Regulation of cell proliferation in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening genetic disorder characterized by the presence of fluid-filled cysts primarily in the kidneys. Mutations in either the PKD1 or PKD2 genes are the underlying cause of ADPKD. It is a systemic disorder and some of the extra-renal manifestations include polycystic liver, cerebral aneurysms, cardiac valve abnormalities and hypertension. Progressive cyst formation and renal enlargement lead to renal insufficiency in these patients which need to be managed by life-long dialysis or renal transplantation. Epithelial cell proliferation and fluid secretion are two hallmark features of PKD. Cux1 is a homeobox gene involved in cell cycle regulation during kidney development. In the developing mouse kidney, Cux1 is highly expressed in the nephrogenic zone where developing nephrons are present. Cux1 regulates the cell cycle by transcriptional repression of the cyclin dependent kinase inhibitors, p21 and p27, thereby increasing cell proliferation. As kidney development ceases, Cux1 is downregulated and adult kidneys show only low levels of Cux1. Cux1 is ectopically expressed in several mouse models of PKD, as well as, in ADPKD patients. Cux1 transgenic mice which overexpress Cux1 develops multiorgan hyperplasia including kidney hyperplasia, but they do not develop PKD. This suggests that the overexpression of Cux1 and the resultant increase in cell proliferation is not sufficient to cause PKD. In this particular study, we addressed the hypothesis that Cux1 is required for cystogenesis and/or cyst progression in ADPKD. Results from our mouse model which carries a collecting duct specific deletion in the Pkd1 gene (Pkd1CD) and a homozygous deletion in the Cux1 gene shows that the complete loss of Cux1 results in slowing the cyst initiation process. Moreover, a reduction in the gene dosage of Cux1 in Pkd1CD mice led to a slow progression of PKD resulting in the amelioration of the disease. The complete loss of the Cux1 gene and a reduction in its gene dosage mediated its effects by the de-repression of the p27 gene resulting in reduced cell proliferation. These studies point towards the importance of cell proliferation in the pathogenesis of PKD and show that Cux1 is required for cyst progression in ADPKD

Standard of Living and Community Perception in the Community Based Ecotourism (CBET) Sites of Kerala: An Inter Zone Analysis

This study is an attempt to situate the quality of life and standard of living of local communities in ecotourism destinations inter alia their perception on forest conservation and the satisfaction level of the local community. 650 EDC/VSS members from Kerala demarcated into three zones constitute the data source. Four variables have been considered for evaluating the quality of life of the stakeholders of ecotourism sites, which is then funneled to the income-education spectrum for hypothesizing into the SLI framework. Zone-wise analysis of the community members working in tourism sector shows that the community members have benefited totally from tourism development in the region as they have got both employments as well as secured livelihood options. Most of the quality of life-indicators of the community in the eco-tourist centres show a promising position. The community perception does not show any negative impact on environment as well as on their local culture. Keywords: Kerala, Community Based Ecotourism, Community Perception, Community Participation, Standard of Living, Local Communitie

Tax Avoidance by MNCs: Blame Firms or Tax Systems?

Tax Avoidance by multinational corporations has become a hot topic across the globe. Many of the biggest corporations in the world have been in the news for not paying their fair share of income to the respective countries. While they have been criticised for dodging tax, the legal loopholes used by them provide shelter for doing so. Many governments and tax authorities are concerned about this subject, as it is causing huge revenue losses to the countries. This research paper evaluates the loopholes in the international tax system. In order to do so, cases of tax avoidance are analysed to find out the tax planning strategies of the corporations. The cases analysed here shows the evidence of profit shifting by the companies. It also depicts the methods they adopted to avoid different taxes. The analysis of six tax avoidance cases shows that there are many common loopholes, which were exploited by these companies. These include the opportunities to create any number of intermediate holding companies and subsidiaries, differences in determining tax residency by different countries, chances to use tax havens, transfer pricing & the difficulty in valuing intangible assets, and intra-group financing arrangements

Comparative study on prediction of paediatric endotracheal tube size by ultrasonography and by age based formulas

Background: Age-based formulas have been widely used to predict the appropriate size of the endotracheal tube (ETT) for intubation in paediatric age group. These formulas often fail to reliably predict the proper size of ETT. The objective of the study is to determine whether the tracheal internal diameter imaged by ultrasound is a better predictor of ETT size than age based formulas.Methods: The study included a total of 60 patients of ASA 1 and 2 aged between 2 and 15 years of either sex posted for elective surgery under general anaesthesia. After institutional ethical committee approval and written consent from the parents, anaesthesia was induced as per the protocol. The tracheal diameter was measured after induction of anaesthesia, during mask ventilation prior to intubation. A linear high frequency ultrasound probe (GE venue 40) was used to measure the tracheal diameter. The size of ETT was selected according to the measured tracheal diameter. The leak test and adequate oxygenation/ventilation were the objective tests used to validate the appropriateness of the ETT chosen. The ETT sizes determined by age based formulas and by the use of ultrasound were statistically compared with the appropriate ETT size used clinically for intubation.Results: The estimation of endotracheal tube size with the aid of ultrasound was found to be superior when compared with age based formulas. Ultrasound tube size determination correlated well with clinically used ETT size.Conclusions: Determination of endotracheal tube size by ultrasound is a good predictor of proper sized ETT in paediatric age group when compared with age based formulas.

Compact Tunable Filters for Broadband Applications

AbstractMicrowave filters are essential components of modern communication systems. Miniaturization of microwave filters is of much demand in today's rapidly changing communication world with ever more growing wireless applications. The paper presents compact tunable band pass filters to provide multiple bands of operation. The filter employs tunable/chip inductors along with an inter-digital coupled line for introducing transmission zeros on both band edges. Tunability is achieved by varying the inductor values. The stop band attenuation is improved by etching Complementary Split Ring Resonators (CSRR's) and Defected Ground Structures (DGS) in the ground plane

Service utilization and suicide among people with schizophrenia spectrum disorders

Objective: To compare individuals with and without schizophrenia spectrum disorders (SSD) (schizophrenia, schizoaffective disorder, or psychotic disorder not otherwise specified) who die by suicide. Method: This is a retrospective case control study which compared all individuals who died by suicide in Ontario, Canada with (cases) and without (controls) SSD between January 1, 2008 and December 31, 2012. Cases (individuals with SSD) were compared to controls on demographics, clinical characteristics, and health service utilization proximal to suicide. A secondary analysis compared the characteristics of those with SSD and those with severe mental illness (defined as those without SSD who have had a psychiatric hospitalization within the five-years before suicide (excluding the 30 days prior to death)). Results: Among 5650 suicides, 663 (11.7%) were by individuals with SSD. Compared to other suicides, SSD suicides were significantly more likely to be between the ages of 25–34. SSD suicide victims were significantly more likely to reside in the lowest income neighbourhoods and to reside in urban areas. SSD victims were also significantly more likely to have comorbid mood and personality disorders and all types of health service utilization, including outpatient mental health service contact in the 30 days prior to death, even when compared only with those who had a history of mental health hospitalization. Conclusions: Individuals with schizophrenia spectrum disorder account for over 1 in 10 suicide deaths, tend to be younger, poorer, urban, more clinically complex, and have higher rates of mental health service contact prior to death. The demographic and service utilization differences persist even when the SSD group is compared with a population with severe mental illness that is not SSD. Suicide prevention strategies for people with schizophrenia spectrum disorder should emphasize the importance of clinical suicide risk assessment during clinical encounters, particularly early in the course of illness

Aspirin in primary prevention of cardiovascular disease and cancer : a systematic review of the balance of evidence from reviews of randomized trials

Background: Aspirin has been recommended for primary prevention of cardiovascular disease (CVD) and cancer, but overall benefits are unclear. We aimed to use novel methods to re-evaluate the balance of benefits and harms of aspirin using evidence from randomised controlled trials, systematic reviews and meta-analyses. Methods and Findings: Data sources included ten electronic bibliographic databases, contact with experts, and scrutiny of reference lists of included studies. Searches were undertaken in September 2012 and restricted to publications since 2008. Of 2,572 potentially relevant papers 27 met the inclusion criteria. Meta-analysis of control arms to estimate event rates, modelling of all-cause mortality and L'Abbé plots to estimate heterogeneity were undertaken. Absolute benefits and harms were low: 60-84 major CVD events and 34-36 colorectal cancer deaths per 100,000 person-years were averted, whereas 46-49 major bleeds and 68-117 gastrointestinal bleeds were incurred. Reductions in all-cause mortality were minor and uncertain (Hazard Ratio 0.96; 95% CI: 0.90-1.02 at 20 years, Relative Risk [RR] 0.94, 95% CI: 0.88-1.00 at 8 years); there was a non-significant change in total CVD (RR 0.85, 95% CI: 0.69-1.06) and change in total cancer mortality ranged from 0.76 (95% CI: 0.66-0.88) to 0.93 (95% CI: 0.84-1.03) depending on follow-up time and studies included. Risks were increased by 37% for gastrointestinal bleeds (RR 1.37, 95% CI: 1.15-1.62), 54%-66% for major bleeds (Rate Ratio from IPD analysis 1.54, 95% CI: 1.30-1.82, and RR 1.62, 95% CI: 1.31-2.00), and 32%-38% for haemorrhagic stroke (Rate Ratio from IPD analysis 1.32; 95% CI: 1.00-1.74; RR 1.38; 95% CI: 1.01-1.82). Conclusions: Findings indicate small absolute effects of aspirin relative to the burden of these diseases. When aspirin is used for primary prevention of CVD the absolute harms exceed the benefits. Estimates of cancer benefit rely on selective retrospective re-analysis of RCTs and more information is needed

Time-Domain Characterization of Dual Band Spiral Antenna with WMTS/UWB Application

A coplanar waveguide- (CPW-) fed spiral antenna with dual band application is presented. The antenna is designed to operate over the UWB (3.1–10.6 GHz) band as well as in a lower band suitable for WMTS (1.395–1.4 GHz). Frequency domain characterization shows that the antenna is well matched with appreciable gain in both bands. Time-domain studies are carried out to check the suitability of the antenna in pulsed communication. A prototype of the antenna is fabricated and measured results show low group delay variation in the UWB. FWHM and ringing of antenna impulse response, fidelity factor, and radiated power spectral density are also presented

Nmp4/CIZ suppresses the response of bone to anabolic parathyroid hormone by regulating both osteoblasts and osteoclasts

How parathyroid hormone (PTH) increases bone mass is unclear, but understanding this phenomenon is significant to the improvement of osteoporosis therapy. Nmp4/CIZ is a nucleocytoplasmic shuttling transcriptional repressor that suppresses PTH-induced osteoblast gene expression and hormone-stimulated gains in murine femoral trabecular bone. To further characterize Nmp4/CIZ suppression of hormone-mediated bone growth, we treated 10-week-old Nmp4-knockout (KO) and wild-type (WT) mice with intermittent human PTH(1–34) at 30 μg/kg daily or vehicle, 7 days/week, for 2, 3, or 7 weeks. Null mice treated with hormone (7 weeks) gained more vertebral and tibial cancellous bone than WT animals, paralleling the exaggerated response in the femur. Interestingly, Nmp4/CIZ suppression of this hormone-stimulated bone formation was not apparent during the first 2 weeks of treatment. Consistent with the null mice enhanced PTH-stimulated addition of trabecular bone, these animals exhibited an augmented hormone-induced increase in serum osteocalcin 3 weeks into treatment. Unexpectedly, the Nmp4-KO mice displayed an osteoclast phenotype. Serum C-terminal telopeptide, a marker for bone resorption, was elevated in the null mice, irrespective of treatment. Nmp4-KO bone marrow cultures produced more osteoclasts, which exhibited elevated resorbing activity, compared to WT cultures. The expression of several genes critical to the development of both osteoblasts and osteoclasts was elevated in Nmp4-KO mice at 2 weeks, but not 3 weeks, of hormone exposure. We propose that Nmp4/CIZ dampens PTH-induced improvement of trabecular bone throughout the skeleton by transiently suppressing hormone-stimulated increases in the expression of proteins key to the required enhanced activity and number of both osteoblasts and osteoclasts