THOR-05F biofidelity evaluation in reclined and upright seated postures subjected to frontal crash pulses.

The THOR 5th percentile female dummy (THOR-05F) was evaluated for two seating postures/positions in frontal impacts using a generic automotive seat environment. The conditions included 2 crash pulses: a 15 km/h test that utilized 4.5 g acceleration and a 3-point restraint with 2 kN load limiter, and a 32 km/h test that utilized 9.5 g acceleration and a 3-point restraint with a 4.5 kN load limiter and pretensioner, and two seatback angles: 25°, a nominal upright posture, and 45°, a moderate reclined posture. The BRS scores were calculated using the NHTSA BioRank method. Overall biofidelity rating was consider excellent for both seating postures. This evaluation provides an understanding of the THOR-05F response and biofidelity evaluation of the ATD in two seating postures (nominal and reclined). This is essential in the assessment and development of safety measures in emerging ADS-equipped vehicles.

An Improved Machine Learning Model for Diagnostic Cancer Recognition Using Artificial Intelligence.

In the medical field, some specialized applications are currently being used to treat various ailments. These activities are being carried out with extra care, especially for cancer patients. Physicians are seeking the help of technology to help diagnose cancer, its dosage, its current status, cancer classification, and appropriate treatment. The machine learning method developed by an artificial intelligence is proposed here in order to effectively assist the doctors in that regard. Its design methods obtain highly complex cancerous inputs and clearly describe its type and dosage. It is also recommending the effects of cancer and appropriate medical procedures to the doctors. This method ensures that a lot of doctors' time is saved. In a saturation point, the proposed model achieved 93.31% of image recognition, 6.69% of image rejection, 94.22% accuracy, 92.42% of precision, 93.94% of recall rate, 92.6% of F1-score, and 2178 ms of computational speed. This shows that the proposed model performs well while compared with the existing methods.

Evaluating thoracolumbar spine response during simulated underbody blast impact using a total human body finite element model.

In a study of spine injuries in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) from 2001-09, spinal fractures sustained by mounted soldiers accounted for 26% of all injuries, and of that, 43% were caused by explosions [1]. The thoracolumbar region is the most vulnerable area of the spine [2], and injuries are often incapacitating, making egress from vehicles difficult. Injury prediction from such events continues to remain a challenge due to the limited availability of studies specifically focused on underbody blasts (UBB) and criteria on related injuries. This study focuses on developing and validating the spine response of an updated 50th percentile male Global Human Body Models Consortium (GHBMC) Finite Element (FE) model using instrumented post-mortem human subject (PMHS) laboratory tests under two unique conditions. The model was validated against response corridors created using scaled thoracic (T12, T8, T5, T1) and sacrum (S1) spine Z-axis accelerations obtained from WSU whole-body PMHS tests. The scores for the updated spine model ranged from 0.557 - 0.756 for condition 1 (Seat- 4 m/s in 10 ms; Floor- 6 m/s in 5 ms) and 0.639-0.849 for condition 2 (Seat- 4 m/s in 55 ms; Floor- 8 m/s in 2 ms). The PMHS tests sustained spinal injuries in the thoracolumbar region. The validated model indicates high stress and strain concentrations at the same locations, providing an explanation for the fractures sustained in the PMHS tests.

Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance.

Despite advances in biology and therapeutic modalities, existence of highly tumorigenic glioma stem-like cells (GSCs) makes glioblastomas (GBMs) invincible. N6-methyl adenosine (m6A), one of the abundant mRNA modifications catalyzed by methyltransferase-like 3 and 14 (METTL3/14), influences various events in RNA metabolism. Here, we report the crucial role of METTL3-mediated m6A modification in GSC (neurosphere) maintenance and dedifferentiation of glioma cells. METTL3 expression is elevated in GSC and attenuated during differentiation. RNA immunoprecipitation studies identified SOX2 as a bonafide m6A target of METTL3 and the m6A modification of SOX2 mRNA by METTL3 enhanced its stability. The exogenous overexpression of 3'UTR-less SOX2 significantly alleviated the inhibition of neurosphere formation observed in METTL3 silenced GSCs. METTL3 binding and m6A modification in vivo required intact three METTL3/m6A sites present in the SOX2-3'UTR. Further, we found that the recruitment of Human antigen R (HuR) to m6A-modified RNA is essential for SOX2 mRNA stabilization by METTL3. In addition, we found a preferential binding by HuR to the m6A-modified transcripts globally. METTL3 silenced GSCs showed enhanced sensitivity to γ-irradiation and reduced DNA repair as evidenced from the accumulation of γ-H2AX. Exogenous overexpression of 3'UTR-less SOX2 in METTL3 silenced GSCs showed efficient DNA repair and also resulted in the significant rescue of neurosphere formation from METTL3 silencing induced radiosensitivity. Silencing METTL3 inhibited RasV12 mediated transformation of mouse immortalized astrocytes. GBM tumors have elevated levels of METTL3 transcripts and silencing METTL3 in U87/TIC inhibited tumor growth in an intracranial orthotopic mouse model with prolonged mice survival. METTL3 transcript levels predicted poor survival in GBMs which are enriched for GSC-specific signature. Thus our study reports the importance of m6A modification in GSCs and uncovers METTL3 as a potential molecular target in GBM therapy.

Integrative functional genomic analysis identifies epigenetically regulated fibromodulin as an essential gene for glioma cell migration.

An integrative functional genomics study of multiple forms of data are vital for discovering molecular drivers of cancer development and progression. Here, we present an integrated genomic strategy utilizing DNA methylation and transcriptome profile data to discover epigenetically regulated genes implicated in cancer development and invasive progression. More specifically, this analysis identified fibromodulin (FMOD) as a glioblastoma (GBM) upregulated gene because of the loss of promoter methylation. Secreted FMOD promotes glioma cell migration through its ability to induce filamentous actin stress fiber formation. Treatment with cytochalasin D, an actin polymerization inhibitor, significantly reduced the FMOD-induced glioma cell migration. Small interfering RNA and small molecule inhibitor-based studies identified that FMOD-induced glioma cell migration is dependent on integrin-FAK-Src-Rho-ROCK signaling pathway. FMOD lacking C-terminus LRR11 domain (ΔFMOD), which does not bind collagen type I, failed to induce integrin and promote glioma cell migration. Further, FMOD-induced integrin activation and migration was abrogated by a 9-mer wild-type peptide from the FMOD C-terminus. However, the same peptide with mutation in two residues essential for FMOD interaction with collagen type I failed to compete with FMOD, thus signifying the importance of collagen type I-FMOD interaction in integrin activation. Chromatin immunoprecipitation-PCR experiments revealed that transforming growth factor beta-1 (TGF-ß1) regulates FMOD expression through epigenetic remodeling of FMOD promoter that involved demethylation and gain of active histone marks with a simultaneous loss of DNMT3A and EZH2 occupancy, but enrichment of Sma- and Mad-related protein-2 (SMAD2) and CBP. FMOD silencing inhibited the TGF-ß1-mediated glioma cell migration significantly. In univariate and multivariate Cox regression analysis, both FMOD promoter methylation and transcript levels predicted prognosis in GBM. Thus, this study identified several epigenetically regulated alterations responsible for cancer development and progression. Specifically, we found that secreted FMOD as an important regulator of glioma cell migration downstream of TGF-ß1 pathway and forms a potential basis for therapeutic intervention in GBM.

Diagnosing and ranking retinopathy disease level using diabetic fundus image recuperation approach.

Retinal fundus images are widely used in diagnosing different types of eye diseases. The existing methods such as Feature Based Macular Edema Detection (FMED) and Optimally Adjusted Morphological Operator (OAMO) effectively detected the presence of exudation in fundus images and identified the true positive ratio of exudates detection, respectively. These mechanically detected exudates did not include more detailed feature selection technique to the system for detection of diabetic retinopathy. To categorize the exudates, Diabetic Fundus Image Recuperation (DFIR) method based on sliding window approach is developed in this work to select the features of optic cup in digital retinal fundus images. The DFIR feature selection uses collection of sliding windows with varying range to obtain the features based on the histogram value using Group Sparsity Nonoverlapping Function. Using support vector model in the second phase, the DFIR method based on Spiral Basis Function effectively ranks the diabetic retinopathy disease level. The ranking of disease level on each candidate set provides a much promising result for developing practically automated and assisted diabetic retinopathy diagnosis system. Experimental work on digital fundus images using the DFIR method performs research on the factors such as sensitivity, ranking efficiency, and feature selection time.

Contour-based brain segmentation method for magnetic resonance imaging human head scans.

The high-resolution magnetic resonance brain images often contain some nonbrain tissues (ie, skin, fat, muscle, neck, eye balls, etc) compared with the functional images such as positron emission tomography, single-photon emission computed tomography, and functional magnetic resonance imaging (MRI) scans, which usually contain few nonbrain tissues. Automatic segmentation of brain tissues from MRI scans remains a challenging task due to the variation in shape and size, use of different pulse sequences, overlapping signal intensities and imaging artifacts. This article presents a contour-based automatic brain segmentation method to segment the brain regions from T1-, T2-, and proton density-weighted MRI of human head scans. The proposed method consists of 2 stages. In stage 1, the brain regions in the middle slice is extracted. Many of the existing methods failed to extract brain regions in the lower and upper slices of the brain volume, where the brain appears in more than 1 connected region. To overcome this problem, in the proposed method, a landmark circle is drawn at the center of the extracted brain region of a middle slice and is likely to pass through all the brain regions in the remaining lower and upper slices irrespective of whether the brain is composed of 1 or more connected components. In stage 2, the brain regions in the remaining slices are extracted with reference to the landmark circle obtained in stage 1. The proposed method is robust to the variability of brain anatomy, image orientation, and image type, and it extracts the brain regions accurately in T1-, T2-, and proton density-weighted normal and abnormal brain images. Experimental results by applying the proposed method on 100 volumes of brain images show that the proposed method exhibits best and consistent performance than by the popular existing methods brain extraction tool, brain surface extraction, watershed algorithm, hybrid watershed algorithm, and skull stripping using graph cuts.

Proximal humeral fractures: the role of calcium sulphate augmentation and extended deltoid splitting approach in internal fixation using locking plates.

UNLABELLED: The aim of our study is to analyse the results of our surgical technique for the treatment of proximal humeral fractures and fracture dislocations using locking plates in conjunction with calcium sulphate bone-substitute augmentation and tuberosity repair using high-strength sutures. We used the extended deltoid-splitting approach for fracture patterns involving displacement of both lesser and greater tuberosities and for fracture-dislocations. Optimal surgical management of proximal humeral fractures remains controversial. Locking plates have become a popular method of fixation. However, failure of fixation may occur if they are used as the sole method of fixation in comminuted fractures, especially in osteopenic bone. METHODS: We retrospectively analysed 22 proximal humeral fractures in 21 patients; 10 were male and 11 female with an average age of 64.6 years (range 37-77). Average follow-up was 24 months. Eleven of these fractures were exposed by the extended deltoid-splitting approach. Fractures were classified according to Neer and Hertel systems. Preoperative radiographs and computed tomography (CT) scans in three- and four-part fractures were done to assess the displacement and medial calcar length for predicting the humeral head vascularity. According to the Neer classification, there were five two-part, six three-part, five four-part fractures and six fracture-dislocations (two anterior and four posterior). Results were assessed clinically with disabilities of the arm, shoulder and hand (DASH) scores, modified Constant and Murley scores and serial postoperative radiographs. RESULTS: The mean DASH score was 16.18 and the modified Constant and Murley score was 64.04 at the last follow-up. Eighteen out of twenty-two cases achieved good clinical outcome. All the fractures united with no evidence of infection, failure of fixation, malunion, tuberosity failure, avascular necrosis or adverse reaction to calcium sulphate bone substitute. There was no evidence of axillary nerve injury. Four patients had a longer recovery period due to stiffness, associated wrist fracture and elbow dislocation. The CaSO4 bone substitute was replaced by normal appearing trabecular bone texture at an average of 6 months in all patients. CONCLUSION: In our experience, we have found the use of locking plates, calcium sulphate bone substitute and tuberosity repair with high-strength sutures to be a safe and reliable method of internal fixation for complex proximal humeral fractures and fracture-dislocations. Furthermore, we have also found the use of the extended deltoid-splitting approach to be safe and to provide excellent exposure facilitating accurate reduction for fixation of the fracture patterns involving displacement of both lesser and greater tuberosities and for fracture-dislocations.

Medical emergencies: atrial fibrillation and myocardial infarction.

In this, the first of two article on medical emergencies, we discuss the definitions, epidemiology, pathophysiology, acute and chronic management of atrial fibrillation and acute myocardial necrosis in the peri-operative and intensive care settings.

Medical emergencies: pulmonary embolism and acute severe asthma.

In this, the second of two articles covering specific medical emergencies, we discuss the definitions, epidemiology, pathophysiology, acute and chronic management of pulmonary embolus and acute severe asthma.

Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor.

The search for molecular markers which predict response to chemotherapy is an important aspect of current neuro-oncology research. MGMT promoter methylation is the only proved marker of glioblastoma. The purpose of this study was to assess the effect of topoisomerase expression on glioblastoma survival and study the mechanisms involved. The transcript levels of all isoforms of the topoisomerase family in all grades of diffuse astrocytoma were assessed. A prospective study of patients with glioblastoma treated by a uniform treatment procedure was performed with the objective of correlating outcome with gene expression. The ability of TOP2A enzyme to relax the super coiled plasmid DNA in the presence of temozolomide was evaluated to assess its effect on TOP2A. The temozolomide cyctotoxicity of TOP2A-silenced U251 cells was assessed. The transcript levels of TOP2A, TOP2B, and TOP3A are upregulated significantly in GBM in comparison with lower grades of astrocytoma and normal brain samples. mRNA levels of TOP2A correlated significantly with survival of the patients. Higher TOP2A transcript levels in GBM patients predicted better prognosis (P = 0.043; HR = 0.889). Interestingly, we noted that temozolomide inhibited TOP2A activity in in-vitro enzyme assays. We also noted that siRNA knock down of TOP2A rendered a glioma cell line resistant to temozolomide chemotherapy. We demonstrated for the first time that temozolomide is also a TOP2A inhibitor and established that TOP2A transcript levels determine the chemosensitivity of glioblastoma to temozolomide therapy. Very high levels of TOP2A are a good prognostic indicator in GBM patients receiving temozolomide chemotherapy.

Tobacco use, its influences, triggers, and associated oral lesions among the patients attending a dental institution in rural Maharashtra, India.

BACKGROUND: World Health Organization (WHO) predicts that tobacco deaths in India may exceed 1.5 million annually by 2020. OBJECTIVES: The aim of this study was to estimate the prevalence of tobacco use, its influences, triggers, and associated oral lesions among the patients of Rural Dental College and Hospital of Loni, Maharashtra. MATERIALS AND METHODS: A hospital based cross-sectional study was conducted from June - December 2010. All the patients from the outpatient department and with tobacco habits were included in the study. Patients were interviewed through a pre-tested structured questionnaire in relation to their tobacco habits, its influences and triggers. Also clinical examination was carried out to check for any tobacco related oral lesions. For the data analysis, Microsoft Excel and chi-square test was used. RESULTS: The overall prevalence of tobacco use was 16.38%. Smokeless form of tobacco was more prevalent in both males (81.84%) and females (100%). Majority of the patients (males - 68.22%, females- 90.62%) were light tobacco users. About 76.09% males and 31.25% females admitted that they developed the habit due to initial influence of friends. The most common oral mucosal lesion in both the males (42.20%) and females (11.07%) was tobacco hyperkeratosis. Most common trigger for tobacco use was "work related" (69.14%) in males and "after meals" (53.13%) in females. CONCLUSION: Since the number of tobacco users visiting the dental hospital is reasonably high; dentists can contribute to restrain the hazard through community educational activities such as de-addiction counseling of tobacco users to quit the habit.

Automatic brain extraction methods for T1 magnetic resonance images using region labeling and morphological operations.

In this work we propose two brain extraction methods (BEM) that solely depend on the brain anatomy and its intensity characteristics. Our methods are simple, unsupervised and knowledge based. Using an adaptive intensity thresholding method on the magnetic resonance images of head scans, a binary image is obtained. The binary image is labeled using the anatomical facts that the scalp is the boundary between head and background, and the skull is the boundary separating brain and scalp. A run length scheme is applied on the labeled image to get a rough brain mask. Morphological operations are then performed to obtain the fine brain on the assumption that brain is the largest connected component (LCC). But the LCC concept failed to work on some slices where brain is composed of more than one connected component. To solve this problem a 3-D approach is introduced in the BEM. Experimental results on 61 sets of T1 scans taken from MRI scan center and neuroimage web services showed that our methods give better results than the popular methods, FSL's Brain Extraction Tool (BET), BrainSuite's Brain Surface Extractor (BSE) gives results comparable to that of Model-based Level Sets (MLS) and works well even where MLS failed. The average Dice similarity index computed using the "Gold standard" and the specificity values are 0.938 and 0.992, respectively, which are higher than that for BET, BSE and MLS. The average processing time by one of our methods is ≈1s/slice, which is smaller than for MLS, which is ≈4s/slice. One of our methods produces the lowest false positive rate of 0.075, which is smaller than that for BSE, BET and MLS. It is independent of imaging orientation and works well for slices with abnormal features like tumor and lesion in which the existing methods fail in certain cases.

Fully automatic brain extraction algorithm for axial T2-weighted magnetic resonance images.

In this paper we propose two brain extraction algorithms (BEA) for T2-weighted magnetic resonance imaging (MRI) scans. The T2-weighted image is first filtered with a low pass filter (LPF) to remove or subdue the background noise. Then the image is diffused to enhance the brain boundaries. Using Ridler's method a threshold value for intensity is obtained. Using the threshold value a rough binary brain image is obtained. By performing morphological operations and using the largest connected component (LCC) analysis, a brain mask is obtained from which the brain is extracted. This method uses only 2D information of slices and is named as 2D-BEA. The concept of LCC failed in few slices. To overcome this problem, 3D information available in adjacent slices is used which resulted in 3D-BEA. Experimental results on 20 MRI data sets show that the proposed 3D-BEA gave excellent results. The performance of this 3D-BEA is better than 2D-BEA and other popular methods, brain extraction tool (BET) and brain surface extractor (BSE).

Essential role of PI3-kinase pathway in p53-mediated transcription: Implications in cancer chemotherapy.

The PI3-kinase pathway is the target of inactivation in achieving better cancer chemotherapy. Here, we report that p53-mediated transcription is inhibited by pharmacological inhibitors and a dominant-negative mutant of PI3-kinase, and this inhibition was relieved by a constitutively active mutant of PI3-kinase. Akt/PKB and mTOR, the downstream effectors of PI3-kinase, were also found to be essential. LY294002 (PI3-kinase inhibitor) pre-treatment altered the post-translational modifications and the sub-cellular localization of p53. Although LY294002 increased the chemosensitivity of cells to low concentrations of adriamycin (adriamycin-low), it protected the cells from cytotoxicity induced by high concentrations of adriamycin (adriamycin-high) in a p53-dependent manner. Further, we found that LY294002 completely abolished the activation of p53 target genes (particularly pro-apoptotic) under adriamycin-high conditions, whereas it only marginally repressed the p53 target genes under adriamycin-low conditions; in fact, it further activated the transcription of NOXA, HRK, APAF1 and CASP5 genes. Thus, the differential effect of PI3-kinase on p53 functions seems to be responsible for the differential regulation of DNA damage-induced cytotoxicity and cell death by PI3-kinase. Our finding becomes relevant in the light of ongoing combination chemotherapy trials with the PI3-kinase pathway inhibitors and underscores the importance of p53 status in the careful formulation of combination chemotherapies.

ErbB-2 expression and its association with other biological parameters of breast cancer among Indian women.

OBJECTIVES: Overexpression of the epidermal growth factor receptor family genes, which include ErbB-1, 2, 3 and 4, has been implicated in a number of cancers. We have studied the extent of ErbB-2 overexpression among Indian women with sporadic breast cancer. METHODS: Immunohistochemistry and genomic polymerase chain reaction (PCR) were used to study the ErbB2 overexpression. ErbB2 status was correlated with other clinico-pathological parameters, including patient survival. RESULTS: ErbB-2 overexpression was detected in 43.2% (159/368) of the cases by immunohistochemistry. For a sub-set of patients (n = 55) for whom total DNA was available, ErbB-2 gene amplification was detected in 25.5% (14/55) of the cases by genomic PCR. While the ErbB2 overexpression was significantly higher in patients with lymphnode (chi2 = 12.06, P < or = 0.001), larger tumor size (chi2 = 8.22, P = 0.042) and ductal carcinoma (chi2 = 15.42, P < or = 0.001), it was lower in patients with disease-free survival (chi2 = 22.13, P < or = 0.001). Survival analysis on a sub-set of patients for whom survival data were available (n = 179) revealed that ErbB-2 status (chi2 =25.94, P < or = 0.001), lymphnode status (chi2 = 12.68, P < or = 0.001), distant metastasis (chi2 = 19.49, P < or = 0.001) and stage of the disease (chi2 = 28.04, P < or = 0.001) were markers of poor prognosis. CONCLUSIONS: ErbB-2 overexpression was significantly greater compared with the Western literature, but comparable to other Indian studies. Significant correlation was found between ErbB-2 status and lymphnode status, tumor size and ductal carcinoma. ErbB-2 status, lymph node status, distant metastasis and stage of the disease were found to be prognostic indicators.

Inhibition of human two-pore domain K+ channel TREK1 by local anesthetic lidocaine: negative cooperativity and half-of-sites saturation kinetics.

TWIK-related K+ channel TREK1, a background leak K+ channel, has been strongly implicated as the target of several general and local anesthetics. Here, using the whole-cell and single-channel patch-clamp technique, we investigated the effect of lidocaine, a local anesthetic, on the human (h)TREK1 channel heterologously expressed in human embryonic kidney 293 cells by an adenoviral-mediated expression system. Lidocaine, at clinical concentrations, produced reversible, concentration-dependent inhibition of hTREK1 current, with IC(50) value of 180 muM, by reducing the single-channel open probability and stabilizing the closed state. We have identified a strategically placed unique aromatic couplet (Tyr352 and Phe355) in the vicinity of the protein kinase A phosphorylation site, Ser348, in the C-terminal domain (CTD) of hTREK1, that is critical for the action of lidocaine. Furthermore, the phosphorylation state of Ser348 was found to have a regulatory role in lidocaine-mediated inhibition of hTREK1. It is interesting that we observed strong intersubunit negative cooperativity (Hill coefficient = 0.49) and half-of-sites saturation binding stoichiometry (half-reaction order) for the binding of lidocaine to hTREK1. Studies with the heterodimer of wild-type (wt)-hTREK1 and Delta119 C-terminal deletion mutant (hTREK1(wt)-Delta119) revealed that single CTD of hTREK1 was capable of mediating partial inhibition by lidocaine, but complete inhibition necessitates the cooperative interaction between both the CTDs upon binding of lidocaine. Based on our observations, we propose a model that explains the unique kinetics and provides a plausible paradigm for the inhibitory action of lidocaine on hTREK1.

An unusual presentation of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem connective tissue disease caused by the damage of tissues and cells by pathogenic auto-antibodies and immune complexes. A 27-year-old female presented with chronic diarrhoea was diagnosed as intestinal tuberculosis. But further evaluation diagnosed it a case of SLE and diarrhoea subsided with treatment. The case is reported because of its atypical presentation.

Current health scenario in rural India.

India is the second most populous country of the world and has changing socio-political-demographic and morbidity patterns that have been drawing global attention in recent years. Despite several growth-orientated policies adopted by the government, the widening economic, regional and gender disparities are posing challenges for the health sector. About 75% of health infrastructure, medical man power and other health resources are concentrated in urban areas where 27% of the population live. Contagious, infectious and waterborne diseases such as diarrhoea, amoebiasis, typhoid, infectious hepatitis, worm infestations, measles, malaria, tuberculosis, whooping cough, respiratory infections, pneumonia and reproductive tract infections dominate the morbidity pattern, especially in rural areas. However, non-communicable diseases such as cancer, blindness, mental illness, hypertension, diabetes, HIV/AIDS, accidents and injuries are also on the rise. The health status of Indians, is still a cause for grave concern, especially that of the rural population. This is reflected in the life expectancy (63 years), infant mortality rate (80/1000 live births), maternal mortality rate (438/100 000 live births); however, over a period of time some progress has been made. To improve the prevailing situation, the problem of rural health is to be addressed both at macro (national and state) and micro (district and regional) levels. This is to be done in an holistic way, with a genuine effort to bring the poorest of the population to the centre of the fiscal policies. A paradigm shift from the current 'biomedical model' to a 'sociocultural model', which should bridge the gaps and improve quality of rural life, is the current need. A revised National Health Policy addressing the prevailing inequalities, and working towards promoting a long-term perspective plan, mainly for rural health, is imperative.

Tumor suppressor p53: regulation and function.

The p53 protein is a transcription factor involved in maintaining genomic integrity by controlling cell cycle progression and cell survival. Mutations in p53 are the most frequently seen genetic alterations in human cancer. The function of p53 is critical to the way many cancer treatments kill cells because radiotherapy and chemotherapy act in part by triggering programmed cell death in response to DNA damage. Consequently, tumors which bear p53 mutations, are often difficult to treat and their prognosis is poor. Since the underlying feature of tumors with p53 mutations is the absence of functional p53, gene replacement therapy with wild-type p53 gene is being considered as an approach for treating a variety of cancers. In recent years, more information has been obtained regarding various pathways leading to the activation of p53, particularly those involving post-translational modifications of p53. Several new target genes of p53 have been identified. This review will summarize current knowledge on the structure, mechanism of activation and effectors of p53 function.