"Why me, why now?" Using clinical immunology and epidemiology to explain who gets nontuberculous mycobacterial infection

BACKGROUND: The prevalence of nontuberculous mycobacterial (NTM) disease is rising. An understanding of known risk factors for disease sheds light on the immunological and physical barriers to infection, and how and why they may be overcome. This review focuses on human NTM infection, supported by experimental and in vitro data of relevance to the practising clinician who seeks to understand why their patient has NTM infection and how to further investigate. DISCUSSION: First, the underlying immune response to NTM disease is examined. Important insights regarding NTM disease susceptibility come from nature's own knockouts, the primary immune deficiency disorders. We summarise the current knowledge surrounding interferon-gamma (IFNγ)-interleukin-12 (IL-12) axis abnormalities, followed by a review of phagocytic defects, T cell lymphopenia and rarer genetic conditions known to predispose to NTM disease. We discuss how these define key immune pathways involved in the host response to NTM. Iatrogenic immunosuppression is also important, and we evaluate the impact of novel biological therapies, as well as bone marrow transplant and chemotherapy for solid organ malignancy, on the epidemiology and presentation of NTM disease, and discuss the host defence dynamics thus revealed. NTM infection and disease in the context of other chronic illnesses including HIV and malnutrition is reviewed. The role of physical barriers to infection is explored. We describe how their compromise through different mechanisms including cystic fibrosis, bronchiectasis and smoking-related lung disease can result in pulmonary NTM colonisation or infection. We also summarise further associations with host factors including body habitus and age. We use the presented data to develop an over-arching model that describes human host defences against NTM infection, where they may fail, and how this framework can be applied to investigation in routine clinical practice

Definition and composition of motor primitives using latent force models and hidden Markov models

In this work a different probabilistic motor primitive parameterization is proposed using latent force models (LFMs). The sequential composition of different motor primitives is also addressed using hidden Markov models (HMMs) which allows to capture the redundancy over dynamics by using a limited set of hidden primitives. The capability of the proposed model to learn and identify motor primitive occurrences over unseen movement realizations is validated using synthetic and motion capture data

Age related deviation of gait from normality in alkaptonuria.

Alkaptonuria is a rare metabolic disease leading to systemic changes including early and severe arthropathy which affects mobility. Due to unknown reasons, the onset of degenerative changes is delayed to around 30 years of age when both objective and subjective symptoms develop. In order to complement describing the structural changes in alkaptonuria with measures of movement function, clinical gait analysis was added to the list of assessments in 2013. The aim of this study was to describe the deviation of gait from normality as a function of age in patients with alkaptonuria. Three-dimensional movement of reflective markers attached to joints were captured during walking in 39 patients and 10 controls. Subsequent to processing the data to emphasise the shape of marker trajectories, the mean Movement Deviation Profile was generated for all participants. This single number measure gives the deviation of a patient’s gait from a distributed definition of gait normality. Results showed that gait deviation roughly follows a sigmoid profile with minimal increase of gait deviations in a younger patient group and an abrupt large increase around the second half of the 4th decade of life. Larger variations of gait deviations were found in the older group than in the younger group suggesting a complex interaction of multiple factors which determine gait function after symptoms manifest. Continued gait analysis of adults with AKU, extended to younger adults and children with AKU, is expected to complete understanding of both the natural history of alkaptonuria and how interventions can affect movement function

A new phage-display tumor-homing peptide fused to antiangiogenic peptide generates a novel bioactive molecule with antimelanoma activity

Phage-display peptide libraries have been widely used to identify specific peptides targeting in vivo tumor cells and the tumor vasculature and playing an important role in the discovery of antitumor bioactive peptides. In the present work, we identified a new melanoma-homing peptide, (-CVNHPAFAC-), using a C7C phage-display library directed to the developing tumor in syngeneic mice. Phage were able to preferentially target melanoma in vivo, with an affinity about 50-fold greater than that with normal tissue, and the respective synthesized peptide displaced the corresponding phage from the tumor. A preferential binding to endothelial cells rather than to melanoma cells was seen in cell ELISA, suggesting that the peptide is directed to the melanoma vasculature. Furthermore, the peptide was able to bind to human sonic hedgehog, a protein involved in the development of many types of human cancers. Using a new peptide approach therapy, we coupled the cyclic peptide to another peptide, HTMYYHHYQHHL-NH(2), a known antagonist of VEGFR-2 receptor, using the GYG linker. The full peptide CVNHPAFACGYGHTMYYHHYQHHL-NH(2) was effective in delaying tumor growth (P < 0.05) and increasing animal survival when injected systemically, whereas a scramble-homing peptide containing the same antagonist did not have any effect. This is the first report on the synthesis of a tumor-homing peptide coupled to antiangiogenic peptide as a new anticancer therapeutics

Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

Radiation-induced root surface caries restored with glass-ionomer cement placed in conventional and ART cavity preparations: Results at two years

The document attached has been archived with permission from the Australian Dental Association (8th Jan 2008). An external link to the publisher’s copy is included.Background: There are no published studies comparing the clinical performances of more-viscous glass-ionomer cement (GIC) restorations when placed using conventional and atraumatic restorative treatment (ART) cavity preparation methods to restore root surface caries. Methods: One dentist used encapsulated Fuji IX GP and Ketac-Molar to restore 72 conventional and 74 ART cavity preparations for 15 patients who had received cervicofacial radiation therapy. Two assessors evaluated the restorations at six, 12, and 24 months for retention, marginal defects and surface wear, and recurrent caries. Results: After two years, the cumulative restoration successes were 65.2 per cent for the conventional and 66.2 per cent for the ART cavity preparations, without statistical or clinical significance (P>0.50). Restoration dislodgement accounted for 82.8 per cent and marginal defects for 17.2 per cent of all failures. There were no instances of unsatisfactory restoration wear or recurrent caries observed. Teeth with three or more restored cervical surfaces accounted for 79.3 per cent of all failures (P<0.0001). Conclusions: For root surface caries restored with GIC, the use of hand instruments only with the ART method was an equally effective alternative to conventional rotary instrumentation for cavity preparation. Larger restorations had higher failures, usually from dislodgement.JY Hu, XC Chen, YQ Li, RJ Smales and KH Yi

Overexpression Of Chd1l Is Positively Associated With Metastasis Of Lung Adenocarcinoma And Predicts Patients Poor Survival

CHD1L (chromodomain helicase/ATPase DNA binding protein 1-like gene) has been demonstrated as an oncogene in hepatocellular carcinoma (HCC), however, the role of CHD1L in non-small-cell lung cancer (NSCLC) tumorigenesis hasn't been elucidated. In this study, the expression and amplification status of CHD1L were examined by immunohistochemistry and fluorescence in situ hybridization respectively in 248 surgically resected NSCLCs. The associations between CHD1L expression and clinicopathologic features and the prognostic value of CHD1L were analyzed. Overexpression and amplification of CHD1L was found in 42.1% and 17.7% of NSCLCs, respectively. The frequency of CHD1L overexpression (53.2% vs. 28.1%, P = 0.002) and amplification (25.2% vs. 8.2%, P = 0.020) in adenocarcinoma (ADC), was much higher than that in squamous cell carcinoma (SCC). CHD1L overexpression was associated closely with ascending pN status (P < 0.001), advanced clinical stage (P = 0.001) and tumor distant metastasis (P = 0.001) in ADCs, but not in SCCs. For the whole cohort and ADC patients, univariate survival analysis demonstrated a significant association of CHD1L overexpression with shortened survival; and in multivariate analysis, CHD1L overexpression was evaluated as a independent predictor for overall survival and distant metastasis free survival. These results suggested that overexpression of CHD1L is positively associated with tumor metastasis of lung ADC, and might serve as a novel prognostic biomarker and potential therapeutic target for lung ADC patients.published_or_final_versio