Sensitization of capsaicin and icilin responses in oxaliplatin treated adult rat DRG neurons

<p>Abstract</p> <p>Background</p> <p>Oxaliplatin chemotherapy induced neuropathy is a dose related cumulative toxicity that manifests as tingling, numbness, and chronic pain, compromising the quality of life and leading to discontinued chemotherapy. Patients report marked hypersensitivity to cold stimuli at early stages of treatment, when sensory testing reveals cold and heat hyperalgesia. This study examined the morphological and functional effects of oxaliplatin treatment in cultured adult rat DRG neurons.</p> <p>Results</p> <p>48 hour exposure to oxaliplatin resulted in dose related reduction in neurite length, density, and number of neurons compared to vehicle treated controls, using Gap43 immunostaining. Neurons treated acutely with 20 μg/ml oxaliplatin showed significantly higher signal intensity for cyclic AMP immunofluorescence (160.5 ± 13 a.u., n = 3, P < 0.05), compared to controls (120.3 ± 4 a.u.). Calcium imaging showed significantly enhanced capsaicin (TRPV1 agonist), responses after acute 20 μg/ml oxaliplatin treatment where the second of paired capsaicin responses increased from 80.7 ± 0.6% without oxaliplatin, to 171.26 ± 29% with oxaliplatin, (n = 6 paired t test, P < 0.05); this was reduced to 81.42 ± 8.1% (P < 0.05), by pretretreatment with the cannabinoid CB2 receptor agonist GW 833972. Chronic oxaliplatin treatment also resulted in dose related increases in capsaicin responses. Similarly, second responses to icilin (TRPA1/TRPM8 agonist), were enhanced after acute (143.85 ± 7%, P = 0.004, unpaired t test, n = 3), and chronic (119.7 ± 11.8%, P < 0.05, n = 3) oxaliplatin treatment, compared to control (85.3 ± 1.7%). Responses to the selective TRPM8 agonist WS-12 were not affected.</p> <p>Conclusions</p> <p>Oxaliplatin treatment induces TRP sensitization mediated by increased intracellular cAMP, which may cause neuronal damage. These effects may be mitigated by co-treatment with adenylyl cyclase inhibitors, like CB2 agonists, to alleviate the neurotoxic effects of oxaliplatin.</p

Effect of Reinforced Concrete Jacketing on Axial Load Capacity of Reinforced Concrete Column

Whenever a member of a structure becomes structurally deficient, it becomes vulnerable to the existing load and for the additional loads that it may be subjected to in the coming future. Since columns are the most important structural element, the structural retrofit of columns, relative to other structural elements is of prime importance. This study intends to investigate the performance and behaviour of an RC column jacketed with Reinforced Concrete columns under axial loads. The objective of this paper is to find out the efficiency of RC jacket in enhancing the strength of an existing RC column. A mathematical design based upon Indian Standards codes has been designed to identify the behaviour of jacketed RC columns. This has been followed by a finite element based numerical simulation using the same material properties as used in the process of designing. The simulation has been done in ABAQUS software with appropriate contact modelling. The analytical model considers that there is no bond slippage between the existing and new concrete surface i.e. the bond between the existing and new concrete is assumed to be perfect. This perfect bond between the surfaces has been modelled by using appropriate constraints in ABAQUS software. The finite element models show fair agreement with the designed values in terms of ultimate capacity and failure mode. The load bearing capacity enhancement of the RC jacketed column has been found to increase substantially. The enhancement capacity results obtained from the finite element software differs about 16-25% from the design values

Assessment, Implication, and Analysis of Online Consumer Reviews: A Literature Review

The onset of e-marketplace, virtual communities and social networking has appreciated the influential capability of online consumer reviews (OCR) and therefore necessitate conglomeration of the body of knowledge. This article attempts to conceptually cluster academic literature in both management and technical domain. The study follows a framework which broadly clusters management research under two heads: OCR Assessment and OCR Implication (business implication). Parallel technical literature has been reviewed to reconcile methodologies adopted in the analysis of text content on the web, majorly reviews. Text mining through automated tools, algorithmic contribution (dominant majorly in technical stream literature) and manual assessment (derived from the stream of content analysis) has been studied in this review article. Literature survey of both the domains is analyzed to propose possible area for further research. Usage of text analysis methods along with statistical and data mining techniques to analyze review text and utilize the knowledge creation for solving managerial issues can possibly constitute further work. Available at: https://aisel.aisnet.org/pajais/vol9/iss2/4

PLIC: protein–ligand interaction clusters

Most of the biological processes are governed through specific protein–ligand interactions. Discerning different components that contribute toward a favorable protein– ligand interaction could contribute significantly toward better understanding protein function, rationalizing drug design and obtaining design principles for protein engineering. The Protein Data Bank (PDB) currently hosts the structure of ∼68 000 protein–ligand complexes. Although several databases exist that classify proteins according to sequence and structure, a mere handful of them annotate and classify protein–ligand interactions and provide information on different attributes of molecular recognition. In this study, an exhaustive comparison of all the biologically relevant ligand-binding sites (84 846 sites) has been conducted using PocketMatch: a rapid, parallel, in-house algorithm. PocketMatch quantifies the similarity between binding sites based on structural descriptors and residue attributes. A similarity network was constructed using binding sites whose PocketMatch scores exceeded a high similarity threshold (0.80). The binding site similarity network was clustered into discrete sets of similar sites using the Markov clustering (MCL) algorithm. Furthermore, various computational tools have been used to study different attributes of interactions within the individual clusters. The attributes can be roughly divided into (i) binding site characteristics including pocket shape, nature of residues and interaction profiles with different kinds of atomic probes, (ii) atomic contacts consisting of various types of polar, hydrophobic and aromatic contacts along with binding site water molecules that could play crucial roles in protein–ligand interactions and (iii) binding energetics involved in interactions derived from scoring functions developed for docking. For each ligand-binding site in each protein in the PDB, site similarity information, clusters they belong to and description of site attributes are provided as a relational database—protein–ligand interaction clusters (PLIC)

Comparison of Outcomes with Hypofractionated Palliative Radiotherapy ‘Christie Regimen’ Versus Standard Palliative Radiation in Head and Neck Squamous Cell Carcinoma

AIM OF THE STUDY: To compare the efficacy and toxicity profile of patients with squamous cell carcinoma of the head and neck (HNSCC) treated with Hypofractionated palliative radiotherapy 'Christie Regimen' versus Standard Palliative radiation METHODS AND MATERIALS: About 60 cases of locally advance Head and Neck cancers were analyzed in 2 arms. Patients were treated with 300 cGy /10 # / 30 Gy / 2 weeks in Arm A (Control arm), and 312.5 cGy / 16 # /50 Gy /3.1 weeks in Arm B (Study arm). RESULTS: At the end of the study Response, Toxicities and QOL assessed. Complete Response (CR) - Arm A ; 9 (30%), Arm B 12 - (40%) . Partial Response (PR) - Arm A ; 16 (53.33%) , Arm B 17 - (56.66%). Static Disease (SD) - Arm A ; 5 (16.66%) Arm B - 1 (3.33%). Locoregional control after the completion of treatment was complete response (CR) (30% and 40%), partial response (PR) (53.33% and 56.66%), and no response (SD) (16.66% and 3.33%) in Arm A and Arm B respectively, but this was not statistically significant (P = 0.209555). Grade II Skin reactions were observed more in both the arms 53.33% and 56.66% in Arm A and Arm B respectively. Grade III radiation skin reactions were 6.66% and 10% in Arm A and Arm B respectively. And also Grade I and II mucosal reactions were observed more in Arm A and Arm B 46.66% vs 40% and 40% vs 46.66%, respectively. Grade III radiation mucosal reactions were equal in both groups (13.33%), statistically not significant. In Oesophagus, Larynx and Salivary glands also Grade III and Grade II reactions are common in both groups. The patients were followed for a minimum period of 6 months. Quality of Life improvement at the end of 6 months was Pain improvement (28% and 59.25%), Performance status improvement (36% and 62.96%), and Weight loss improvement (20% and 33.33%%) in Arm A and Arm B respectively. CONCLUSION: Hence, it can be concluded that although there was no significant difference in Response rates, QOL improvement was in favor of Christie regimen schedules with manageable toxicities. The total time needed were less in hypofractionated radiotherapy regimen, and this radiobiological superiority is beneficial for centers like ours where the patient load is much higher than the facility available for radiation. Further studies with longer follow-up will be needed for confirmation to establish the long-term effects of this regime

Sodium channel Nav1.7 immunoreactivity in painful human dental pulp and burning mouth syndrome

Background Voltage gated sodium channels Nav1.7 are involved in nociceptor nerve action potentials and are known to affect pain sensitivity in clinical genetic disorders. Aims and Objectives To study Nav1.7 levels in dental pulpitis pain, an inflammatory condition, and burning mouth syndrome (BMS), considered a neuropathic orofacial pain disorder. Methods Two groups of patients were recruited for this study. One group consisted of patients with dental pulpitis pain (n = 5) and controls (n = 12), and the other patients with BMS (n = 7) and controls (n = 10). BMS patients were diagnosed according to the International Association for the Study of Pain criteria; a pain history was collected, including the visual analogue scale (VAS). Immunohistochemistry with visual intensity and computer image analysis were used to evaluate levels of Nav1.7 in dental pulp tissue samples from the dental pulpitis group, and tongue biopsies from the BMS group. Results There was a significantly increased visual intensity score for Nav1.7 in nerve fibres in the painful dental pulp specimens, compared to controls. Image analysis showed a trend for an increase of the Nav1.7 immunoreactive % area in the painful pulp group, but this was not statistically significant. When expressed as a ratio of the neurofilament % area, there was a strong trend for an increase of Nav1.7 in the painful pulp group. Nav1.7 immunoreactive fibres were seen in abundance in the sub-mucosal layer of tongue biopsies, with no significant difference between BMS and controls. Conclusion Nav1.7 sodium channel may play a significant role in inflammatory dental pain. Clinical trials with selective Nav1.7 channel blockers should prioritise dental pulp pain rather than BMS

A comparative clinical study on efficacy of Mashaparni and Kapikachu in Oligospermia

Introduction: Oligospermia is deficiency of sperm cells in semen. It is one of the main causes for male infertility. Prevalence of male infertility is around 7%. Recent studies showed that nearly 2-5% couple around world is suffering from the problems of inability to achieve conception. The normal process of spermatogenesis will be affected due to mechanical life, stress, strain and unhealthy food and various changes occur in the life style. Objective: To evaluate the efficacy of Mashaparni and Kapikachu in Oligospermia. Materials and Methods: Data was collected by randomized sampling through lottery method with a minimum of 30 subjects of Oligospermia with respect to age and sex, irrespective of caste, religion and socio economic status. These subjects were assigned into 2 groups A and B with 15 subjects in each group. Duration of the intervention was 3 months. Results: Results obtained were statistically insignificant between both the groups. Conclusion: On the basis of the result of this study it was concluded that, both prescribed drugs will increase sperm count significantly

Influence of pregnancy and labor on the occurrence of nerve fibers expressing the capsaicin receptor TRPV1 in human corpus and cervix uteri

<p>Abstract</p> <p>Background</p> <p>Cervical ripening is a prerequisite for a normal obstetrical outcome. This process, including labor, is a painful event that shares features with inflammatory reactions where peripheral nociceptive pathways are involved. The capsaicin and heat receptor TRPV1 is a key molecule in sensory nerves involved in peripheral nociception, but little is known regarding its role in the pregnant uterus. Therefore, the aim of this study was to investigate human corpus and cervix uteri during pregnancy and labor and non-pregnant controls for the presence of TRPV1.</p> <p>Methods</p> <p>We have investigated human uterine corpus and cervix biopsies at term pregnancy and parturition. Biopsies were taken from the upper edge of the hysterotomy during caesarean section at term (n = 8), in labor (n = 8) and from the corresponding area in the non-pregnant uterus after hysterectomy (n = 8). Cervical biopsies were obtained transvaginally from the anterior cervical lip. Serial frozen sections were examined immunohistochemically using specific antibodies to TRPV1 and nerve markers (neurofilaments/peripherin).</p> <p>Results</p> <p>In cervix uteri, TRPV1-immunoreactive fibers were scattered throughout the stroma and around blood vessels, and appeared more frequent in the sub-epithelium. Counts of TRPV1-immunoreactive nerve fibers were not significantly different between the three groups. In contrast, few TRPV1-immunoreactive fibers were found in nerve fascicles in the non-pregnant corpus, and none in the pregnant corpus.</p> <p>Conclusion</p> <p>In this study, TRPV1 innervation in human uterus during pregnancy and labor is shown for the first time. During pregnancy and labor there was an almost complete disappearance of TRPV1 positive nerve fibers in the corpus. However, cervical innervation remained throughout pregnancy and labor. The difference in TRPV1 innervation between the corpus and the cervix is thus very marked. Our data suggest that TRPV1 may be involved in pain mechanisms associated with cervical ripening and labor. Furthermore, these data support the concept that cervix uteri may be the major site from which labor pain emanates. Our findings also support the possibility of developing alternative approaches to treat labor pain.</p

Functional MRI brain imaging studies using the Contact Heat Evoked Potential Stimulator (CHEPS) in a human volunteer topical capsaicin pain model

Acute application of topical capsaicin produces spontaneous burning and stinging pain similar to that seen in some neuropathic states, with local hyperalgesia. Use of capsaicin applied topically or injected intradermally has been described as a model for neuropathic pain, with patterns of activation in brain regions assessed using functional magnetic resonance imaging (fMRI) and positron emission tomography. The Contact Heat Evoked Potential Stimulator (CHEPS) is a noninvasive clinically practical method of stimulating cutaneous A-delta nociceptors. In this study, topical capsaicin (1%) was applied to the left volar forearm for 15 minutes of twelve adult healthy human volunteers. fMRI scans and a visual analog pain score were recorded during CHEPS stimulation precapsaicin and postcapsaicin application. Following capsaicin application there was a significant increase in visual analog scale (mean ± standard error of the mean; precapsaicin 26.4 ± 5.3; postcapsaicin 48.9 ± 6.0; P < 0.0001). fMRI demonstrated an overall increase in areas of activation, with a significant increase in the contralateral insular signal (mean ± standard error of the mean; precapsaicin 0.434 ± 0.03; postcapsaicin 0.561 ± 0.07; P = 0.047). The authors of this paper recently published a study in which CHEPS-evoked A-delta cerebral potential amplitudes were found to be decreased postcapsaicin application. In patients with neuropathic pain, evoked pain and fMRI brain responses are typically increased, while A-delta evoked potential amplitudes are decreased. The protocol of recording fMRI following CHEPS stimulation after topical application of capsaicin could be combined with recording of evoked potentials to provide a simple, rapid, and robust volunteer model to develop novel drugs for neuropathic pain