Eltrombopag for the treatment of chronic idiopathic (immune) thrombocytopenic purpura : A Single Technology Appraisal

Evidence Review Group (ERG) final report for the National Institute for Health and Clinical ExcellencePublisher PD

Assembling the thymus medulla:Development and function of epithelial cell heterogeneity

The thymus is a unique primary lymphoid organ that supports the production of self-tolerant T-cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus-dependent T-cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive T-cell clones, thereby counterbalancing the potential for random T-cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self-tolerant T-cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function.</p

Gain-of-Function Mutations in the K_ATP Channel (KCNJ11) Impair Coordinated Hand-Eye Tracking

Background: Gain-of-function mutations in the ATP-sensitive potassium channel can cause permanent neonatal diabetes mellitus (PNDM) or neonatal diabetes accompanied by a constellation of neurological symptoms (iDEND syndrome). Studies of a mouse model of iDEND syndrome revealed that cerebellar Purkinje cell electrical activity was impaired and that the mice exhibited poor motor coordination. In this study, we probed the hand-eye coordination of PNDM and iDEND patients using visual tracking tasks to see if poor motor coordination is also a feature of the human disease.Methods: Control participants (n = 14), patients with iDEND syndrome (n = 6 or 7), and patients with PNDM (n = 7) completed three computer-based tasks in which a moving target was tracked with a joystick-controlled cursor. Patients with PNDM and iDEND were being treated with sulphonylurea drugs at the time of testing.Results: No differences were seen between PNDM patients and controls. Patients with iDEND syndrome were significantly less accurate than controls in two of the three tasks. The greatest differences were seen when iDEND patients tracked blanked targets, i.e. when predictive tracking was required. In this task, iDEND patients incurred more discrepancy errors (p = 0.009) and more velocity errors (p  = 0.009) than controls.Conclusions: These results identify impaired hand-eye coordination as a new clinical feature of iDEND. The aetiology of this feature is likely to involve cerebellar dysfunction. The data further suggest that sulphonylurea doses that control the diabetes of these patients may be insufficient to fully correct their neurological symptoms.</p

Stratifying Brain Tumour Histological Sub-Types: The Application of ATR-FTIR Serum Spectroscopy in Secondary Care

Patients living with brain tumours have the highest average years of life lost of any cancer, ultimately reducing average life expectancy by 20 years. Diagnosis depends on brain imaging and most often confirmatory tissue biopsy for histology. The majority of patients experience non-specific symptoms, such as headache, and may be reviewed in primary care on multiple occasions before diagnosis is made. Sixty-two per cent of patients are diagnosed on brain imaging performed when they deteriorate and present to the emergency department. Histological diagnosis from invasive surgical biopsy is necessary prior to definitive treatment, because imaging techniques alone have difficulty in distinguishing between several types of brain cancer. However, surgery itself does not necessarily control tumour growth, and risks morbidity for the patient. Due to their similar features on brain scans, glioblastoma, primary central nervous system lymphoma and brain metastases have been known to cause radiological confusion. Non-invasive tests that support stratification of tumour subtype would enhance early personalisation of treatment selection and reduce the delay and risks associated with surgery for many patients. Techniques involving vibrational spectroscopy, such as attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, have previously demonstrated analytical capabilities for cancer diagnostics. In this study, infrared spectra from 641 blood serum samples obtained from brain cancer and control patients have been collected. Firstly, we highlight the capability of ATR-FTIR to distinguish between healthy controls and brain cancer at sensitivities and specificities above 90%, before defining subtle differences in protein secondary structures between patient groups through Amide I deconvolution. We successfully differentiate several types of brain lesions (glioblastoma, meningioma, primary central nervous system lymphoma and metastasis) with balanced accuracies >80%. A reliable blood serum test capable of stratifying brain tumours in secondary care could potentially avoid surgery and speed up the time to definitive therapy, which would be of great value for both neurologists and patients

A novel method to allow noninvasive, longitudinal imaging of the murine immune system in vivo

In vivo imaging has revolutionized understanding of the spatiotemporal complexity that subserves the generation of successful effector and regulatory immune responses. Until now, invasive surgery has been required for microscopic access to lymph nodes (LNs), making repeated imaging of the same animal impractical and potentially affecting lymphocyte behavior. To allow longitudinal in vivo imaging, we conceived the novel approach of transplanting LNs into the mouse ear pinna. Transplanted LNs maintain the structural and cellular organization of conventional secondary lymphoid organs. They participate in lymphocyte recirculation and exhibit the capacity to receive and respond to local antigenic challenge. The same LN could be repeatedly imaged through time without the requirement for surgical exposure, and the dynamic behavior of the cells within the transplanted LN could be characterized. Crucially, the use of blood vessels as fiducial markers also allowed precise re-registration of the same regions for longitudinal imaging. Thus, we provide the first demonstration of a method for repeated, noninvasive, in vivo imaging of lymphocyte behavior

Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells

The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEClow subsets distinguished by surface, intracellular and secreted molecules, and identify LTβR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTβR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTβR controls CD104+ CCL21+ mTEClow that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues

Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells

The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEClow subsets distinguished by surface, intracellular and secreted molecules, and identify LTβR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTβR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTβR controls CD104+ CCL21+ mTEClow that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues

Developing infrared spectroscopic detection for stratifying brain tumour patients: glioblastoma multiforme vs. lymphoma

Over a third of brain tumour patients visit their general practitioner more than five times prior to diagnosis in the UK, leading to 62% of patients being diagnosed as emergency presentations. Unfortunately, symptoms are non-specific to brain tumours, and the majority of these patients complain of headaches on multiple occasions before being referred to a neurologist. As there are currently no methods in place for the early detection of brain cancer, the affected patients’ average life expectancy is reduced by 20 years. These statistics indicate that the current pathway is ineffective, and there is a vast need for a rapid diagnostic test. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy is sensitive to the hallmarks of cancer, as it analyses the full range of macromolecular classes. The combination of serum spectroscopy and advanced data analysis has previously been shown to rapidly and objectively distinguish brain tumour severity. Recently, a novel high-throughput ATR accessory has been developed, which could be cost-effective to the National Health Service in the UK, and valuable for clinical translation. In this study, 765 blood serum samples have been collected from healthy controls and patients diagnosed with various types of brain cancer, contributing to one of the largest spectroscopic studies to date. Three robust machine learning techniques - random forest, partial least squares-discriminant analysis and support vector machine - have all provided promising results. The novel high-throughput technology has been validated by separating brain cancer and non-cancer with balanced accuracies of 90% which is comparable to the traditional fixed diamond crystal methodology. Furthermore, the differentiation of brain tumour type could be useful for neurologists, as some are difficult to distinguish through medical imaging alone. For example, the highly aggressive glioblastoma multiforme and primary cerebral lymphoma can appear similar on magnetic resonance imaging (MRI) scans, thus are often misdiagnosed. Here, we report the ability of infrared spectroscopy to distinguish between glioblastoma and lymphoma patients, at a sensitivity and specificity of 90.1% and 86.3%, respectively. A reliable serum diagnostic test could avoid the need for surgery and speed up time to definitive chemotherapy and radiotherapy

The Vehicle, April 1960, Vol. 2 no. 2

Vol. 2, No. 2 Table of Contents A White Man\u27s BurdenRobert Mills Frenchpage 2 RealistA.B. Carterpage 4 The Two MatchesLouise A. Kemperpage 5 Thought Upon Looking at a Modern Painting Titled Grass Thomas McPeakpage 7 BewareDennis Lewispage 7 WavesJean Nightingalepage 7 The SpectatorKathleen Ferreepage 8 Animal RugAl Brookspage 8 Success Comes to CulturevilleJ.B. Youngpage 9 On Giving Up Religion in DespairThe Skepticpage 11 The DecisionGeorge Fosterpage 12 Wisdom ConfoundedJames D. Rannepage 15 Smalltown: 5 A.M.James M. Jenkinsonpage 15 Man of MettleC.E.S.page 16https://thekeep.eiu.edu/vehicle/1005/thumbnail.jp