Multiscale model for the effects of adaptive immunity suppression on the viral therapy of cancer

Oncolytic virotherapy - the use of viruses that specifically kill tumor cells - is an innovative and highly promising route for treating cancer. However, its therapeutic outcomes are mainly impaired by the host immune response to the viral infection. In the present work, we propose a multiscale mathematical model to study how the immune response interferes with the viral oncolytic activity. The model assumes that cytotoxic T cells can induce apoptosis in infected cancer cells and that free viruses can be inactivated by neutralizing antibodies or cleared at a constant rate by the innate immune response. Our simulations suggest that reprogramming the immune microenvironment in tumors could substantially enhance the oncolytic virotherapy in immune-competent hosts. Viable routes to such reprogramming are either in situ virus-mediated impairing of CD$8^+$ T cells motility or blockade of B and T lymphocytes recruitment. Our theoretical results can shed light on the design of viral vectors or new protocols with neat potential impacts on the clinical practice.Comment: 14 pages, 4 figure

Variability assessment and construction of infectious clone of Indian Apple Scar Skin Viroid

Apple scar skin viroid (ASSVd) is widely distributed and economically important pome-fruit infecting viroid belonging to the genus Apscaviroid. It causes huge economic losses to the apple industry. Apple fruits with dappling, scarring, cracking and deformation symptoms were noticed during survey of apple growing regions of Himachal Pradesh, India. ASSVd was detected from four isolates showing dappled fruits. Molecular characterization of the viroid was done. Ten clones each from five isolates were sequenced out of which seven new sequence variants of ASSVd were found. Four of the clones were 330 nucleotides (nt) long and the other eight had an additional nucleotide. The clones showed significant sequence variability (94-100%) with each other. Variability was more common in the pathogenic domain of the viroid genome. Present isolates grouped with some Chinese and Korean isolates in phylogenetic analysis. The study reports seven new sequence variants of ASSVd and also gives a first molecular evidence of a viroid infection (ASSVd) in apple from India. Infectious clone of ASSVd were constructed for in vitro mutagenic studies. Keywords: Apple scar skin viroid, cloning, DNA sequencing, phylogenetic analysi

Nucleotide analysis of pome fruit virus isolates detected in apple and pear samples from Italy and India

In the framework of a joint research project between Italy and India field surveys were done in different pear and apple growing areas of North of India and Central and Southern Italy. Samples were collected from plants belonging to common and local varieties and molecularly analyzed for the detection of the main pome fruit viruses (Apple stem pitting virus, Apple stem groving virus, Apple chlorotic leaf spot virus, Apple mosaic virus) by using harmonized diagnostic protocols.The sequence homology was evaluated and a phylogenetic tree was built, on the basis of which, the Indian isolate of ASGV showed maximum sequence identity at a nucleotide level to Italian isolates when analyzed by BLAST (http://blast.ncbi.nlm.nih.gov/Blast.cgi). Similarly, a maximum identity, ranging from 90-93%, was found for the Italian isolates of ASPV and pear and apple isolates from Poland, while a sequence homology ranging from 83 to86% was observed within the Indian isolates of ASPV. Multiple alignment of the Indian pome ACLSV-isolates indicate maximum variability in the middle portion while the first 140 nucleotides are maximally conserved and shared a percent identity at nucleotide level of 86-100% with the Italian isolates.The ApMV Indian isolates showed maximum (92-99%) sequence homology to the Korean isolate (AY125977) from apple. However, a comparison with other isolates from different host plant species revealed a clustering of Indian isolates with a Czech isolate from pear and a sequence homology of 84 to 98%. Phylogenetic analysis showed that sequence variability was independent to the geographical origin or the host for all the investigated viruses.Keywords: ACLSV, ASPV, ASGV, ApMV, sequences analysis, Italy, India

History of Foot Ulcer Increases Mortality Among Individuals With Diabetes: Ten-year follow-up of the Nord-Trøndelag Health Study, Norway

OBJECTIVE To compare mortality rates for individuals with diabetes with and without a history of foot ulcer (HFU) and with that for the nondiabetic population. RESEARCH DESIGN AND METHODS This population-based study included 155 diabetic individuals with an HFU, 1,339 diabetic individuals without an HFU, and 63,632 nondiabetic individuals who were all followed for 10 years with mortality as the end point. RESULTS During the follow-up period, a total of 49.0% of diabetic individuals with an HFU died, compared with 35.2% of diabetic individuals without an HFU and 10.5% of those without diabetes. In Cox regression analyses adjusted for age, sex, education, current smoking, and waist circumference, having an HFU was associated with more than a twofold (2.29 [95% CI 1.82–2.88]) hazard risk for mortality compared with that of the nondiabetic group. In corresponding analyses comparing diabetic individuals with and without an HFU, an HFU was associated with 47% increased mortality (1.47 [1.14–1.89]). Significant covariates were older age, male sex, and current smoking. After inclusion of A1C, insulin use, microalbuminuria, cardiovascular disease, and depression scores in the model, each was significantly related to life expectancy. CONCLUSIONS AN HFU increased mortality risk among community-dwelling adults and elderly individuals with diabetes. The excess risk persisted after adjustment for comorbidity and depression scores, indicating that close clinical monitoring might be warranted among individuals with an HFU, who may be particularly vulnerable to adverse outcomes. Hospital-based studies have shown that mortality rates in individuals with diabetic foot ulcers are about twice those observed in individuals with diabetes without foot ulcers (1,2). A diabetic foot ulcer reflects the presence of underlying pathological conditions, and the risk of recurrent ulcers is high (3,4). It has been suggested that the elevated mortality rate among individuals with diabetic foot ulcers is related to comorbid disease such as cardiovascular disease and nephropathy (5) or to psychological factors including depression (6). Although the mortality rate in individuals with diabetes is high, no large population-based studies have examined the impact on mortality of a history of foot ulcers (HFU) among individuals with diabetes. The purpose of this study was to compare mortality rates for individuals with diabetes reporting an HFU with those for individuals without an HFU and the nondiabetic population. These issues were investigated in the Nord-Trøndelag Health Study (HUNT 2), which includes a very large population-based sample of men and women from a well-defined geographic area. Participants with self-reported diabetes were well characterized with regard to their diabetes, and information on demographics, lifestyle, and prevalent disease including depression was available

Low documentation of chronic kidney disease among high-risk patients in a managed care population: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Early detection of chronic kidney disease (CKD) is sub-optimal among the general population and among high risk patients. The prevalence and impact of major CKD risk factors, diabetes (DM) and hypertension (HTN), on CKD documentation among managed care populations have not been previously reported. We examined this issue in a Kaiser Permanente Georgia (KPG) CKD cohort.</p> <p>Methods</p> <p>KPG enrollees were included in the CKD cohort if they had eGFRs between 60 and 365 days apart that were <90 ml/min during 1999-2006. The current analysis is restricted to participants with eGFR 10-59 ml/min/1.73 m². CKD documentation was defined as a presenting diagnosis of CKD by a primary care physician or nephrologist using ICD-9 event codes. The association between CKD documentation and DM and HTN were assessed with multivariate logistic regression models.</p> <p>Results</p> <p>Of the 50,438 subjects within the overall KPG CKD cohort, 20% (N = 10,266) were eligible for inclusion in the current analysis. Overall, CKD diagnosis documentation was low; only 14.4% of subjects had an event-based CKD diagnosis at baseline. Gender and types 2 diabetes interacted on CKD documentation. The prevalence of CKD documentation increased with the presence of hypertension and/or type 2 diabetes, but type 2 diabetes had a lower effect on CKD documentation. In multivariate analysis, significant predictors of CKD documentation were eGFR, hypertension, type 2 diabetes, congestive heart failure, peripheral artery disease, statin use, age and gender. CKD documentation was lower among women than similarly affected men.</p> <p>Conclusion</p> <p>Among patients with an eGFR 10-59, documentation of CKD diagnosis by primary and subspecialty providers is low within a managed care patient cohort. Gender disparities in CKD documentation observed in the general population were also present among KPG CKD enrollees.</p

Insufficient Control of Blood Pressure and Incident Diabetes

Incidence of type 2 diabetes might be associated with preexisting hypertension. There is no information on whether incident diabetes is predicted by blood pressure control. We evaluated the hazard of diabetes in relation to blood pressure control in treated hypertensive patients.Nondiabetic, otherwise healthy, hypertensive patients (N = 1,754, mean +/- SD age 52 +/- 11 years, 43\% women) participated in a network over 3.4 +/- 1 years of follow-up. Blood pressure was considered uncontrolled if systolic was >or=140 mmHg and/or diastolic was >or=90 mmHg at the last outpatient visit. Diabetes was defined according to American Diabetes Association guidelines.Uncontrolled blood pressure despite antihypertensive treatment was found in 712 patients (41\%). At baseline, patients with uncontrolled blood pressure were slightly younger than patients with controlled blood pressure (51 +/- 11 vs. 53 +/- 12 years, P < 0.001), with no differences in sex distribution, BMI, duration of hypertension, baseline blood pressure, fasting glucose, serum creatinine and potassium, lipid profile, or prevalence of metabolic syndrome. During follow-up, 109 subjects developed diabetes. Incidence of diabetes was significantly higher in patients with uncontrolled (8\%) than in those with controlled blood pressure (4\%, odds ratio 2.08, P < 0.0001). In Cox regression analysis controlling for baseline systolic blood pressure and BMI, family history of diabetes, and physical activity, uncontrolled blood pressure doubled the risk of incident diabetes (hazard ratio [HR] 2.10, P < 0.001), independently of significant effects of age (HR 1.02 per year, P = 0.03) and baseline fasting glucose (HR 1.10 per mg/dl, P < 0.001).In a large sample of treated nondiabetic hypertensive subjects, uncontrolled blood pressure is associated with twofold increased risk of incident diabetes independently of age, BMI, baseline blood pressure, or fasting glucose

Impact of hip arthroplasty registers on orthopaedic practice and perspectives for the future

Total hip arthroplasty (THA) registers are established in several countries to collect data aiming to improve the results after THA. Monitoring of adverse outcomes after THA has focused mainly on revision surgery, but patient-reported outcomes have also been investigated.Several surgery-related factors influencing the survival of the THA have been thoroughly investigated and have changed clinical practice. These factors include surgical approach, specific implants, the size of the components, type of fixation and different bone cements.Register data have been used to examine the risk of venous thromboembolism and bleeding after THA. These investigations have resulted in shorter duration of thromboprophylaxis and a reduced frequency of blood transfusion.Registers may provide specific information to surgeons on the outcome of all THAs that they have performed with a detailed analysis of revisions rates and reasons for the revisions.A number of other stakeholders can use register data to provide benchmarks. The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man supplies data to the Orthopaedic Device Evaluation Panel (ODEP), which provides benchmarks at 3, 5, 7, 10, and 13 years graded from A*, A, B and C.Future perspectives: National registers have to play a major role in documenting the quality of THA in order to describe best practice and report implant outliers. The registers have to be used for research and post-market surveillance and register data may be a source for intelligent decision tools

Association of Mild to Moderate Chronic Kidney Disease With Venous Thromboembolism Pooled Analysis of Five Prospective General Population Cohorts

BACKGROUND: Recent findings suggest that chronic kidney disease (CKD) may be associated with increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted. METHODS AND RESULTS: We pooled individual participant data from five community-based cohorts from Europe (HUNT2, PREVEND and Tromsø study) and United States (ARIC and CHS study) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria and CKD with objectively verified VTE. To estimate adjusted hazard ratios (HRs) for VTE, categorical and continuous spline models were fit using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1,178 VTE events occurred over 599,453 person-years follow-up. Relative to eGFR 100 mL/min/1.73m(2), HRs for VTE were 1.29 (95%CI, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for 60, 1.82 (1.27-2.60) for 45 and 1.95 (1.26-3.01) for 30 mL/min/1.73m(2). Compared with albumin-creatinine ratio (ACR) of 5.0 mg/g, the HRs for VTE were 1.34 (1.04-1.72) for 30 mg/g, 1.60 (1.08-2.36) for 300 mg/g and 1.92 (1.19-3.09) for 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted HR for CKD defined as eGFR <60 mL/min/1.73m(2) or albuminuria ≥30 mg/g (vs. no CKD) was 1.54 (95%CI, 1.15-2.06). Associations were consistent in subgroups according to age, gender, and comorbidities as well as for unprovoked versus provoked VTE. CONCLUSIONS: Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges