A Type 1 diabetes technology pathway: consensus statement for the use of technology in Type 1 diabetes

In both adults and children with diabetes, technologies such as continuous subcutaneous insulin infusion using insulin pumps and continuous glucose monitoring can help improve diabetes control, reduce hypoglycaemia and improve quality of life. Access to these technologies in the UK is very variable. Some technologies are recommended by the National Institute for Health and Care Excellence, while others have not been appraised, and new technologies are emerging all the time. Additionally, different guidelines for adults and children further complicate access to diabetes technology in the transition from paediatric to adult care. Against this background, Diabetes UK and NHS England have brought together a multidisciplinary group of experts, including clinicians and people with diabetes, to develop this consensus guideline, combining the different technologies into a common pathway to aid clinical and policy decision‐making. We created a pathway that supports the incremental addition of technology as monotherapy and then dual therapy in the same way that we incrementally add in therapeutic agents to support people with Type 2 diabetes to achieve their personalized glycaemic targets. The pathway emphasizes the importance of structured education, specialist support and appropriate access to psychological therapies, as essential pillars for optimized use of diabetes‐related technology, and recommends the re‐evaluation of its use when the individual is unable either to use the technology appropriately or to achieve the intended outcomes. This pathway is endorsed by UK‐wide clinical and patient associations and we recommend that providers and commissioners use it to ensure the right individual with diabetes has access to the right technology in a timely way to help achieve better outcomes.     

Effects of IFN-gamma and interleukin-1beta on major histocompatibility complex antigen and intercellular adhesion molecule-1 expression by 9L gliosarcoma: relevance to its cytolysis by alloreactive cytotoxic T lymphocytes.

To enhance the efficacy of cellular immunotherapy for gliomas, we tested the concept of using proinflammatory cytokine treatment with interferon-gamma (IFN-gamma) or interleukin-1beta (IL-1beta) or both to render glioma cells more susceptible to cytolysis by alloreactive cytotoxic T lymphocytes (aCTL). The cytokines, separately or in combination, were able to upregulate major histocompatibility complex (MHC) class I antigen or intercellular adhesion molecule-1 (ICAM-1) on Fischer rat 9L gliosarcoma cells. 9L cells were incubated in vitro for 24, 48, or 72 h with varying concentrations of rat IFN-gamma (0-2000 U/ml) or recombinant human IL-1 (rHUIL-1) (0-1000 U/ml) or both. By 48 h, IFN-gamma (500 U/ml) maximally induced the percentage of positive expressing cells and the relative antigen density of MHC class I and ICAM-1 on 9L cells, whereas IL-1 induced only ICAM-1 expression. Simultaneous incubation of IL-1 with IFN-gamma did not further affect the induction of class I on 9L cells more than that achieved with IFN-gamma alone. 9L cells with upregulated MHC class I and ICAM-1 expression were more sensitive to lysis by aCTL in in vitro cytotoxicity assays, regardless of whether the precursor aCTL came from naive or from 9L-immunized rats. Furthermore, inhibition of 9L cytotoxicity in assays that included blocking antibodies to MHC class I or to ICAM-1 revealed that T cell receptor (TCR) interactions with MHC class I and that ICAM-1 interactions with lymphocyte function-associated-1 (LFA-1) antigen account for a portion of the glioma lysis by aCTL.     

Pancreatoblastoma (infantile pancreatic carcinoma)--a case report

Pancreatoblastoma or infantile pancreatic carcinoma is a rare pancreatic tumor with distinct acinar and squamoid cell differentiation that generally affects infants and young children. Ultrasound and CT scan may be useful but preoperative diagnosis is often quite difficult. The outcome is generally favourable. A such case of 10 years old boy with an abdominal mass is being presented.     

Intrathoracic pressure fluctuations move blood during CPR: Comparison of hemodynamic data with predictions from a mathematical model

Whether blood flow during cardiopulmonary resuscitation (CPR) results from intrathoracic pressure fluctuations or direct cardiac compression remains controversial. We developed a mathematical model that predicts that blood flow due to intrathoracic pressure fluctuations should be insensitive to compression rate over a wide range but dependent on the applied force and compression duration. If direct compression of the heart plays a major role, however, the model predicts that flow should be dependent on compression rate and force, but above a threshold, insensitive to compression duration. These differences in hemodynamics produced by changes in rate and duration form a basis for determining whether blood flow during CPR results from intrathoracic pressure fluctuations or from direct cardiac compression. The model was validated for direct cardiac compression by studying the hemodynamics of cyclic cardiac deformation following thoracotomy in four anesthetized, 21–32-kg dogs. As predicted by the model, there was no change in myocardial or cerebral perfusion pressures when the duration of compression was increased from 15% to 45% of the cycle at a constant rate of 60/min. There was, however, a significant increase in perfusion pressures when rate was increased from 60 to 150/min at a constant duration of 45%. The model was validated for intrathoracic pressure changes by studying the hemodynamics produced by a thoracic vest (vest CPR) in eight dogs. The vest contained a bladder that was inflated and deflated. Vest CPR changed intrathoracic pressure without direct cardiac compression, since sternal displacement was <0.8 cm. As predicted by the model and opposite to direct cardiac compression, there was no change in perfusion pressures when the rate was increased from 60 to 150/min at a constant duration of 45% of the cycle. Manual CPR was then studied in eight dogs. There was no surgical manipulation of the chest. Myocardial and cerebral blood flows were determined with radioactive microspheres and behaved as predicted from the model of intrathoracic pressure, not direct cardiac compression. At nearly constant peak sternal force (378–426 N), flow was significantly increased when the duration of compression was increased from short (13%–19% of the cycle) to long (40%–47%), at a rate of 60/min. Flow was unchanged, however, for an increase in rate from 60 to 150/min at constant compression duration. In addition, myocardial and cerebral flow correlated with their respective perfusion pressures. Thus vital organ perfusion pressures and flow for manual external chest compression are dependent on the duration of compression, but not on rates of compression of 60 and 150/min. These data are of course similar to those produced by vest CPR, where intrathoracic pressure is manipulated without sternal displacement, and to those predicted for movement of blood by intrathoracic pressure changes. These data are, however, opposite to those produced by cardiac deformation and to those predicted for movement blood by direct cardiac compression. We conclude that intrathoracic pressure fluctuations generate blood flow during manual CPR.     

Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture

Epilepsy affects approximately 1% of the population worldwide, and there is a pressing need to develop new anti-epileptic drugs (AEDs) and understand their mechanisms of action. Levetiracetam (LEV) is a novel AED and despite its increasingly widespread clinical use, its mechanism of action is as yet undetermined. Intracellular calcium ([Ca²⁺]_i) regulation by both inositol 1,4,5-triphosphate receptors (IP3R) and ryanodine receptors (RyR) has been implicated in epileptogenesis and the maintenance of epilepsy. To this end, we investigated the effect of LEV on RyR and IP3R activated calcium-induced calcium release (CICR) in hippocampal neuronal cultures. RyR-mediated CICR was stimulated using the well-characterized RyR activator, caffeine. Caffeine (10 mM) caused a significant increase in [Ca²⁺]_i in hippocampal neurons. Treatment with LEV (33 μM) prior to stimulation of RyR-mediated CICR by caffeine led to a 61% decrease in the caffeine induced peak height of [Ca²⁺]_i when compared to the control. Bradykinin stimulates IP3R-activated CICR—to test the effect of LEV on IP3R-mediated CICR, bradykinin (1 μM) was used to stimulate cells pre-treated with LEV (100 μM). The data showed that LEV caused a 74% decrease in IP3R-mediated CICR compared to the control. In previous studies we have shown that altered Ca²⁺ homeostatic mechanisms play a role in seizure activity and the development of spontaneous recurrent epileptiform discharges (SREDs). Elevations in [Ca²⁺]_i mediated by CICR systems have been associated with neurotoxicity, changes in neuronal plasticity, and the development of AE. Thus, the ability of LEV to modulate the two major CICR systems demonstrates an important molecular effect of this agent on a major second messenger system in neurons.     

Clinical profile of AIDS: a study at a referral hospital

The present study describes the clinical and epidemiological features of 74 patients with human immunodeficiency virus (HIV) infection who presented to a referral hospital. Sixty two patients (83.7%) were diagnosed to have acquired immune deficiency syndrome (AIDS). Mean age of the patients was 34.9 +/- 12 years and male to female ratio was 3:1. Majority of patients (80%) were from lower socio-economic class. Multiple unprotected heterosexual contact with commercial sex workers in metropolitan cities of India, mainly Mumbai, was major risk factor in 82.1% male patients while most of the females (66.6%) had acquired infection from HIV positive husbands. Blood transfusion was the risk factor in 9(12.1%) patients. Sixty eight patients were infected with HIV 1, one with HIV 2, and five patients with both HIV 1 and HIV 2. Fever and weight loss were the commonest presenting symptoms. Tuberculosis, oropharyngeal candidiasis, and interstitial pneumonitis were present in 54.8%, 40.3% and 20.9% patients, respectively. Fourteen patients (22.5%) had generalised lymphadenopathy. Herpes zoster, cryptococcal meningitis, and peripheral neuropathy were infrequent. Response to standard antifungal and antitubercular treatment was satisfactory. Kaposi's sarcoma, lymphoma, and CNS toxoplasmosis were not found. The clinical manifestations of AIDS patients are strikingly different from that in the Western countries. It, thus, necessitates setting up of different guidelines for the clinical diagnosis and management of AIDS in India.