Concordance between two phenotypic assays and ultradeep pyrosequencing for determining HIV-1 tropism

There have been few studies on the concordance between phenotypic assays for predicting human immunodeficiency virus type 1 (HIV-1) coreceptor usage. The sensitivity of ultradeep pyrosequencing combined with genotyping tools is similar to that of phenotypic assays for detecting minor CXCR4-using variants. We evaluated the agreement between two phenotypic assays, the Toulouse tropism test (TTT) and the Trofile assay, and ultradeep pyrosequencing for determining the tropism of HIV-1 quasispecies. The concordance between the TTT and Trofile assays was assessed for 181 samples successfully phenotyped by both assays. The TTT was 86% concordant with the standard Trofile assay and 91.7% with its enhanced-sensitivity version. The concordance between phenotypic characterization of HIV-1 tropism and ultradeep pyrosequencing genotypic prediction was further studied in selected samples. The HIV-1 tropism inferred from ultradeep pyrosequencing of 11 samples phenotyped as X4 and dualtropic and 12 phenotyped as R5-tropic agreed closely with the results of phenotyping. However, ultradeep pyrosequencing detected minor CXCR4-using variants in 3 of 12 samples phenotyped as R5-tropic. Ultradeep pyrosequencing also detected minor CXCR4-using variants that had been missed by direct sequencing in 6 of 9 samples phenotyped as X4-tropic but genotyped as R5-tropic by direct sequencing. Ultradeep pyrosequencing was 87% concordant with the Trofile and TTT phenotypic assays and was in the same range of sensitivity (0.4%) than these two phenotypic assays (0.3 to 0.5%) for detecting minor CXCR4-using variants. Ultradeep pyrosequencing provides a new way to improve the performance of genotypic prediction of HIV-1 tropism to match that of the phenotypic assays.     

Impact of cortical plasticity on information signaled by populations of neurons in the cerebral cortex

The performance of neural codes to represent attributes of sensory signals has been evaluated in the vertebrate peripheral and central nervous system. Here, we determine how information signaled by populations of neurons is modified by plasticity. Suprathreshold neuronal responses from a large number of neurons were recorded in the juvenile mouse barrel cortex using dithered random-access scanning. Pairing of one input with another resulted in a long-lasting, input-specific modification of the cortical responses. Mutual information analysis indicated that cortical plasticity efficiently changed information signaled by populations of neurons. The contribution of neural correlations to the change in mutual information was negative. The largest factor limiting fidelity of mutual information after pairing was a low reliability of the modified cortical responses.     

Antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic Wistar rats

The present study aims to evaluate the antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic male Wistar rats. To induce diabetes mellitus, rats were injected with streptozotocin intraperitoneally at a single dose of 40 mg/kg. Streptozotocin induced diabetic rats showed significant (P < 0.05) increase in the levels of blood glucose, glycosylated haemoglobin and significant (P < 0.05) decrease in the levels of plasma insulin, body weight and total haemoglobin. Diabetic rats also showed significant (P < 0.05) decrease in the activity of hepatic hexokinase and significant (P < 0.05) increase in the activities of glucose-6-phosphatase and fructose-1, 6-bisphosphatase. The pancreatic thiobarbituric acid reactive substances and lipid hydroperoxides were significantly (P < 0.05) increased and the activities of pancreatic superoxide dismutase, catalase and glutathione peroxidase were significantly (P < 0.05) decreased in diabetic rats. Oral treatment with gallic acid (10 and 20 mg/kg) daily for a period of 21 days showed significant (P < 0.05) protective effects on all the biochemical parameters studied. Histopathology of pancreas confirmed the protective effects of gallic acid in diabetic rats. In vitro study also revealed the potent antioxidant effect of gallic acid. Thus, the study shows the antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic rats. The effect exerted by 20mg/kg body weight of gallic acid was more effective than 10 mg/kg body weight of gallic acid.     

A prospective evaluation of the biochemical, metabolic, hormonal and structural bone changes associated with bortezomib response in multiple myeloma patients

We prospectively evaluated the bone changes associated with proteasome inhibition using single agent bortezomib in relapsed or refractory myeloma patients. Ten patients received bortezomib 1.3 mg/m(2) per days 1, 4, 8 and 11 for three 21-day cycles, and 6 patients received 1 mg/m(2) per day with the same schedule. Bone architecture and metabolism changes were assessed by bone markers, micro-CT, bone histomorphometry, tetracycline labeling and serum parathormone levels. Bone parameter variations were compared by response to treatment. Microarchitectural changes were observed in all evaluable responsive patients. Bone alkaline phosphatase changes were associated with disease response (≥PR vs. others P=0.03 cycle 1, day 11) serum parathormone levels were also significantly increased (P=0.04 on days 11, 21, 33) in responding individuals. This study demonstrates that the myeloma control produced by proteasome inhibition is associated with bone changes and to a discrete pattern of hormonal variation.     

Epidemiology of nasopharyngeal colonization by S. pneumoniae in Indian infants in the first 2 years of life

Background

Streptococcus pneumoniae is a leading cause of invasive disease in developing countries like India. Although the 13 valent pneumococcal vaccine has already been introduced in the country, there is very little epidemiological data regarding S. pneumoniae colonization and antibiotic susceptibility in Indian infants.

Methods

We studied serogroup/serotype (SGT) distribution and antibiotic susceptibility pattern of S. pneumoniae in unvaccinated Indian infants by performing monthly nasopharyngeal swabbing of a birth cohort for 2 years.

Results

Colonization began soon after birth and was complete in the first year of life in the majority of those colonized. Carriage rates increased during winter (p < 0.01) and in those with upper respiratory infection (URI) (p < 0.01). The most frequently (76.1%) isolated SGT were 19, 6, 15, 23, 9, 35 and 10. Vaccine SGT accounted for 60.5% of all colonizers. Antibiotic resistance was maximum for cotrimoxazole (94.3%) and least for erythromycin (11.2%) with no penicillin resistance. Ten of the commonest SGT which cause invasive disease among Indian infants comprised 46.9% of the colonizers. Serogroups 1, 5, 45 and 12 which cause invasive disease in under-fives were not seen in this birth cohort in the first year.

Conclusions

S. pneumoniae colonization in Indian infants commences soon after birth and chiefly occurs in the first year of life. The 13 valent vaccine may protect against a little less than half the commonly seen invasive SGT of S. pneumoniae.     

Inequities in global cancer surgery: Challenges and solutions

The disparity in access to and quality of surgical cancer care between high and low resource settings impacts immediate and long-term oncological outcomes. With cancer incidence and mortality set to increase rapidly in the next few decades, we examine the factors leading to inequities in global cancer surgery, and look at potential solutions to overcome these challenges.     

Modified look-locker inversion recovery T1 mapping indices: assessment of accuracy and reproducibility between magnetic resonance scanners

Background

Cardiovascular magnetic resonance (CMR) T1 mapping indices, such as T1 time and partition coefficient (λ), have shown potential to assess diffuse myocardial fibrosis. The purpose of this study was to investigate how scanner and field strength variation affect the accuracy and precision/reproducibility of T1 mapping indices.

Methods

CMR studies were performed on two 1.5T and three 3T scanners. Eight phantoms were made to mimic the T1/T2 of pre- and post-contrast myocardium and blood at 1.5T and 3T. T1 mapping using MOLLI was performed with simulated heart rate of 40-100 bpm. Inversion recovery spin echo (IR-SE) was the reference standard for T1 determination. Accuracy was defined as the percent error between MOLLI and IR-SE, and scan/re-scan reproducibility was defined as the relative percent mean difference between repeat MOLLI scans. Partition coefficient was estimated by ΔR1myocardium phantom/ΔR1blood phantom. Generalized linear mixed model was used to compare the accuracy and precision/reproducibility of T1 and λ across field strength, scanners, and protocols.

Results

Field strength significantly affected MOLLI T1 accuracy (6.3% error for 1.5T vs. 10.8% error for 3T, p<0.001) but not λ accuracy (8.8% error for 1.5T vs. 8.0% error for 3T, p=0.11). Partition coefficients of MOLLI were not different between two 1.5T scanners (47.2% vs. 47.9%, p=0.13), and showed only slight variation across three 3T scanners (49.2% vs. 49.8% vs. 49.9%, p=0.016). Partition coefficient also had significantly lower percent error for precision (better scan/re-scan reproducibility) than measurement of individual T1 values (3.6% for λ vs. 4.3%-4.8% for T1 values, approximately, for pre/post blood and myocardium values).

Conclusion

Based on phantom studies, T1 errors using MOLLI ranged from 6-14% across various MR scanners while errors for partition coefficient were less (6-10%). Compared with absolute T1 times, partition coefficient showed less variability across platforms and field strengths as well as higher precision.     

Atlas-based analysis of cardiac shape and function: correction of regional shape bias due to imaging protocol for population studies

Background

Cardiovascular imaging studies generate a wealth of data which is typically used only for individual study endpoints. By pooling data from multiple sources, quantitative comparisons can be made of regional wall motion abnormalities between different cohorts, enabling reuse of valuable data. Atlas-based analysis provides precise quantification of shape and motion differences between disease groups and normal subjects. However, subtle shape differences may arise due to differences in imaging protocol between studies.

Methods

A mathematical model describing regional wall motion and shape was used to establish a coordinate system registered to the cardiac anatomy. The atlas was applied to data contributed to the Cardiac Atlas Project from two independent studies which used different imaging protocols: steady state free precession (SSFP) and gradient recalled echo (GRE) cardiovascular magnetic resonance (CMR). Shape bias due to imaging protocol was corrected using an atlas-based transformation which was generated from a set of 46 volunteers who were imaged with both protocols.

Results

Shape bias between GRE and SSFP was regionally variable, and was effectively removed using the atlas-based transformation. Global mass and volume bias was also corrected by this method. Regional shape differences between cohorts were more statistically significant after removing regional artifacts due to imaging protocol bias.

Conclusions

Bias arising from imaging protocol can be both global and regional in nature, and is effectively corrected using an atlas-based transformation, enabling direct comparison of regional wall motion abnormalities between cohorts acquired in separate studies.     

Increasing HIV subtype diversity and its clinical implications in a sentinel North American population

BACKGROUND:

HIV-1 is a highly diverse virus; subtypes may exhibit differences in rates of transmission, disease progression, neurotoxicity, antiretroviral treatment failure profiles and accuracy of viral load measurements. To date, the HIV epidemic in Canada and the rest of the developed world has been largely due to subtype B; however, shifts in subtype epidemiology could have significant implications.

OBJECTIVE:

To determine whether there has been an increase in HIV subtype diversity in southern Alberta, Canada.

METHODS:

All 2358 patients receiving any HIV care between December 31, 2001 and December 31, 2010 were included in a retrospective analysis of subtype prevalence and incidence. In an indexed analysis, subtype trends from 1994 to 2010 were also evaluated.

RESULTS:

Between 2001 and 2010, the prevalence of non-B HIV subtypes in patients with a known subtype increased from 7% to 24%. In 2010, the most prevalent non-B subtypes were C (65%), A (11%), CRF02_AG (9.7%), CRF01_AE (4.9%), D (3.9%), G (2.9%) and CRF06_cpx (1.5%). In the indexed analysis, there was an overall proportional increase in non-B subtypes of 2.3% per year. The year-over-year increase in the prevalence of patients infected with a nonsubtype B virus increased from 13% from 1995 to 2002 to 27% from 2003 to 2010 (P=0.01). Incident non-B subtype cases increased from 9.6% to 32.4% over these time periods.

CONCLUSIONS:

This recent and dramatic shift in HIV strain diversity in Canada is unprecedented and may have important public health, research and clinical consequences.