A Virtual Noninvasive Way of Constructing a Nasoalveolar Molding Plate for Cleft Babies, Using Intraoral Scanners, CAD, and Prosthetic Milling.

Presurgical nasoalveolar molding (PNAM) is a key step in the early management of cleft babies. It involves making an impression of the alveolar segments and the lip elements, after which an appliance is fabricated and activated to achieve optimal alveolar and nasal positions for a superior surgical result. These appliances are fabricated and activated in babies as young as 10 days, and the molding is ideally carried on till the baby is ready for the primary lip repair. This article outlines in detail a digital method of fabricating the PNAM appliance using a combination of intraoral scans, computer-assisted digital software, and computer-assisted machining, facilitated by milling machines. This process obviates impression making and the subsequent laboratory procedures.

3-Methyl-3-buten-1-ol (isoprenol) confers longevity and stress tolerance in Caenorhabditis elegans.

The present investigation demonstrates the longevity-promoting effects of 3-methyl-3-buten-1-ol (isoprenol) in the animal model Caenorhabditis elegans that might be served as a lead nutraceutical in geriatric research. Our results showed that 0.5 mM isoprenol extended the mean lifespan of worms by 25% in comparison to control worms. Isoprenol also significantly enhanced survival of the worms under various stress conditions. It was found that the longevity-promoting effects of isoprenol were associated with improved age-associated physiological behaviour and reduced intracellular reactive oxygen species (ROS) accumulation. Finally, studies with gene-specific mutants revealed the involvement of pro-longevity transcription factors (TFs) DAF-16 and SKN-1 with simultaneous over-expression of GST-4 and SOD-3 in isoprenol treated worms. In silico analysis revealed the binding affinity of isoprenol with DAF-16 and SKN-1 TFs. Together, the findings suggest that isoprenol is able to enhance the lifespan of C. elegans and embarks its potential in the developments of formulations for age-related ailments.

Identification of potential pathways and biomarkers linked to progression in ALS.

OBJECTIVE: To identify potential diagnostic and prognostic biomarkers for clinical management and clinical trials in amyotrophic lateral sclerosis. METHODS: We analysed proteomics data of ALS patient-induced pluripotent stem cell-derived motor neurons available through the AnswerALS consortium. After stratifying patients using clinical ALSFRS-R and ALS-CBS scales, we identified differentially expressed proteins indicative of ALS disease severity and progression rate as candidate ALS-related and prognostic biomarkers. Pathway analysis for identified proteins was performed using STITCH. Protein sets were correlated with the effects of drugs using the Connectivity Map tool to identify compounds likely to affect similar pathways. RNAi screening was performed in a Drosophila TDP-43 ALS model to validate pathological relevance. A statistical classification machine learning model was constructed using ridge regression that uses proteomics data to differentiate ALS patients from controls. RESULTS: We identified 76, 21, 71 and 1 candidate ALS-related biomarkers and 22, 41, 27 and 64 candidate prognostic biomarkers from patients stratified by ALSFRS-R baseline, ALSFRS-R progression slope, ALS-CBS baseline and ALS-CBS progression slope, respectively. Nineteen proteins enhanced or suppressed pathogenic eye phenotypes in the ALS fly model. Nutraceuticals, dopamine pathway modulators, statins, anti-inflammatories and antimicrobials were predicted starting points for drug repurposing using the connectivity map tool. Ten diagnostic biomarker proteins were predicted by machine learning to identify ALS patients with high accuracy and sensitivity. INTERPRETATION: This study showcases the powerful approach of iPSC-motor neuron proteomics combined with machine learning and biological confirmation in the prediction of novel mechanisms and diagnostic and predictive biomarkers in ALS.

Amelioration of Radiation-Induced Cell Death in Neuro2a Cells by Neutralizing Oxidative Stress and Reducing Mitochondrial Dysfunction Using N-Acetyl-L-Tryptophan.

The deleterious effects of ionizing radiation on the central nervous system (CNS) are poorly understood. Radiation exposure during an accidental nuclear explosion, nuclear war, or radiotherapy causes severe brain damage. As a result, the current work is carried out to assess the radioprotective potential of N-acetyl-L-tryptophan (L-NAT) in neuronal cells. Radiation-induced cell death and its amelioration by L-NAT pretreatment were investigated using MTT, SRB, CFU, and comet assays. Flow cytometric and microscopic fluorescence assays were used to investigate radiation-induced oxidative stress, alteration in mitochondrial redox, Ca2+ homeostasis, depolarization of mitochondrial membrane potential, and its prevention with L-NAT pretreatment. Western blot analysis of Caspase-3, γ-H2aX, p53, ERK-1/2, and p-ERK-1/2 expression was carried out to identify the effects of L-NAT pretreatment on radiation-induced apoptosis and its regulatory proteins expression. The study demonstrated (MTT, SRB, and CFU assay) significant (~80%; p <0.001%) radioprotection in irradiated (LD50 IR dose) Neuro2a cells that were pretreated with L-NAT. In comparison to irradiated cells, L-NAT pretreatment resulted in significant (p <0.001%) DNA protection. A subsequent study revealed that L-NAT pretreatment of irradiated Neuro2a cells establishes oxidative stress by increasing antioxidant enzymes and mitochondrial redox homeostasis by inhibiting Ca2+ migration from the cytoplasm to the mitochondrial matrix and thus protects the mitochondrial membrane hyperpolarization. Caspase-3 and γ-H2aX protein expression decreased, while p-ERK1/2 and p53 expression increased in L-NAT pretreated irradiated cells compared to irradiated cells. Hence, L-NAT could be a potential radioprotective that may inhibit oxidative stress and DNA damage and maintain mitochondrial health and Ca2+ levels by activating p-ERK1/2 and p53 expression in Neuronal cells.

Hemiterpene compound, 3,3-dimethylallyl alcohol promotes longevity and neuroprotection in Caenorhabditis elegans.

Terpenes and their derivatives have been used conventionally as potential dietary supplements to boost the nutritional value of endless food products. Several plant-based complex terpenoid and their derivatives have been reported for a wide range of medicinal and nutritional properties. However, their simple counterparts, whose production is relatively easy, sustainable, and economic from food-grade microbial sources, have not been studied yet for any such biological activities. The present study aimed to investigate the longevity-promoting property and neuromodulatory effects of 3,3-dimethylallyl alcohol (Prenol), one of the simplest forms of terpenoid and a constituent of fruit aroma, in the animal model Caenorhabditis elegans. Prenol supplementation (0.25 mM) augmented the lifespan of wild-type nematodes by 22.8% over the non-treated worms. Moreover, a suspended amyloid-ß induced paralysis and reduced α-synuclein aggregation were observed in Prenol-treated worms. The lifespan extending properties of Prenol were correlated with ameliorated physiological parameters and increased stress (heat and oxidative) tolerance in C. elegans. In silico and gene-specific mutant studies showed that pro-longevity transcription factors DAF-16, HSF-1, and SKN-1 were involved in the improved lifespan and health-span of Prenol-treated worms. Transgenic green fluorescent protein-reporter gene expression analysis and relative mRNA quantification (using real-time PCR) demonstrated an increase in the expression of DAF-16, HSF-1, and SKN-1 transcription factors and their downstream target genes in Prenol-treated worms. Together, the findings suggest that small molecules, like Prenol, could be explored as a potential alternate to develop therapeutics against aging and age-related ailments.

Metagenomics Analysis of Thrombus Samples Retrieved from Mechanical Thrombectomy.

PURPOSE: The purpose of this study was to assess the microbiota in middle cerebral artery thrombi retrieved in mechanical thrombectomy arising out of symptomatic carotid plaque within 6 hours of acute ischemic stroke. Thrombi were subjected to next-generation sequencing for a bacterial signature to determine their role in atherosclerosis. MATERIALS AND METHODS: We included 4 human middle cerebral artery thrombus samples (all patients were male). The median age for the patients was 51±13.6 years. Patients enrolled in the study from Pacific Medical University and Hospital underwent mechanical thrombectomy in the stroke window period. All patients underwent brain magnetic resonance angiography (MRA) and circle of Willis and neck vessel MRA along with the standard stroke workup to establish stroke etiology. Only patients with symptomatic carotid stenosis and tandem lesions with ipsilateral middle cerebral artery occlusion were included in the study. Thrombus samples were collected, stored at -80 degrees, and subjected to metagenomics analysis. RESULTS: Of the 4 patients undergoing thrombectomy for diagnosis with ischemic stroke, all thrombi recovered for bacterial DNA in qPCR were positive. More than 27 bacteria were present in the 4 thrombus samples. The majority of bacteria were Lactobacillus, Stenotrophomonas, Pseudomonas, Staphylococcus, and Finegoldia. CONCLUSION: Genesis of symptomatic atherosclerotic carotid plaque leading to thromboembolism could be either due to direct mechanisms like acidification and local inflammation of plaque milieu with lactobacillus, biofilm dispersion leading to inflammation like with pseudomonas fluorescence, or enterococci or indirect mechanisms like Toll 2 like signaling by gut microbiota.

A review of quantitative risk-benefit methodologies for assessing drug safety and efficacy-report of the ISPOR risk-benefit management working group.

OBJECTIVE: Although regulatory authorities evaluate the risks and benefits of any new drug therapy during the new drug-approval process, quantitative risk-benefit assessment (RBA) is not typically performed, nor is it presented in a consistent and integrated framework when it is used. Our purpose is to identify and describe published quantitative RBA methods for pharmaceuticals. METHODS: Using MEDLINE and other Internet-based search engines, a systematic literature review was performed to identify quantitative methodologies for RBA. These distinct RBA approaches were summarized to highlight the implications of their differences for the pharmaceutical industry and regulatory agencies. RESULTS: Theoretical models, parameters, and key features were reviewed and compared for the 12 quantitative RBA methods identified in the literature, including the Quantitative Framework for Risk and Benefit Assessment, benefit-less-risk analysis, the quality-adjusted time without symptoms and toxicity, number needed to treat (NNT), and number needed to harm and their relative-value-adjusted versions, minimum clinical efficacy, incremental net health benefit, the risk-benefit plane (RBP), the probabilistic simulation method, multicriteria decision analysis (MCDA), the risk-benefit contour (RBC), and the stated preference method (SPM). Whereas some approaches (e.g., NNT) rely on subjective weighting schemes or nonstatistical assessments, other methods (e.g., RBP, MCDA, RBC, and SPM) assess joint distributions of benefit and risk. CONCLUSIONS: Several quantitative RBA methods are available that could be used to help lessen concern over subjective drug assessments and to help guide authorities toward more objective and transparent decision-making. When evaluating a new drug therapy, we recommend the use of multiple RBA approaches across different therapeutic indications and treatment populations in order to bound the risk-benefit profile.

Clinical Usefulness of Cell-Free DNA as a Prognostic Marker in Acute Ischemic Stroke.

OBJECTIVE: Stroke has become the second most common cause of death. Several biomarkers have been detected in the peripheral blood from stroke patients, but none has found a place in clinical practice. Cell-free DNA (cf-DNA) liberated into the blood soon after the onset of stroke might be useful for assessing disease severity and prognosis. STUDY DESIGN AND METHODS: A total of 54 patients presenting with ischemic stroke were recruited consecutively with the exclusion of patients having trauma, tumor, infections, and organ failure. The cf-DNA was extracted by circulating nucleic acid kit from Qiagen and measured by real-time quantitative polymerase chain reaction assay for ß-globin gene. The primary outcome measure was poststroke modified Rankin scale Score at 3 months after the onset of symptoms. RESULTS: Higher cf-DNA levels were associated with severity at the time of admission measured by National Institutes of Health Stroke Scale (P=0.003) and poor outcome as measured by modified Rankin scale 3-month scores (P=0.001). Therapeutic intervention in the form of a mechanical thrombectomy or IV thrombolysis was associated with improved outcome in patients with cf-DNA<10,000 kilogenome-equivalents/L (P≤0.01). CONCLUSIONS: cf-DNA level correlates well with the severity of stroke at admission and long-term prognosis. It can be used as an additional marker to predict the outcome of therapeutic intervention.

Betula utilis extract prolongs life expectancy, protects against amyloid-ß toxicity and reduces Alpha Synuclien in Caenorhabditis elegans via DAF-16 and SKN-1.

Betula utilis (BU), an important medicinal plant that grows in high altitudes of the Himalayan region, has been utilized traditionally due to it's antibacterial, hepatoprotective, and anti-tumor properties. Here, we demonstrated the longevity and amyloid-ß toxicity attenuating activity of B. utilis ethanolic extract (BUE) in Caenorhabditis elegans. Lifespan of the worms was observed under both the standard laboratory and stress (oxidative and thermal) conditions. Effect of BUE was also observed on the attenuation of age-dependent physiological parameters. Further, gene-specific mutants and green fluorescent protein (GFP)-tagged strains were used to investigate the molecular mechanism underlying the beneficial effects mediated by BUE supplementation. Our results showed that BUE (50 µg/ml) extended the mean lifespan of C. elegans by 35.99% and increased its survival under stress conditions. The BUE also reduced the levels of intracellular reactive oxygen species (ROS) by 22.47%. A delayed amyloid-ß induced paralyses was observed in CL4176 transgenic worms. Interestingly, the BUE supplementation was also able to reduce the α-synuclein aggregation in NL5901 transgenic strain. Gene-specific mutant studies suggested that the BUE-mediated lifespan extension was dependent on daf-16, hsf-1, and skn-1 but not on sir-2.1 gene. Furthermore, transgenic reporter gene expression assay showed that BUE treatment enhanced the expression of stress-protective genes such as sod-3 and gst-4. Present findings suggested that ROS scavenging activity, together with multiple longevity mechanisms, were involved in BUE-mediated lifespan extension. Thus, BUE might have potential to increase the lifespan and to attenuate neuro-related disease progression.

Withanolide A offers neuroprotection, ameliorates stress resistance and prolongs the life expectancy of Caenorhabditis elegans.

Withanolide A (steroidal lactone) forms the major constituent of the most popular herbal drug in Ayurvedic medicine, Ashwagandha. It has been used since ancient times as an alternative medicine for the treatment of a variety of age related disorders. Here we provide multiple lines of evidence indicating that Withanolide A improves healthspan, delays age-associated physiological changes and also extends the lifespan of Caenorhabditis elegans. We also report several neuroprotective benefits of this natural product, including its anti-amyloidogenic effects, alleviation of α-synuclein aggregation and neuroprotection through modulation of neural mediators like acetylcholine. We observed that Withanolide A mediates lifespan extension and promotes stress resistance via insulin/insulin-like growth factor signaling pathway. Such findings could be helpful to develop a therapeutic medicine from this natural product for the prevention or reversal of age-related ailments and to improve the survival of patients suffering from Alzheimer's or Parkinson's disease.

Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans.

Folic acid (FA) is an essential nutrient that the human body needs but cannot be synthesized on its own. Fortified foods and plant food sources such as green leafy vegetables, beans, fruits, and juices are good sources of FA to meet the daily requirements of the body. The aim was to evaluate the effect of dietary FA levels on the longevity of well-known experimental aging model Caenorhabditis elegans. Here, we show for first time that FA extends organism life span and causes a delay in aging. We observed that FA inhibits mechanistic target of rapamycin (mTOR) and insulin/insulin growth factor 1 (IGF-1) signaling pathways to control both oxidative stress levels and life span. The expression levels of stress- and life span-relevant gerontogenes, viz. daf-16, skn-1, and sir. 2.1, and oxidative enzymes, such as glutathione S-transferase 4 (GST-4) and superoxide dismutase 3 (SOD-3), were also found to be highly enhanced to attenuate the intracellular reactive oxygen species (ROS) damage and to delay the aging process. Our study promotes the use of FA to mitigate abiotic stresses and other aging-related ailments.

Stereomicroscopic evaluation of dentinal defects induced by new rotary system: "ProTaper NEXT".

INTRODUCTION: The objective of this study was to evaluate dentinal defects formed by new rotary system - Protaper next™ (PTN). MATERIALS AND METHODS: Sixty single-rooted premolars were selected. All specimens were decoronated and divided into four groups, each group having 15 specimens. Group I specimens were prepared by Hand K-files (Mani), Group II with ProTaper Universal (PT; Dentsply Maillefer), Group III with Hero Shaper (HS; Micro-Mega, Besancon, France), and Group IV with PTN (Dentsply Maillefer). Roots of each specimen were sectioned at 3, 6, and 9mm from the apex and were then viewed under a stereomicroscope to evaluate presence or absence of dentinal defects. RESULTS: In roots prepared with hand files (HFs) showed lowest percentage of dentinal defects (6.7%); whereas in roots prepared with PT, HS, and PTN it was 40, 66.7, and 26.7%, respectively. There was significant difference between the HS group and the PTN group (P < 0.05). CONCLUSION: All rotary files induced defects in root dentin, whereas the hand instruments induced minimal defects.

Specioside ameliorates oxidative stress and promotes longevity in Caenorhabditis elegans.

Specioside (6-O-coumaroylcatalpol) is an iridoid glucoside which possesses multifunctional activities viz. analgesic, antidyspeptic, astringent, liver stimulating and wound healing properties. The present study for the first time delineates stress alleviating and lifespan prolonging action of specioside (SPC), isolated from Stereospermum suaveolens in the free living, multicellular nematode model Caenorhabditis elegans. A strong correlation between lifespan extension and stress modulation in adult worms was established in a dose dependent manner. The dietary intake of this phytomolecule elevated juglone induced oxidative and heat induced thermal stress tolerance in C. elegans. On evaluation, it was found that 25 µM dose of SPC significantly extended lifespan by 15.47% (P≤0.0001) with reduction in stress level. Furthermore, SPC enhanced mean survival in mev-1 mutant suggesting its oxidative stress reducing potential. Furthermore, SPC augmented stress modulatory enzymes superoxide dismutase (SOD) and catalase (CAT) level in C. elegans. Altogether, these findings broaden current perspectives concerning stress alleviating potentials of SPC and have implications in development of therapeutics for curing age related disorders.

To evaluate and compare the effect of different Post Surface treatments on the Tensile Bond Strength between Fiber Posts and Composite Resin.

BACKGROUND: Fiber posts are widely used for restoration of mutilated teeth that lack adequate coronal tooth structure to retain a core for definitive restoration, bond between the fiber post and composite material depends upon the chemical reaction between the post surface and the resin material used for building up the core. In attempt to maximize the resin bonding with fiber post, different post surface conditioning is advocated. Therefore the purpose of the study is to examine the interfacial strength between fiber post and composite, as core build-up material after different surface treatments of fiber posts. MATERIALS & METHODS: Twenty fiber posts were split into four groups off five each according to different surface treatments viz. Group I-(Negative Control), Group II-Silanization (Positive control), Group III-(37% Phosphoric Acid & Silanization) ,Group IV- (10% Hydrogen Peroxide and Silanization). With the preformed plastic mould, a core of dual cure composite resin around the fiber post having the uniform thickness was created. Tensile bond strength of each specimen was measured under Universal Testing Machine (UTM) at the cross head speed of 3mm/min. RESULTS: The results achieved with 10% Hydrogen peroxide had a marked effect on micro tensile bond strength values between the tested materials. CONCLUSION: Immense enhancement in the silanization efficiency of quartz fiber phase was observed with different surface chemical treatment of the resin phase of fiber posts with the marked increase in the micro-tensile bond strength between fiber post and composite core. HOW TO CITE THIS ARTICLE: Shori D, Pandey S, Kubde R, Rathod Y, Atara R, Rathi S. To evaluate and compare the effect of different Post Surface treatments on the Tensile Bond Strength between Fiber Posts and Composite Resin. J Int Oral Health 2013; 5(5):27-32.

Myocardial protection during off pump coronary artery bypass surgery: a comparison of inhalational anesthesia with sevoflurane or desflurane and total intravenous anesthesia.

AIMS AND OBJECTIVES: The objective of the study was to evaluate the myocardial protective effect of volatile agents-sevoflurane and desflurane versus total intravenous anesthesia (TIVA) with propofol in offpump coronary artery bypass surgery (OPCAB) by measuring cardiac troponin-T (cTnT) as a marker of myocardial cell death. MATERIALS AND METHODS: The study was conducted on 139 patients scheduled to undergo elective OPCAB surgery. The patients were randomly allocated to receive anesthesia with sevoflurane, desflurane or TIVA with propofol. The cTnT levels were measured preoperatively, at arrival in postoperative intensive care unit, at 8, 24, 48 and 96 hours thereafter. RESULTS: The changes in cTnT levels at all time intervals were comparable in the three groups. CONCLUSION: The study did not reveal any difference in myocardial protection after OPCAB with either sevoflurane or desflurane or TIVA using propofol as assessed by measuring serial cTnT values.