Immortalization of human bronchial epithelial (hBE) cells often entails loss of differentiation. Bmi-1 is a protooncogene that maintains stem cells, and its expression creates cell lines that ...recapitulate normal cell structure and function. We introduced Bmi-1 and the catalytic subunit of telomerase (hTERT) into three non-cystic fibrosis (CF) and three DeltaF508 homozygous CF primary bronchial cell preparations. This treatment extended cell life span, although not as profoundly as viral oncogenes, and at passages 14 and 15, the new cell lines had a diploid karyotype. Ussing chamber analysis revealed variable transepithelial resistances, ranging from 200 to 1,200 Omega.cm(2). In the non-CF cell lines, short-circuit currents were stimulated by forskolin and inhibited by CFTR(inh)-172 at levels mostly comparable to early passage primary cells. CF cell lines exhibited no forskolin-stimulated current and minimal CFTR(inh)-172 response. Amiloride-inhibitable and UTP-stimulated currents were present, but at lower and higher amplitudes than in primary cells, respectively. The cells exhibited a pseudostratified morphology, with prominent apical membrane polarization, few apoptotic bodies, numerous mucous secretory cells, and occasional ciliated cells. CF and non-CF cell lines produced similar levels of IL-8 at baseline and equally increased IL-8 secretion in response to IL-1beta, TNF-alpha, and the Toll-like receptor 2 agonist Pam3Cys. Although they have lower growth potential and more fastidious growth requirements than viral oncogene transformed cells, Bmi-1/hTERT airway epithelial cell lines will be useful for several avenues of investigation and will help fill gaps currently hindering CF research and therapeutic development.
Although postmenopausal combined hormone replacement therapy reduces the risk of hip fracture, long-term use may be associated with an increased risk of breast cancer, and in women more than 10 years ...after menopause it is associated with an increased risk of cardiovascular disease. Isoflavones, because of preferential binding to estrogen receptor beta, may retain the beneficial effects on bone but lessen the adverse effects on the breast.
The objective of this study was to study the effects of an isoflavone obtained from red clover (Rimostil) on bone mineral density, and on low-density lipoprotein (LDL) cholesterol.
In a double-blind, randomized, placebo-controlled trial, 50 mg of Rimostil was given to women who were menopausal for at least 1 year. Bone mineral density of the spine, femoral neck and forearm and serum LDL cholesterol were measured at baseline and at 6-month intervals. The duration of follow-up was 2 years.
There was no beneficial effect of Rimostil on bone density at any site. There was a 12% fall in serum LDL cholesterol in the Rimostil-treated arm, which was significantly greater than the 2% drop seen in the control arm (P=0.005).
Inappropriate sinus tachycardia (IST) is an incompletely understood condition, characterised by an elevation in heart rate (HR) accompanied by wide ranging symptoms in the absence of an underlying ...physiological stimulus. The condition often takes a chronic course with significant adverse effects on quality of life. Currently, there is no effective treatment for IST. Beta‐blockers, generally considered the cornerstone of treatment, are often ineffective and poorly tolerated. Ivabradine is a novel sinus node If ‘funny current’ inhibitor, which reduces the HR. It has been approved for the treatment of beta‐blocker refractory chronic systolic heart failure and chronic stable angina but more recently has shown promise in the treatment of IST. This review provides an overview of IST prevalence and mechanisms followed by an examination of the evidence for the role and efficacy of ivabradine in the treatment of IST.
Pancreatogenic diabetes is characterised by recurrent severe hypoglycaemia due to changes in both endocrine and exocrine functions. There are no guidelines to manage these individuals. Herein, we ...describe the post-operative management of two people who developed pancreatogenic diabetes following total pancreatectomy for neuroendocrine malignancy. In both individuals, diabetes was managed using sensor-augmented predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII). We demonstrate the benefit of sensor-augmented CSII in averting hypoglycaemia whilst optimising glycaemic control. Expected rates of severe hypoglycaemia in individuals with pancreatogenic diabetes can be averted with the use of continuous glucose monitoring (CGM) technology, optimising quality of life and reducing the risk of diabetes-related complications. Learning points: There are no clear guidelines to manage people with pancreatogenic diabetes. We describe the use of CGM with predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII) in the management of two individuals post-pancreatectomy. Predictive low-glucose suspend technology can achieve excellent glycaemic control whilst avoiding recurrent and severe hypoglycaemia in people with pancreatogenic diabetes. Predictive low-glucose suspend CGM should be considered as an effective therapeutic option for the management of pancreatogenic diabetes.
This study was undertaken to evaluate the effects of varying doses of phytoestrogens on lipid and bone metabolism in postmenopausal women.
A novel red clover isoflavone preparation (Rimostil) ...containing genistein, daidzein, formononetin, and biochanin was administered to 46 postmenopausal women in a double-blind protocol after a single-blind placebo phase and followed by a single-blind washout phase. Patients were randomized to receive either 28.5 mg, 57 mg, or 85.5 mg of phytoestrogens daily for a 6-month period.
At 6 months, the serum high-density lipoprotein cholesterol had risen significantly by 15.7-28.6% with different doses (p = 0.007, p = 0.002, p = 0.027), although the magnitude of the response was independent of the dose used. The serum apolipoprotein B fell significantly by 11.5-17.0% with different doses (p = 0.005, p = 0.043, p = 0.007) and the magnitude of the response was independent of the dose used. The bone mineral density of the proximal radius and ulna rose significantly by 4.1% over 6 months with 57 mg/day (p = 0.002) and by 3.0% with 85.5 mg/day (p = 0.023) of isoflavones. The response with 28.5 mg/day of isoflavones was not significant. There was no significant increase in endometrial thickness with any of the doses of isoflavone used.
These results show that the administration of an isoflavone combination extracted from red clover was associated with a significant increase in high-density lipoprotein cholesterol, a significant fall in apolipoprotein B, and a significant increase in the predominantly cortical bone of the proximal radius and ulna after 6 months of treatment. Interpretation of the results is undertaken cautiously because of the absence of a simultaneously studied control group.
For life insurers in the United Kingdom (UK), the risk margin is one of the most controversial aspects of the Solvency II regime which came into force in 2016. The risk margin is the difference ...between the technical provisions and the best estimate liabilities. The technical provisions are intended to be market-consistent, and so are defined as the amount required to be paid to transfer the business to another undertaking. In practice, the technical provisions cannot be directly calculated, and so the risk margin must be determined using a proxy method; the method chosen for Solvency II is known as the cost-of-capital method. Following the implementation of Solvency II, the risk margin came under considerable criticism for being too large and too sensitive to interest rate movements. These criticisms are particularly valid for annuity business in the UK – such business is of great significance to the system for retirement provision. A further criticism is that mitigation of the impact of the risk margin has led to an increase in reinsurance of longevity risks, particularly to overseas reinsurers. This criticism has led to political interest, and the risk margin was a major element of the Treasury Committee inquiry into EU Insurance Regulation. The working party was set up in response to this criticism. Our brief is to consider both the overall purpose of the risk margin for life insurers and solutions to the current problems, having regard to the possibility of post-Brexit flexibility. We have concluded that a risk margin in some form is necessary, although its size depends on the level of security desired, and so is primarily a political question. We have reviewed possible alternatives to the current risk margin, both within the existing cost-of-capital methodology and considering a wide range of alternatives. We believe that requirements for the risk margin will depend on future circumstances, in particular relating to Brexit, and we have identified a number of possible changes to methodology which should be considered, depending on circumstances.
The APV25 is a 128-channel analogue pipeline chip for the readout of silicon microstrip detectors in the CMS tracker at the LHC. Each channel comprises a low noise amplifier, a 192-cell analogue ...pipeline and a deconvolution readout circuit. Output data are transmitted on a single differential current output via an analogue multiplexer. The chip is fabricated in a standard 0.25
μm CMOS process to take advantage of the radiation tolerance, lower noise and power, and high circuit density. Experimental characterisation of this circuit shows full functionality and good performance both in pre- and post-irradiation (20
Mrad) conditions. The measured noise is significantly reduced compared to earlier APV versions. A description of the design and results from measurements prior to irradiation are presented.
Background. Anaemia is a common finding in patients with diabetes and constitutes an additional burden in patients with advancing age and comorbid vascular disease. This study examines the prevalence ...and predictors of anaemia in long-term outpatients with type 2 diabetes from three large clinical centres. Methods. A full blood count was obtained in addition to routine testing in a cross-sectional survey of all patients with type 2 diabetes in long-term follow-up at the Austin Medical Centre, Melbourne (n = 670) and the Royal Prince Alfred Hospital (n = 915) and the Royal North Shore Hospital (n = 540), Sydney, Australia. The prevalence and correlates of anaemia (haemoglobin < 130 g/l in men and < 120 g/l in women) were identified using multivariate logistic regression. Results. Roughly, one in five patients in each centre had anaemia. Patients at greatest risk could be readily identified by the presence of renal disease, manifested as impaired renal function and/or albuminuria in > 75% of patients with anaemia. Patients with diabetes and mild renal impairment creatinine clearance (CCr) 60–90 ml/min/1.73 m2 were twice as likely to have anaemia as those with normal renal function (CCr > 90 ml/min/1.73 m2). Diabetics with moderate renal impairment (CCr < 60 ml/min/1.73 m2) were also twice as likely to have anaemia as those with mild renal impairment. Patients with anaemia were also more likely to have macrovascular disease, reflecting the high prevalence of nephropathy in these patients. Conclusions. Anaemia is a prevalent finding in patients with type 2 diabetes and represents a significant unrecognized burden. Patients at greatest risk can be identified by the presence of renal disease, either in the form of renal impairment and/or albuminuria.
During Run-1 of the LHC, many operational procedures have been automated in the run control system of the Compact Muon Solenoid (CMS) experiment. When detector high voltages are ramped up or down or ...upon certain beam mode changes of the LHC, the DAQ system is automatically partially reconfigured with new parameters. Certain types of errors such as errors caused by single-event upsets may trigger an automatic recovery procedure. Furthermore, the top-level control node continuously performs cross-checks to detect sub-system actions becoming necessary because of changes in configuration keys, changes in the set of included front-end drivers or because of potential clock instabilities. The operator is guided to perform the necessary actions through graphical indicators displayed next to the relevant command buttons in the user interface. Through these indicators, consistent configuration of CMS is ensured. However, manually following the indicators can still be inefficient at times. A new assistant to the operator has therefore been developed that can automatically perform all the necessary actions in a streamlined order. If additional problems arise, the new assistant tries to automatically recover from these. With the new assistant, a run can be started from any state of the sub-systems with a single click. An ongoing run may be recovered with a single click, once the appropriate recovery action has been selected. We review the automation features of CMS Run Control and discuss the new assistant in detail including first operational experience.
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