intra-muscular haematoma make up the remainder of the musculoskeletal manifestations of this systemic condition. Radiological assessment is vital in the assessment and follow-up of these haemophilic complications and MRI is the reference standard. This article summarises the radiological findings relevant to the diagnosis and monitoring of this complex patient group.

Variables associated with survival in patients with invasive bladder cancer with and without surgery.

We recorded the survival of 141 patients assessed for radical cystectomy, which included cardiopulmonary exercise testing. The median Kaplan-Meier survival estimates were: 1540 days for the whole cohort; 2200 days after cystectomy scheduled (n = 108); and 843 days without surgery. The mortality hazard remained double that expected for a matched general population, but survival was better in patients scheduled for surgery than those who were not: the mortality hazard ratio (95%CI) after cystectomy was 0.43 (0.26-0.73) the mortality hazard without surgery, p = 0.001. The mortality hazard ratios for the three-variable Bayesian Model Averaging survival model for all 141 patients were: referral for surgery (0.5); haemoglobin concentration (0.98); and efficiency of carbon dioxide output (1.05). Efficiency of carbon dioxide output was the single variable in the postoperative model (n = 108), mortality hazard 1.08 (per unit increase). The ratio of observed to expected peak oxygen consumption associated best with mortality in 33 patients not referred for surgery, hazard ratio 0.001. Our results can inform consultations with patients with invasive bladder cancer and suggest that interventions to increase fitness and haemoglobin may improve survival in patients who do and who do not undergo radical cystectomy.

Myeloid-derived suppressor cell-like fibrocytes are increased and associated with preserved lung function in chronic obstructive pulmonary disease.

BACKGROUND: The role of fibrocytes in chronic obstructive pulmonary disease (COPD) is unknown. We sought to enumerate blood and tissue fibrocytes in COPD and determine the association of blood fibrocytes with clinical features of disease. METHODS: Utilizing flow cytometry to identify circulating, collagen type 1+ cells, we found two populations: (i) CD45+ CD34+ (fibrocytes) and (ii) CD45+ CD34- [myeloid-derived suppressor cell (MDSC)-like fibrocytes] cells in stable COPD (n = 41) and control (n = 29) subjects. Lung resection material from a separate group of subjects with (n = 11) or without (n = 11) COPD was collected for tissue fibrocyte detection. We examined circulating fibrocyte populations for correlations with clinical parameters including quantitative computed tomography (qCT) and determined pathways of association between correlated variables using a path analysis model. RESULTS: Blood and tissue fibrocytes were not increased compared to control subjects nor were blood fibrocytes associated with lung function or qCT, but were increased in eosinophilic COPD. Myeloid-derived suppressor cell-like fibrocytes were increased in COPD compared to controls [2.3 (1.1-4.9), P = 0.038]. Our path analysis model showed that collagen type 1 intensity for MDSC-like fibrocytes was positively associated with lung function through associations with air trapping, predominately in the upper lobes. CONCLUSION: We have demonstrated that two circulating populations of fibrocyte exist in COPD, with distinct clinical associations, but are not prevalent in proximal or small airway tissue. Blood MDSC-like fibrocytes, however, are increased and associated with preserved lung function through a small airway-dependent mechanism in COPD.

Cardiopulmonary exercise testing and survival after elective abdominal aortic aneurysm repair†.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is increasingly used in the preoperative assessment of patients undergoing major surgery. The objective of this study was to investigate whether CPET can identify patients at risk of reduced survival after abdominal aortic aneurysm (AAA) repair. METHODS: Prospectively collected data from consecutive patients who underwent CPET before elective open or endovascular AAA repair  (EVAR) at two tertiary vascular centres between January 2007 and October 2012 were analysed. A symptom-limited maximal CPET was performed on each patient. Multivariable Cox proportional hazards regression modelling was used to identify risk factors associated with reduced survival. RESULTS: The study included 506 patients with a mean age of 73.4 (range 44-90). The majority (82.6%) were men and most (64.6%) underwent EVAR. The in-hospital mortality was 2.6%. The median follow-up was 26 months. The 3-year survival for patients with zero or one sub-threshold CPET value ([Formula: see text] at AT<10.2 ml kg(-1) min(-1), peak [Formula: see text]<15 ml kg(-1) min(-1) or [Formula: see text] at AT>42) was 86.4% compared with 59.9% for patients with three sub-threshold CPET values. Risk factors independently associated with survival were female sex [hazard ratio (HR)=0.44, 95% confidence interval (CI) 0.22-0.85, P=0.015], diabetes (HR=1.95, 95% CI 1.04-3.69, P=0.039), preoperative statins (HR=0.58, 95% CI 0.38-0.90, P=0.016), haemoglobin g dl(-1) (HR=0.84, 95% CI 0.74-0.95, P=0.006), peak [Formula: see text]<15 ml kg(-1) min(-1) (HR=1.63, 95% CI 1.01-2.63, P=0.046), and [Formula: see text] at AT>42 (HR=1.68, 95% CI 1.00-2.80, P=0.049). CONCLUSIONS: CPET variables are independent predictors of reduced survival after elective AAA repair and can identify a cohort of patients with reduced survival at 3 years post-procedure. CPET is a potentially useful adjunct for clinical decision-making in patients with AAA.

Effects of spin-dependent interactions on polarization of bright polariton solitons.

We report on the spin properties of bright polariton solitons supported by an external pump to compensate losses. We observe robust circularly polarized solitons when a circularly polarized pump is applied, a result attributed to phase synchronization between nondegenerate TE and TM polarized polariton modes at high momenta. For the case of a linearly polarized pump, either σ+ or σ- circularly polarized bright solitons can be switched on in a controlled way by a σ+ or σ- writing beam, respectively. This feature arises directly from the widely differing interaction strengths between co- and cross-circularly polarized polaritons. In the case of orthogonally linearly polarized pump and writing beams, the soliton emission on average is found to be unpolarized, suggesting strong spatial evolution of the soliton polarization. The observed results are in agreement with theory, which predicts stable circularly polarized solitons and unstable linearly polarized solitons.

Preoperative cardiopulmonary exercise testing and risk of early mortality following abdominal aortic aneurysm repair.

BACKGROUND: Cardiopulmonary exercise testing (CPET) provides an objective assessment of functional capacity. The aim of this study was to assess whether preoperative CPET identifies patients at risk of early death following elective open and endovascular abdominal aortic aneurysm (AAA) repair. METHODS: Prospective data were collected from a pilot study between September 2005 and February 2007, and from all patients who underwent CPET before elective AAA repair at two vascular centres between February 2007 and November 2011. Symptom-limited, maximal CPET was performed on each patient. Univariable and multivariable analyses were used to identify risk factors for 30- and 90-day mortality. RESULTS: Some 415 patients underwent CPET before elective AAA repair. Anaerobic threshold (AT), peak oxygen consumption (peak V.O(2) ) and ventilatory equivalents for carbon dioxide were associated with 30- and 90-day mortality on univariable analysis. On multivariable analysis, open repair (odds ratio (OR) 4·92, 95 per cent confidence interval 1·55 to 17·00; P = 0·008), AT below 10·2 ml per kg per min (OR 6·35, 1·84 to 29·80; P = 0·007), anaemia (OR 3·27, 1·04 to 10·50; P = 0·041) and inducible cardiac ischaemia (OR 6·16, 1·48 to 23·07; P = 0·008) were associated with 30-day mortality. Anaemia, inducible cardiac ischaemia and peak V.O(2) less than 15 ml per kg per min (OR 8·59, 2·33 to 55·75; P = 0·005) were associated with 90-day mortality on multivariable analysis. Patients with two or more subthreshold CPET values were at increased risk of both 30- and 90-day mortality. CONCLUSION: An AT below 10·2 ml per kg per min, peak V.O(2) less than 15 ml per kg per min and at least two subthreshold CPET values identify patients at increased risk of early death following AAA repair.

Polygamain, a new microtubule depolymerizing agent that occupies a unique pharmacophore in the colchicine site.

Bioassay-guided fractionation was used to isolate the lignan polygamain as the microtubule-active constituent in the crude extract of the Mountain torchwood, Amyris madrensis. Similar to the effects of the crude plant extract, polygamain caused dose-dependent loss of cellular microtubules and the formation of aberrant mitotic spindles that led to G(2)/M arrest. Polygamain has potent antiproliferative activities against a wide range of cancer cell lines, with an average IC(50) of 52.7 nM. Clonogenic studies indicate that polygamain effectively inhibits PC-3 colony formation and has excellent cellular persistence after washout. In addition, polygamain is able to circumvent two clinically relevant mechanisms of drug resistance, the expression of P-glycoprotein and the ßIII isotype of tubulin. Studies with purified tubulin show that polygamain inhibits the rate and extent of purified tubulin assembly and displaces colchicine, indicating a direct interaction of polygamain within the colchicine binding site on tubulin. Polygamain has structural similarities to podophyllotoxin, and molecular modeling simulations were conducted to identify the potential orientations of these compounds within the colchicine binding site. These studies suggest that the benzodioxole group of polygamain occupies space similar to the trimethoxyphenyl group of podophyllotoxin but with distinct interactions within the hydrophobic pocket. Our results identify polygamain as a new microtubule destabilizer that seems to occupy a unique pharmacophore within the colchicine site of tubulin. This new pharmacophore will be used to design new colchicine site compounds that might provide advantages over the current agents.

Differential protection of neuromuscular sensory and motor axons and their endings in Wld(S) mutant mice.

Orthograde Wallerian degeneration normally brings about fragmentation of peripheral nerve axons and their sensory or motor endings within 24-48 h in mice. However, neuronal expression of the chimaeric, Wld(S) gene mutation extends survival of functioning axons and their distal endings for up to 3 weeks after nerve section. Here we studied the pattern and rate of degeneration of sensory axons and their annulospiral endings in deep lumbrical muscles of Wld(S) mice, and compared these with motor axons and their terminals, using neurone-specific transgenic expression of the fluorescent proteins yellow fluorescent protein (YFP) or cyan fluorescent protein (CFP) as morphological reporters. Surprisingly, sensory endings were preserved for up to 20 days, at least twice as long as the most resilient motor nerve terminals. Protection of sensory endings and axons was also much less sensitive to Wld(S) gene-copy number or age than motor axons and their endings. Protection of γ-motor axons and their terminals innervating the juxtaequatorial and polar regions of the spindles was less than sensory axons but greater than α-motor axons. The differences between sensory and motor axon protection persisted in electrically silent, organotypic nerve-explant cultures suggesting that residual axonal activity does not contribute to the sensory-motor axon differences in vivo. Quantitative, Wld(S)-specific immunostaining of dorsal root ganglion (DRG) neurones and motor neurones in homozygous Wld(S) mice suggested that the nuclei of large DRG neurones contain about 2.4 times as much Wld(S) protein as motor neurones. By contrast, nuclear fluorescence of DRG neurones in homozygotes was only 1.5 times brighter than in heterozygotes stained under identical conditions. Thus, differences in axonal or synaptic protection within the same Wld(S) mouse may most simply be explained by differences in expression level of Wld(S) protein between neurones. Mimicry of Wld(S)-induced protection may also have applications in treatment of neurotoxicity or peripheral neuropathies in which the integrity of sensory endings may be especially implicated.

Gastro-intestinal stromal tumours (GISTs) - the Pretoria experience and a literature review.

AIM: To analyse the presentation and management of patients with gastrointestinal stromal tumours (GISTs) at Pretoria hospitals. DESIGN: A retrospective study was done in which all available clinical records of primary c-KIT positive GISTs were analysed. SETTING: Secondary and tertiary care institutions in Pretoria, including both private and public hospitals. Subjects. The population studied included all individuals treated at Pretoria hospitals from 17 July 2000 to 1 April 2009 who had a GIST confirmed with immunohistochemical c KIT staining. Patients with incomplete or inaccessible clinical records were excluded. Outcome measures. Patient demographics including gender, age and race; presenting symptoms and signs; results of special investigations; and treatment. RESULTS: Fifty-four cases were identified for inclusion in the study. The age of the subjects ranged from 15 to 83 years. The male-to-female ratio was 1.5:1. The organ most commonly affected was the stomach, and abdominal pain and weight loss were the most common presenting symptoms. Seventy-six per cent of the patients were treated surgically, and 24% received Imatinib. CONCLUSION: GISTs often present late with non-specific symptoms, and are frequently discovered incidentally. Large tumours tend to be malignant.

Vortex lattices in coherently pumped polariton microcavities.

We propose a new class of vortex lattices supported by the parametric conversion of polaritons in wide aperture semiconductor microcavities operating in the strong coupling regime and pumped by a coherent beam. We present numerical and analytical results confirming the existence and robustness of the polaritonic vortex lattices in practically relevant settings and discuss their melting scenarios.

Force networks and elasticity in granular silos.

We have made experimental observations of the force networks within a two-dimensional granular silo similar to the classical system of Janssen. Models like that of Janssen predict that pressure within a silo saturates with depth as the result of vertical forces being redirected to the walls of the silo where they can then be carried by friction. We use photoelastic particles to obtain information not available in previous silo experiments --the internal force structure. We directly compare various predictions with the results obtained by averaging ensembles of experimentally obtained force networks. We identify several differences between the mean behavior in our system and that predicted by Janssen-like models: We find that the redirection parameter describing how the force network transfers vertical forces to the walls varies with depth. We find that changes in the preparation of the material can cause the pressure within the silo to either saturate or to continue building with depth. Most strikingly, we observe a nonlinear response to overloads applied to the top of the material in the silo. For larger overloads we observe the previously reported "giant overshoot" effect where overload pressure decays only after an initial increase (G. Ovarlez et al., Phys. Rev. E 67, 060302(R) (2003)). For smaller overloads we find that additional pressure propagates to great depth. Analysis of the differences between the inter-grain contact and force networks suggests that, for our system, when the load and the particle weight are comparable, particle elasticity acts to stabilize the force network, allowing deep propagation. For larger loads, the force network rearranges, resulting in the expected, Janssen-like behavior. Thus, a meso-scale network phenomenon results in an observable nonlinearity in the mean pressure profile.

Long-term outcomes of breast cancer in women aged 30 years or younger, based on family history, pathology and BRCA1/BRCA2/TP53 status.

BACKGROUND: There are relatively few articles addressing long-term follow-up in women with breast cancer at very young ages. METHODS: We have updated and extended our population-based analysis of breast cancer diagnosed at the age < or =30 years in North-west England to include an extra 15 patients with mutation testing in BRCA1, BRCA2 and TP53, with 115 of 288 consecutive cases being tested. Kaplan-Meier curves were generated to assess overall survival, contralateral breast cancer and other second primaries. RESULTS: Survival analysis of all 288 patients showed poor overall survival, although this improved from a 15-year survival of only 46% in those diagnosed between 1980 and 1989 to 58% in those diagnosed between 1990 and 1997 (P=0.05). Contralateral breast cancer rates were at a steady rate of 0.6 per 1000, although the rates in mutation carriers were approximately 2 per 1000. Altogether, 16 BRCA1, 9 BRCA2 and 6 TP53 mutations have now been found among the 115 cases on whom DNA analysis has been performed. BRCAPRO accurately predicted the number of carriers for BRCA1 and BRCA2 and was sensitive and specific at the 10 and 20% threshold, respectively. However, BRCAPRO did not seem to give any weight to DCIS, which accounted for two BRCA1 carriers and three TP53 carriers and overpredicted mutations at the high end of the spectrum, with only 6 of 11 (54%) with a >90% probability having identifiable BRCA1/2 mutations. INTERPRETATION: Rates of new primaries are predicted to some extent by mutation status. BRCAPRO is useful at determining those patients aged < or =30 years to be tested.

Polyribosome analysis for investigating mRNA translation in Xenopus oocytes, eggs and embryos.

The earliest stages of animal development occur without the benefit of zygotic transcription. The absence of transcription necessitates that all changes in the levels of specific proteins must be controlled by post-transcriptional mechanisms, such as the regulated translation of stored maternal mRNAs. One of the major challenges to investigating translational mechanisms is the availability of reliable methods for assaying the translational state of specific mRNAs. The most definitive assay of an mRNA's translational state is polyribosome association; mRNAs actively translated are engaged with polyribosomes while mRNAs translationally repressed are not. While linear gradient centrifugation is commonly used to purify polyribosomes from a wide variety of cell types in different organisms, the isolation of polyribosomes from Xenopus oocytes, eggs and embryos presents some unique challenges. Here we detail the methodology for the isolation and analysis of polyribosomes from Xenopus oocytes, eggs and embryos using step gradient centrifugation. We present detailed protocols, describe the critical controls and provide several examples to guide the interpretation of experimental results regarding the translational state of specific mRNAs.

Long-term outcome after carpal tunnel decompression - a prospective randomised study of the Indiana Tome and a standard limited palmar incision.

This randomised trial compared the results of carpal tunnel decompression using the TM Indiana Tome (Biomet, Warsaw, Indiana, USA) and a standard limited palmar open incision. Two hundred patients were randomly selected to have a carpal tunnel decompression with either the Indiana Tome or a limited palmar technique. They were assessed clinically for 3 months and using the Levine-Katz self-assessment evaluation for 7 years. After 7 years, there were 62 returned questionnaires from the open group and 53 from the Tome group. There were no significant differences in functional scores, pain, scar tenderness, pinch and grip strength at 3 months. There were two complications in the open group and nine in the Tome group, including one median nerve injury. There was both a higher rate of immediate complications, and more recurrences and persisting symptoms at 7 years in the Indiana Tome group.

Why do granular materials stiffen with shear rate? Test of novel stress-based statistics.

Recent experiments exhibit a rate dependence for granular shear such that the stress grows linearly in the logarithm of the shear rate, gamma. Assuming a generalized activated process mechanism, we show that these observations are consistent with a recent proposal for a stress-based statistical ensemble. By contrast, predictions for rate dependence using conventional energy-based statistical mechanics to describe activated processes, predicts a rate dependence of (ln(gamma))(1/2).

A case of a periaortic lymphoma presenting with the features of descending thoracic aorta dissection.

We report the case of a 68-year-old male in whom an intrathoracic non-Hodgkin's lymphoma was diagnosed late after he presented with the clinical and radiological features of a descending aortic dissection due to penetrating ulcer. An endovascular stent was implanted in the descending aorta. At follow up, a CT scan showed the presence of a mediastinal mass thought to be a periaortic haematoma as a consequence of the endovascular stent implantation. A further CT scan showed an increase in size of the mediastinal mass encasing the whole descending aorta. A biopsy of the mass was performed which was shown to be non-Hodgkin's lymphoma. This is the first report of a penetrating ulcer of the descending aorta due to lymphoma, which probably caused the dissection.