Pro-apoptotic, anti-metastatic, and anti-telomerase activity of Tinospora cordifolia and its active polysaccharide arabinogalactan during Benzo(a)pyrene-induced lung carcinogenesis.

BACKGROUND: The present study aims to unravel the pro-apoptotic, anti-metastatic, and anti-telomerase activity of aqueous extract of Tinospora cordifolia stem (Aq.Tc) and its active component arabinogalactan (AG) during Benzo(a)pyrene [B(a)P]-induced lung tumorigenesis in mice. MATERIALS AND METHODS: Lung tumors were induced in male BALB/c mice using B(a)P as a carcinogen. Animals were administered twice with 50 mg/kg b.wt (i.p.) dosage of B(a)P at the 2nd and 4th week of the study. Mice were orally treated with Aq.Tc and AG on alternate days at a dose of 200 mg/kg b.wt and 7.5 mg/kg b.wt, respectively, for continuous 22 weeks. RESULTS: Oral administration of animals with Aq.Tc and AG suppressed the development of lung carcinogenesis by modulating the mRNA and protein expressions of different apoptotic genes; bcl-2, bax, caspase 3, and caspase 9. The pro-apoptotic proficiency of Aq.Tc and AG was further confirmed by DNA agarose gel electrophoresis showing fragmentation in B(a)P + Aq.Tc group and smear formation in B(a)P + AG group. In contrast to the control group, an increase in tumor invasion factors such as matrix metalloproteinases-2 (MMP-2) and MMP-9 was also observed in B(a)P treated animals. Nevertheless, Aq.Tc and AG treatment effectively mitigated the B(a)P-induced upregulation of MMP-2 and MMP-9. The activity of the telomerase enzyme was also observed to be upregulated in B(a)P treated animals which consecutively found to get normalized with the parallel administration of Aq.Tc and AG. CONCLUSION: Aq.Tc and AG successfully mitigated the altered expression of apoptosis, metastasis, and telomerase activity-associated genes during pulmonary carcinogenesis.

Role of neurotransmitters in the regulation of cutaneous wound healing.

Wound healing is a highly coordinated and dynamic process of tissue repair after injury. The global burden of disease associated with wounds, both acute and chronic, is a significantly rising health concern. Upon skin wounding, neurons have the ability to sense the disruption to mediate the release of neurotransmitters into the wound microenvironment. Serotonin that has long been recognised as a potential vasoconstrictor is now also being contemplated to play a role in re-epithelialisation of wounds. While the role of neuropeptides in stimulating diabetic wound healing is being increasingly emphasised, on the other hand, dopamine is being widely studied for its dual role in mediating both pro- and antiangiogenic effects at the site of the wounds. Similarly, epinephrine levels that are known to be elevated during stress is now recognised as a contributing factor towards delayed wound closure, thereby serving as an inhibitor of wound healing. Thus, each neurotransmitter regulates wound repair and their active regeneration in a typical way. Strengthening our understanding of the molecular pathways via which the neurotransmitter modulates the immune system to control wound healing can yield potential therapeutic measures. Further investigations regarding the safety, efficacy, and cost-effectiveness of these processes are a prerequisite for their possible translation into clinical trials.

A critical assessment of stillbirths at a tertiary care hospital.

Background: Globally in 2015, 2.6 million stillbirths occurred with estimated stillbirth rate (SBR) of 18.4/1000 births. India is the world capital of stillbirth accounting for 22.6% of world's stillbirths. Objectives: The objective of the study is to study the demographic profile of women experiencing stillbirth, to understand the risk factors for stillbirth in low resource settings, and to find the etiology of stillbirth so as to facilitate designing of a stillbirth prevention strategy. Methods: This was a cross-sectional observational study done at a tertiary care hospital of Delhi from June 2017 to December 2019. All babies delivered after 20 weeks of gestation showing no sign of life after birth were considered stillborn. Prestructured proforma was filled for each case and data were analyzed. Results: A total of 50,461 births took place during the study period, out of which 1824 were stillborn, making SBR of 36.15/1000 births of our institution. Most of the women belonged to age group 21-25 years and more than 50% of women were illiterate. Twenty-nine percent of women were completely unbooked, 48% were referred from other centers and 23% were registered at our hospital. Placental causes accounted for 22%, hypertension for 23%, and labor complications for 9% of cases while in 22% cases, cause could not be found. Conclusion: Stillbirth remains a neglected issue. A significant proportion of stillbirths are preventable by adequate antenatal care. Notification of stillbirths will give us the exact figures and realization of the seriousness of the problem which will help us work towards the solutions.

Diabetic neuropathy: an insight on the transition from synthetic drugs to herbal therapies.

The global pandemic of prediabetes and diabetes has led to a severe corresponding complication of these disorders. Neuropathy is one of the most prevalent complication of diabetes is, affecting blood supply of the peripheral nervous system that may eventually results into loss of sensations, injuries, diabetic foot and death. The utmost identified risk of diabetic neuropathy is uncontrolled high blood glucose levels. However, aging, body mass index (BMI), oxidative stress, inflammation, increased HbA1c levels and blood pressure are among the other key factors involved in the upsurge of this disease. The so far treatment to deal with diabetic neuropathy is controlling metabolic glucose levels. Apart from this, drugs like reactive oxygen species (ROS) inhibitors, aldose reductase inhibitors, PKC inhibitors, Serotonin-norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, N-methyl-D-aspartate receptor (NMDAR) antagonists, are the other prescribed medications. However, the related side-effects (hallucinations, drowsiness, memory deficits), cost, poor pharmacokinetics and drug resistance brought the trust of patients down and thus herbal renaissance is occurring all over the word as the people have shifted their intentions from synthetic drugs to herbal remedies. Medicinal plants have widely been utilized as herbal remedies against number of ailments in Indian medicinal history. Their bioactive components are very much potent to handle different chronic disorders and complications with lesser-known side effects. Therefore, the current article mainly concludes the etiology and pathophysiology of diabetic neuropathy. Furthermore, it also highlights the important roles of medicinal plants and their naturally occurring bioactive compounds in addressing this disease.

Evaluation of commercial SARS-CoV-2 serological assays in Canadian public health laboratories.

The COVID-19 pandemic has led to the influx of immunoassays for the detection of antibodies towards severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the global market. The Canadian Public Health Laboratory Network Serology Task Force undertook a nationwide evaluation of twelve laboratory and 6 point-of-care based commercial serological assays for the detection of SARS-CoV-2 antibodies. We determined that there was considerable variability in the performance of individual tests and that an orthogonal testing algorithm should be prioritized to maximize the accuracy and comparability of results across the country. The manual enzyme immunoassays and point-of-care tests evaluated had lower specificity and increased coefficients of variation compared to automated enzyme immunoassays platforms putting into question their utility for large-scale sero-surveillance. Overall, the data presented here provide a comprehensive approach for applying accurate serological assays for longitudinal sero-surveillance and vaccine trials while informing Canadian public health policy.

Chemopreventive role of arabinogalactan against experimentally induced pulmonary carcinogenesis: a study in relation to its initiation phase.

The aim of the present study is to divulge the chemopreventive potential of arabinogalactan (AG) on benzo(a)pyrene [B(a)P] induced initiation of lung carcinogenesis. AG is one of the naturally occurring bioactive polysaccharides which is widely found in medicinal plants. Male Balb/c mice were divided into four experimental groups. Group I served as control. Group II animals were injected with B(a)P (50 mg/kg b. wt. i.p.). Group III animals were administered with AG (7.5 mg/kg b.wt.) orally. Group IV animals received B(a)P and AG as in group II and group III, respectively. B(a)P treatment in mice resulted in imbalance of carcinogen metabolizing enzymes and respiratory marker enzymes at 2nd, 6th and 10th week of the experimental protocol. Also, it leads to the increased protein synthesis as depicted by increased argyrophilic nucleolar organizer regions (AgNOR) positive cells and altered histopathological features. Studies on bronchoalveolar lavage fluid (balf) of B(a)P exposed animals revealed increase in surface tension when compared with control counterparts. Apart from target tissue (lung), B(a)P also led to the clastogenic damage in other tissues (spleen and bone marrow) as depicted by increase in percentage of micronucleus cells at different time intervals. Treatment with AG efficiently counteracted all the above anomalies and restored cellular homeostasis. These observations suggest that AG has the potential to modulate B(a)P induced changes in the pulmonary tissue as well as other tissues which could have implications in delaying the initiation of carcinogenesis, however, further investigations are required to explore its complete mechanism of action.

Azadirachta indica mitigates DMBA-induced hepatotoxicity: a biochemical and radiometric study.

The hepatoprotective potential of aqueous Azadirachta indica leaf extract (AAILE) was assessed against DMBA-induced hepatotoxicity. DMBA (7,12-dimethylbenz[a] anthracene) treatment (40 mg/kg body weight, ip) to male Balb/c mice resulted in the derailment of liver function as revealed by extremely slow clearance of 99mTc-mebrofenin from liver, elevated levels of alkaline phosphatase (ALP) and alanine transaminase (ALT), compared to control group. In addition, elevated micronuclei score and high apoptotic index indicated hepatogenotoxicity in DMBA-treated mice. DMBA treatment also upregulated cytochrome P450 (CYP), cytochrome b5 (Cyt b5) and decreased glutathione-S-transferase activity in hepatic tissue, compared to control group. Enhanced lipid peroxidation (LPO) levels along with decreased reduced glutathione (GSH) level were also observed in DMBA group, compared to control group. AAILE co-treatment (200 mg/kg body weight, po, thrice a week) for 8 weeks followed by DMBA injection showed significant improvement in hepatic status, as revealed by normalization of 99mTc-mebrofenin clearance rate, decreased ALP and ALT levels, reduced genotoxicity in terms of micronuclei score and apoptotic index. Levels of LPO were significantly decreased along with increased hepatic GST and GSH levels in AAILE + DMBA group, compared to DMBA group. However, no significant change was observed in hepatic CYP and Cyt b5 levels, compared to DMBA group. The results indicated that AAILE effectively ameliorated DMBA-induced hepatotoxicity.

Estimation of Myocardial Volume at Risk from CT Angiography.

The determination of myocardial volume at risk distal to coronary stenosis provides important information for prognosis and treatment of coronary artery disease. In this paper, we present a novel computational framework for estimating the myocardial volume at risk in computed tomography angiography (CTA) imagery. Initially, epicardial and endocardial surfaces, and coronary arteries are extracted using an active contour method. Then, the extracted coronary arteries are projected onto the epicardial surface, and each point on this surface is associated with its closest coronary artery using the geodesic distance measurement. The likely myocardial region at risk on the epicardial surface caused by a stenosis is approximated by the region in which all its inner points are associated with the sub-branches distal to the stenosis on the coronary artery tree. Finally, the likely myocardial volume at risk is approximated by the volume in between the region at risk on the epicardial surface and its projection on the endocardial surface, which is expected to yield computational savings over risk volume estimation using the entire image volume. Furthermore, we expect increased accuracy since, as compared to prior work using the Euclidean distance, we employ the geodesic distance in this work. The experimental results demonstrate the effectiveness of the proposed approach on pig heart CTA datasets.

Development of stereotactic mass spectrometry for brain tumor surgery.

BACKGROUND: Surgery remains the first and most important treatment modality for the majority of solid tumors. Across a range of brain tumor types and grades, postoperative residual tumor has a great impact on prognosis. The principal challenge and objective of neurosurgical intervention is therefore to maximize tumor resection while minimizing the potential for neurological deficit by preserving critical tissue. OBJECTIVE: To introduce the integration of desorption electrospray ionization mass spectrometry into surgery for in vivo molecular tissue characterization and intraoperative definition of tumor boundaries without systemic injection of contrast agents. METHODS: Using a frameless stereotactic sampling approach and by integrating a 3-dimensional navigation system with an ultrasonic surgical probe, we obtained image-registered surgical specimens. The samples were analyzed with ambient desorption/ionization mass spectrometry and validated against standard histopathology. This new approach will enable neurosurgeons to detect tumor infiltration of the normal brain intraoperatively with mass spectrometry and to obtain spatially resolved molecular tissue characterization without any exogenous agent and with high sensitivity and specificity. RESULTS: Proof of concept is presented in using mass spectrometry intraoperatively for real-time measurement of molecular structure and using that tissue characterization method to detect tumor boundaries. Multiple sampling sites within the tumor mass were defined for a patient with a recurrent left frontal oligodendroglioma, World Health Organization grade II with chromosome 1p/19q codeletion, and mass spectrometry data indicated a correlation between lipid constitution and tumor cell prevalence. CONCLUSION: The mass spectrometry measurements reflect a complex molecular structure and are integrated with frameless stereotaxy and imaging, providing 3-dimensional molecular imaging without systemic injection of any agents, which can be implemented for surgical margins delineation of any organ and with a rapidity that allows real-time analysis.

Tubular surface segmentation for extracting anatomical structures from medical imagery.

This work provides a model for tubular structures, and devises an algorithm to automatically extract tubular anatomical structures from medical imagery. Our model fits many anatomical structures in medical imagery, in particular, various fiber bundles in the brain (imaged through diffusion-weighted magnetic resonance (DW-MRI)) such as the cingulum bundle, and blood vessel trees in computed tomography angiograms (CTAs). Extraction of the cingulum bundle is of interest because of possible ties to schizophrenia, and extracting blood vessels is helpful in the diagnosis of cardiovascular diseases. The tubular model we propose has advantages over many existing approaches in literature: fewer degrees-of-freedom over a general deformable surface hence energies defined on such tubes are less sensitive to undesirable local minima, and the tube (in 3-D) can be naturally represented by a 4-D curve (a radius function and centerline), which leads to computationally less costly algorithms and has the advantage that the centerline of the tube is obtained without additional effort. Our model also generalizes to tubular trees, and the extraction algorithm that we design automatically detects and evolves branches of the tree. We demonstrate the performance of our algorithm on 20 datasets of DW-MRI data and 32 datasets of CTA, and quantify the results of our algorithm when expert segmentations are available.

Imaging of meningioma progression by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

Often considered benign, meningiomas represent 32% of intracranial tumors with three grades of malignancy defined by the World Health Organization (WHO) histology based classification. Malignant meningiomas are associated with less than 2 years median survival. The inability to predict recurrence and progression of meningiomas induces significant anxiety for patients and limits physicians in implementing prophylactic treatment approaches. This report presents an analytical approach to tissue characterization based on matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry imaging (MSI) which is introduced in an attempt to develop a reference database for predictive classification of brain tumors. This pilot study was designed to evaluate the potential of such an approach and to begin to address limitations of the current methodology. Five recurrent and progressive meningiomas for which surgical specimens were available from the original and progressed grades were selected and tested against nonprogressive high-grade meningiomas, high-grade gliomas, and nontumor brain specimens. The common profiling approach of data acquisition was compared to imaging and revealed significant benefits in spatially resolved acquisition for improved spectral definition. A preliminary classifier based on the support vector machine showed the ability to distinguish meningioma image spectra from the nontumor brain and from gliomas, a different type of brain tumor, and to enable class imaging of surgical tissue. Although the development of classifiers was shown to be sensitive to data preparation parameters such as recalibration and peak picking criteria, it also suggested the potential for maturing into a predictive algorithm if provided with a larger series of well-defined cases.

Finsler tractography for white matter connectivity analysis of the cingulum bundle.

In this paper, we present a novel approach for the segmentation of white matter tracts based on Finsler active contours. This technique provides an optimal measure of connectivity, explicitly segments the connecting fiber bundle, and is equipped with a metric which is able to utilize the directional information of high angular resolution data. We demonstrate the effectiveness of the algorithm for segmenting the cingulum bundle.

Locally-Constrained Region-Based Methods for DW-MRI Segmentation.

In this paper, we describe a method for segmenting fiber bundles from diffusion-weighted magnetic resonance images using a locally-constrained region based approach. From a pre-computed optimal path, the algorithm propagates outward capturing only those voxels which are locally connected to the fiber bundle. Rather than attempting to find large numbers of open curves or single fibers, which individually have questionable meaning, this method segments the full fiber bundle region. The strengths of this approach include its ease-of-use, computational speed, and applicability to a wide range of fiber bundles. In this work, we show results for segmenting the cingulum bundle. Finally, we explain how this approach and extensions thereto overcome a major problem that typical region-based flows experience when attempting to segment neural fiber bundles.