Inducible protective processes in animal systems. X. Influence of nicotinamide in methyl methanesulfonate-adapted mouse bone marrow cells.

The adaptive response is an error-free DNA repair mechanism induced by low levels of physical or chemical agents. Cells pre-exposed to such agents are resistant to genetic damage induced by subsequent treatment at a high dose. There are many reports on such adaptive responses. Recently we have shown the existence of adaptive responses in vivo in the grasshopper Poecilocerus pictus and the mouse and in vitro in human lymphocytes. Different enzymes are implicated in this DNA repair pathway. In an attempt to understand the molecular mechanism of the methyl methanesulfonate (MMS)-induced adaptive response, the present investigations have been undertaken employing nicotinamide, an inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). Pre-, inter- and post-treatments with nicotinamide of MMS-treated mouse bone marrow cells were carried out. The results revealed that there is a significant reduction in the frequency of chromosomal aberrations compared with combined treatment, suggesting an enhancement of the adaptive response by nicotinamide. Further, the results of NAD+ assay in the inter-treatment experiment showed that there is no depletion of NAD+. Thus, it can be stated that PARP is not involved in the MMS-induced adaptive response in mouse bone marrow cells.     

Molecular composition of the alveolar lining fluid in the aging lung

As we age, there is an increased risk for the development of pulmonary diseases, including infections, but few studies have considered changes in lung surfactant and components of the innate immune system as contributing factors to the increased susceptibility of the elderly to succumb to infections. We and others have demonstrated that human alveolar lining fluid (ALF) components, such as surfactant protein (SP)-A, SP-D, complement protein C3, and alveolar hydrolases, play a significant innate immune role in controlling microbial infections. However, there is a lack of information regarding the effect of increasing age on the level and function of ALF components in the lung. Here we addressed this gap in knowledge by determining the levels of ALF components in the aging lung that are important in controlling infection. Our findings demonstrate that pro-inflammatory cytokines, surfactant proteins and lipids, and complement components are significantly altered in the aged lung in both mice and humans. Further, we show that the aging lung is a relatively oxidized environment. Our study provides new information on how the pulmonary environment in old age can potentially modify mucosal immune responses, thereby impacting pulmonary infections and other pulmonary diseases in the elderly population.     

Supravalvular aortic stenosis and coronary ostial stenosis in homozygous familial hypercholesterolemia

Patients with homozygous familial hypercholesterolemia exhibit severe hypercholesterolemia, cutaneous and tendon xanthomata, and premature atherosclerosis from childhood. A rare presentation of this condition with supravalvular aortic stenosis and coronary ostial stenosis is described.     

Relative percentage signal intensity recovery of perfusion metrics—an efficient tool for differentiating grades of glioma

Objective:

Glioma classification and characterization may be facilitated by a multiparametric approach of perfusion metrics, which could not be achieved by conventional MRI alone. Our aim is to explore the potential of relative percentage signal intensity recovery (rPSR) values, in addition to relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) of first-pass T₂* dynamic susceptibility contrast (DSC) perfusion MRI, in differentiating high- and low-grade glioma.

Methods:

This prospective study included 39 patients with low-grade and 25 patients with high-grade glioma. rPSR, rCBV and rCBF were calculated from the first-pass T₂* DSC perfusion MRI. rPSR was calculated using standard software and validated with dedicated perfusion metrics analysis software. The statistical analysis was performed using analysis of variance and receiver operating characteristic (ROC) curves.

Results:

Variation in rPSR, rCBV and rCBF values between low- and high-grade gliomas were statistically significant (p < 0.005). The ROC curve analysis for each of them yielded 96% sensitivity and 71.8% specificity; 88% sensitivity and 69.2% specificity; and 72% sensitivity and 66.7% specificity. The area under the curve (AUC) from the ROC curve analysis yielded 0.893, 0.852 and 0.702 for rPSR, rCBV and rCBF, respectively. The rPSR calculation with the validation software yielded 92.3% sensitivity and 72% specificity with an AUC of 0.864.

Conclusion:

rPSR inversely correlates while rCBV and rCBF values directly correlate with the tumour grade. Furthermore, the overall diagnostic performance of rPSR is better than rCBV and rCBF values.

Advances in knowledge:

rPSR of T₂* DSC perfusion is an indicator of blood–brain barrier status and lesion leakiness, which has not been explored yet compared with the usual haemodynamic parameters, rCBV and rCBF.Gliomas, the most common primary brain tumour of the brain, are heterogeneous, showing highly varied histopathological features during malignant transformation of the tumour reflecting alterations in the tumour vasculature.¹ The broad category of glioma represents approximately 30% of all the tumours. Low-grade astrocytomas (60–70%) and oligodendrogliomas (10–30%) are two common subtypes of low-grade gliomas. Among them, glioblastoma and astrocytoma account for 75% of gliomas.² With the advent of advanced imaging technologies, heterogeneity in gliomas such as neovascularization, angiogenesis, loss of blood–brain barrier (BBB) integrity, tortuousness, disorganized and highly permeable vessels may be non-invasively measured with the help of perfusion imaging.^3–5 Dynamic susceptibility contrast (DSC) perfusion MRI is a widely accepted tool for evaluating the haemodynamic characteristics of the brain, which are of great interest since it helps in assessing the malignancy of the tumour. The common haemodynamic parameters assessed using perfusion MRI are relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF).^6–8 In this study, we use a comparatively newer parameter, relative percentage signal intensity recovery (rPSR), whose potential has not been exploited to its best for haemodynamic calculations, even though this parameter has shown promise in the differentiation of brain tumours.^9–11 PSR is the percentage of the signal intensity recovered at the end of the first pass of the contrast agent with respect to the pre-contrast baseline signal intensity. After the administration of the contrast agent, there is a sudden decrease in the signal intensity owing to the variation in the local magnetic field leading to T₂* decay, which is seen as a dip in the mean signal intensity–time curve, and then the signal returns towards the baseline.^9–11The tumour rCBV provides information about the tumour blood levels and degree of angiogenesis but fails to provide information regarding capillary permeability. This drawback of DSC-MR perfusion imaging can be addressed by evaluating the rPSR obtained from the signal intensity–time curve formed at the end of the first pass of contrast agent in DSC-MR perfusion imaging.^9,10 Previous studies have observed that the contrast agent leakage, size of the extravascular space and the rate of blood flow that reflects the alterations in capillary permeability are related to rPSR.^10,11 There are reports which state that information regarding capillary permeability and lesion leakiness can be gathered from the signal intensity–time curve obtained from the first-pass T₂* DSC perfusion. Usually, this is performed using dynamic contrast-enhanced perfusion MRI, which involves additional scan time and also post-processing assumptions and extrapolations.^9–11Lupo et al⁴ was the first to report the characterization of high-grade gliomas using the PSR and peak height. rPSR is the only parameter among the different perfusion metrics which takes into account the leakage factor for the characterization of heterogeneity of brain tissues, compared with the other two parameters rCBV and rCBF where the leakage is neglected during the evaluation. The rPSR values of lower grade gliomas have not been explored, and hence an effort to differentiate between high- and low-grade gliomas using this new parameter will be advantageous. Hence, in the present study, we have evaluated all the parameters rPSR, rCBV and rCBF of low- and high-grade gliomas to find the potential of rPSR to differentiate different grades of glioma over the other two conventionally used parameters rCBV and rCBF. rPSR values were evaluated using two different standard software programs. Furthermore, we have performed a test for correlation between these parameters.     

Childhood cancer incidence in India: A review of population-based cancer registries

Objectives

To summarize and provide an overview of the childhood cancer incidence reported in 25 population-based cancer registries of India.

Methods

Secondary data on age-adjusted rates of cancer incidence for children (0–14 years) were collected from the report of the National Cancer Registry Programme in the year 2013. range of age-adjusted-rates per million children were tabulated for six regions of the country.

Results

Age-adjusted cancer incidence rates ranged from 18.6 per million to 159.6 per million for boys and 11.3 to 112.4 for girls. The highest incidence was observed for males (159.6) in Southern region of the country and the lowest in North-east in both boys (18.6) and girls (11.3). Leukemia and lymphoma were the commonest malignancies in boys whereas leukemia and brain tumors were commonest in girls.

Conclusion

Childhood cancer indicidence appears to be increasing in India.     

Health-related quality of life in children with cerebral palsy and their families

Objective

To determine the health-related quality of life in children with cerebral palsy and their families.

Methods

One hundred children (3–10 years of age) receiving regular rehabilitation therapy for cerebral palsy for last 1 year at a Child Development Centrer were enrolled and the Lifestyle assessment questionnaire — cerebral palsy was administered to the parents.

Results

9% had good, 24% had mildly-affected, 37% had moderately-affected and 30% had severely-affected healthrelated quality of life. The physical independence, mobility and social integration dimensions were much more severely affected than the clinical burden, economic burden and schooling dimensions.

Conclusion

Health-related quality of child is affected in most children with cerebral palsy.     

Addition of Algenpantucel-L Immunotherapy to Standard Adjuvant Therapy for Pancreatic Cancer: a Phase 2 Study

Background

Despite continued investigation, limited progress has been made in the adjuvant treatment of resected pancreatic cancer. Novel or targeted therapies are needed.

Methods

Multi-institutional, open-label, dose-finding, phase 2 trial evaluating the use of algenpantucel-L (NewLink Genetics Corporation, Ames, IA) immunotherapy in addition to chemotherapy and chemoradiotherapy in the adjuvant setting for resected pancreatic cancer (ClinicalTrials.gov identifier, NCT00569387). The primary outcome was 12-month disease-free survival. Secondary outcomes included overall survival and toxicity.

Results

Seventy patients were treated with gemcitabine and 5-fluorouracil-based chemoradiotherapy as well as algenpantucel-L (mean 12 doses, range 1–14). After a median follow-up of 21 months, the 12-month disease-free survival was 62 %, and the 12-month overall survival was 86 %. The most common adverse events were injection site pain and induration.

Conclusions

The addition of algenpantucel-L to standard adjuvant therapy for resected pancreatic cancer may improve survival. A multi-institutional, phase 3 study is ongoing (ClinicalTrials.gov identifier, NCT01072981).