Epithelial-mesenchymal transition contrast in the amputated tail and limb of the northern house gecko, Hemidactylus flaviviridis.

The northern house gecko Hemidactylus flaviviridis exhibits appendage-specific responses to injuries. The autotomized tail regenerates, whereas the severed limb fails to regrow. Many site-specific cellular processes influence tail regeneration. Herein, we analyzed the epithelial-mesenchymal transition contrast in the lizard's amputated appendages (tail and limb). Morphological observations in the healing frame indicated the formation of regeneration blastema in the tail and scar formation in limb. Histology of the tail showed that epithelial cells closer to mesenchyme appeared less columnar and loosely packed, with little intercellular matrix. Whereas in the limb, the columnar epithelial cells remained tightly packed. Collagen deposition was seen in the limb at the intersection of wound epithelium and mesenchyme, favoring scarring by blocking the epithelial-mesenchymal transition. Markers for epithelial-mesenchymal transition were assessed at transcript and protein levels. The regenerating tail showed upregulation of N-cadherin, vimentin, and PCNA, favoring epithelial-mesenchymal transition, cell migration, and proliferation, respectively. In contrast, the scarring limb showed persistently elevated levels of E-cadherin and EpCAM, indicating retention of epithelial characteristics. An attempt was made to screen the resident epithelial stem cell population in both appendages to check their potential role in the epithelial-mesenchymal transition (EMT), hence the differential wound healing. Upregulation in transcript and protein levels of Nanog and Sox2 was observed in the regenerating tail. Fluorescence-activated cell sorting (FACS) provided supporting evidence that the epithelial stem cell population in tail remained significantly higher than in limb. Thus, this study focuses on the mechanistic role of the epithelial-mesenchymal transition in wound healing, highlighting the molecular details of regeneration and scarring events.

Subretinal Neovascular Membrane in Wet Age-Related Macular Degeneration Managed With Intravitreal Ranibizumab.

This case report depicts how a case of the subretinal neovascular membrane was managed with intravitreal ranibizumab injections. A 59-year-old female patient presented with complaints of diminution of vision in her right eye for one month. Various necessary examinations were carried out and the patient was diagnosed with both forms of age-related macular degeneration (ARMD) disorder - wet ARMD in the right eye and dry ARMD in the left eye. Pseudophakia was also seen in both eyes. Drusen deposits, characteristic of the disorder, were seen in the macular area of the oculus sinister (OS). The patient was treated for the wet ARMD with intravitreal injections of 0.5 mg ranibizumab administered one month apart in the right eye. The patient showed improvements in her visual acuity and a complete resolution of the subretinal fluid.

Treatment Landscape of Macular Disorders in Indian Patients with the Advent of Razumab™ (World's First Biosimilar Ranibizumab): A Comprehensive Review.

Ranibizumab is approved for the treatment of several macular disorders, including wet age-related macular degeneration (wet AMD), diabetic macular edema (DME), retinal vein occlusion (RVO) and myopic choroidal neovascularization (mCNV), among others. The unaffordability of the innovator ranibizumab among patients from developing countries such as India led to the development of the world's first biosimilar ranibizumab, which is a cost-effective alternative that does not compromise efficacy and safety. Razumab™, developed and produced by Intas Pharmaceuticals Ltd., India, is the world's first biosimilar of ranibizumab, and is approved in India for the treatment of various macular disorders, including wet AMD, DME, RVO and mCNV. The efficacy and safety of Razumab for the treatment of these macular disorders have been evaluated in both prospective and real-world retrospective studies. Razumab has shown an efficacy similar to that of the innovator ranibizumab, achieving improved visual acuity, as measured by the best corrected visual acuity, and reduction in the central macular thickness, leading to improved patient outcomes. The safety profile of Razumab is comparable to that of the innovator ranibizumab and is well tolerated without any new safety concerns. Here, we review the clinical and real-world data of Razumab in the treatment of macular disorders.

Safety and efficacy of Razumab™ (world's first biosimilar ranibizumab) in wet age-related macular degeneration: a post-marketing, prospective ASSET study.

BACKGROUND: Razumab™ (world's first biosimilar ranibizumab) is approved for several macular disorders including wet age-related macular degeneration (AMD). We evaluated the safety and efficacy of biosimilar ranibizumab in wet AMD. METHODS: This prospective, multicentre, rAnibizumab bioSimilar Safety Efficacy postmarkeTing (ASSET) study enrolled patients aged ≥ 50 years with wet AMD having best-corrected visual acuity (BCVA) between 20/40 and 20/320. The patients received intravitreal biosimilar ranibizumab 0.5 mg every 4 weeks for 24 weeks. Safety endpoints included the incidence of adverse events (AEs), serious AEs (SAEs), and immunoreactivity after 6 months. The efficacy endpoints were the proportion of patients who lose fewer than 15 letters, increase in BCVA, change in central retinal thickness (CRT), and change in Visual Function Questionnaire-25 (VFQ-25) score, from baseline to 24 weeks. RESULTS: Of the 126 enrolled patients, majority (95.24%) of the patients received all 6 doses of biosimilar ranibizumab (total 3 mg). Nineteen AEs were reported (n = 16; 12.7%); majority (78.9%) were mild. There were no serious AEs reported, except one AE of death which was unrelated to the study drug. None of the patients discontinued the study due to an AE. The most common ocular AE was increase in intraocular pressure (4 events) and non-ocular AE was pyrexia (5 events). A total of 7.9% (10/126) patients prior to dosing and 7.1% (9/126) patients post-treatment were positive for anti-ranibizumab antibodies. No AEs suggestive of immunogenicity were noted. At 24-weeks, 97.60% patients in the intent-to-treat (ITT) population (N = 125) and 97.41% patients in the per-protocol (PP) population (N = 116) lost < 15 letters from baseline visual acuity. In the ITT and PP populations, 31.20% and 32.76% patients, respectively, showed improved visual acuity by ≥ 15 letters. Significant improvements in BCVA (mean difference: 8.8, 9.2, p < 0.001 for ITT, PP) and VFQ-25 (8.5, 9.2, p < 0.001 for ITT, PP) were seen; CRT reduced significantly (125 µm, 119.3 µm, p < 0.001 for ITT, PP). CONCLUSION: Razumab™ (world's first biosimilar ranibizumab) was well-tolerated without new safety concerns and significantly improved visual acuity in wet AMD patients. Trial registration CTRI/2016/03/006739. Registered 18 March 2016-Prospectively registered, http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=13141&EncHid=&userName=2016/03/006739.

Early embryonic exposure to chlorpyrifos-cypermethrin combination induces pattern deficits in the heart of domestic hen.

Exposure to chlorpyrifos-cypermethrin combination during early development resulted in defective looping and ventricular noncompaction of heart in domestic chicken. The study was extended to elucidate the molecular basis of this novel observation. The primary culture of chicken embryonic heart cells showed a concentration-dependent loss of viability when challenged with this combination of technical-grade insecticides. Comet assay, DNA ladder assay, and analyses of appropriate markers at transcript and protein levels, revealed that chlorpyrifos-cypermethrin combination induced cell death by activating apoptosis. Parallelly, the tissues derived from control and experimental group hearts were checked for apoptotic markers, and the result was much similar to that of the in-vitro study. Further analysis showed that chlorpyrifos-cypermethrin combination deranged the expression pattern of the transcriptional regulators of cardiogenesis, namely TBX20, GATA5, HAND2, and MYOCD. This, together with heightened apoptosis, could well be the reason behind the observed structural anomalies in the heart of chlorpyrifos-cypermethrin poisoned embryos.

Epidural Fever: Hiding in the Shadows.

Recent research has focused on inflammation and oxidative stress that is seen in women developing intrapartum fever. The interleukin-6 (IL-6) levels have been found to be elevated in women who receive epidural analgesia and become febrile. This suggests that the epidural itself induces an inflammatory response and it is not a physiologic process of labour. Similar findings with additional proinflammatory mediators and reactive oxygen species seem to support this theory. Epidural analgesia also affects the body's thermoregulatory mechanisms. It causes an increase in shivering and appears to be associated with a decrease in heat dissipation via sweating and hyperventilation, most likely because of blockade of the sympathetic stimulation. Considering these factors, it is probable that epidurals do contribute to the development of the associated fever. There remains the possibility that subclinical chorioamnionitis might be the underlying cause of a subset of maternal intrapartum fevers. In summary, histologic chorioamnionitis and epidural analgesia appear to be the independent contributors to intrapartum fever.

A Multicenter, Retrospective Study (RE-ENACT 2) on Razumab™ (World's First Biosimilar Ranibizumab) in Retinal Vein Occlusion.

PURPOSE: The REal life assessmENt of safety And effeCTiveness of Razumab 2 (RE-ENACT 2) study evaluated the long-term effectiveness of biosimilar ranibizumab. We present the subgroup analysis of patients with retinal vein occlusion (RVO). METHODS: Data of patients who received pro re nata (PRN) biosimilar ranibizumab (November 2015 to December 2018, 17 centers) were analyzed. Endpoints were change from baseline in best corrected visual acuity (BCVA, Snellen's/logMAR), central subfield thickness (CSFT), intraocular pressure (IOP), and proportions of patients having intraretinal fluid (IRF) and subretinal fluid (SRF) at weeks 4, 8, 12, 16, 20, 24, 30, 36, and 48. RESULTS: Of 101 patients, 48.51% were men, and the majority (79.21%) were treatment naïve and had received 3 (range 1-5) injections (53.5%). Significant improvements (P < 0.05) were observed from baseline to all timepoints for BCVA [baseline, 0.89 ± 0.06 (n = 94); week 48, 0.41 ± 0.08 (n = 14)] and CSFT [baseline, 527.58 ± 19.9 (n = 85); week 48, 307.47 ± 16.4 (n = 15)]. Changes in IOP (mmHg) were non-significant [baseline, 15.38 ± 0.4 (n = 94); week 48, 13.94 ± 0.6 (n = 16); P = 0.5575). Proportions of patients having IRF [baseline, 71.3% (n = 84) vs week 48, 0% (n = 15)] and SRF [baseline, 52.5% (n = 83) vs week 48, 0% (n = 15)] were decreased. Similar results for BCVA, CSFT, IOP, IRF, and SRF were observed for BRVO and CRVO subgroups. There were no new safety concerns. CONCLUSIONS: Biosimilar ranibizumab demonstrated improvements in visual acuity and disease outcomes up to 48 weeks in patients with RVO without any new safety concerns.

Efficacy of erector spinae plane block for postoperative analgesia in total mastectomy and axillary clearance: A randomized controlled trial.

BACKGROUND: The erector spinae plane block is a newer technique of analgesia to the chest wall. OBJECTIVE: The study was carried out to establish the efficacy and safety of this block in patients undergoing total mastectomy and axillary clearance. DESIGN: Prospective randomized controlled study. SETTING: Single tertiary care center, the study was conducted over a period of 1 year. PATIENTS: 65 patients were included; final analysis was done for 60 female patients undergoing total mastectomy and axillary clearance under general anesthesia were randomly allocated to two groups. INTERVENTION: Group B (block group) received ultrasound-guided erector spinae plane block at T5 level with ropivacaine (0.5%, 0.4 mL/kg) while the control group did not receive any intervention. Postoperatively, patients in both groups received morphine via intravenous patient-controlled analgesia device. Patients were followed up for 24 h postoperatively. MAIN OUTCOME MEASURES: The 24-hour morphine consumption was considered as the primary outcome and secondary outcomes included time to first rescue analgesia, pain scores at 0, ½, 1, 2, 4, 6, 8, 12, and 24 h and characteristics and complications associated with block procedure. RESULTS: The 24-hour morphine consumption was 42% lower in block group compared to control group [mean (SD), 2.9 (2.5) mg vs 5.0 (2.1) mg in group B and group C, respectively, P = 0.01]. The postoperative pain score was lower in group B vs group C at 0, 1/2, 1, 2, 4, 6, 12, and 24 h (P < 0.05). 26 patients in group C against 14 in group B used rescue analgesia within 1 h of surgery (P = 0.01). CONCLUSION: Erector spinae block may prove to be a safe and reliable technique of analgesia for breast surgery. Further studies comparing this technique with other regional techniques are required to identify the most appropriate technique.

A Multicenter, Retrospective Study (RE-ENACT 2) on the Use of Razumab™ (World's First Biosimilar Ranibizumab) in Wet Age-Related Macular Degeneration.

INTRODUCTION: The REal life assessmENt of safety And effeCTiveness of Razumab (RE-ENACT) and long-term RE-ENACT 2 retrospective studies have evaluated the use of Razumab™ (world's first biosimilar ranibizumab) in retinal disorders in Indian patients. This report presents the subgroup analysis from the RE-ENACT 2 study in patients with wet age-related macular degeneration (wet AMD). METHODS: Medical charts of patients administered biosimilar ranibizumab injections as PRN treatment regimen between September 2015 and June 2018, at 17 centers across India, were reviewed. Changes from baseline in best-corrected visual acuity (BCVA, based on Snellen's or logMAR chart), central subfield thickness (CSFT), intraocular pressure (IOP), and proportions of patients having intraretinal fluid (IRF) and subretinal fluid (SRF) at weeks 4, 8, 12, 16, 20, 24, 30, 36, and 48 were evaluated. RESULTS: Of 103 patients with wet AMD, 62.1% were men and the majority (74.8%) were treatment naïve. The majority (57.9%) of the patients had received 3 (range 1-5) injections. Significant improvements were observed from baseline to all timepoints for BCVA (baseline, 0.92 ± 0.6 [n = 94]; week 48, 0.51 ± 0.4 [n = 14]; P = 0.0014) and CSFT (baseline, 430.83 ± 14.4 [n = 85]; week 48, 301.26 ± 11.6 [n = 15]; P < 0.0001). Changes in IOP from baseline to 48 weeks were minimal and not significant (14.92 ± 3.2 [n = 94] vs. 14.50 ± 2.1 [n = 18]; P = 0.9068). A decrease in proportions of patients having IRF (baseline, 63.6% [n = 99] vs. week 48, 15% [n = 20]) and SRF (baseline, 82.3% [n = 96] vs. week 48, 5% [n = 20]) were also observed. Similar results were observed for occult and classic subgroups. There were no new safety concerns. CONCLUSION: Razumab (biosimilar ranibizumab) demonstrated improvements in visual acuity and disease outcomes in patients with wet age-related macular degeneration without new safety issues.

A combination insecticide at sub-lethal dose debilitated the expression pattern of crucial signalling molecules that facilitate craniofacial patterning in domestic chick Gallus domesticus.

Pesticides despite being agents that protect the plants and humans from noxious pests, are infamous for their potential to cause detrimental health issues in nontargeted species. In order to ascertain the latter, a set of experiments were conducted by exposing early chick embryos to a widely used combination insecticide (Ci, 50% chlorpyrifos and 5% cypermethrin). The results revealed a myriad of congenital defects pertaining to craniofacial development such as anophthalmia, microphthalmia, exencephaly as well as deformed beak and cranial structures. These teratological manifestations could be attributed to the Ci induced alteration in the titre of major regulators of neurulation and ossification. Therefore, the mRNA and/or the protein level expression pattern of genes which are reported to be involved in the craniofacial development were studied at selected time points of embryonic development. The analysis of the result showed that there have been significant alternations in the expression patterns of the signalling molecules such as SHH, WNTs, CDH1, CDH2, L1CAM, PAX6, HOX, PCNA, GLI3, BMP7, FGF8, GLIs, SOX9, RUNX2, DLX5, COL10A1, CASPASE3 etc. on embryonic days 2, 4 and/or 10. Concurrently, on day 10, whole-mount skeletal staining and biochemical estimation of hydroxyproline were carried out in the cranial tissues of the embryos. The overall result of the current study indicates that exposure to Ci during early development impede the crucial regulatory signals that orchestrate the morphogenesis of cranial neural crest cells thereby hindering the normal progression of neural tube and endochondral ossification which collectively lead to craniofacial dysmorphism in domestic chicks.

Real-Life Clinical Effectiveness of Razumab® (the World's First Biosimilar of Ranibizumab) in Retinal Vein Occlusion: A Subgroup Analysis of the Pooled Retrospective RE-ENACT Study.

BACKGROUND: This subgroup analysis of the RE-ENACT study evaluates the effectiveness of Razumab® (the world's first biosimilar of ranibizumab by Intas Pharmaceuticals Ltd.) in Indian patients with retinal vein occlusion (RVO). METHODS: The data on patients with RVO who had received ≥3 injections of Razumab® between January and August 2016 were analyzed. Endpoints were: improvement in best corrected visual acuity (BCVA), and a decrease in central macular thickness (CMT), intraretinal fluid (IRF), and subretinal fluid (SRF) from baseline at weeks 4, 8, and 12. RESULTS: Of 160 patients, the majority (61.87%) were men. The mean (±SE) BCVA improved from baseline (0.76 ± 0.04) to week 4 (0.73 ± 0.03; p = 0.0656), which attained significance at week 8 (0.55 ± 0.02; p < 0.0001) and week 12 (0.47 ± 0.02; p < 0.0001). The mean (±SE) CMT significantly decreased from baseline (447.60 ± 10.91 µm) to week 4 (431.84 ± 10.92 µm; p = 0.0028), week 8 (339.28 ± 8.12 µm; p < 0.0001), and week 12 (298.23 ± 6.68 µm; p < 0.0001). The proportion of patients with IRF and SRF significantly (p < 0.0001) decreased from baseline to weeks 4, 8, and 12 (IRF: from 70.63 to 45.63, 39.38, and 30.00%, respectively; SRF: from 65.63 to 37.50, 28.13, and 24.38%, respectively). A subgroup analysis of branch RVO and central RVO showed similar results. No new safety concerns were observed. CONCLUSION: Razumab® (biosimilar of ranibizumab) effectively improved visual acuity and disease outcomes in patients with RVO in a real-world setting with no new safety concerns.

Exposure to sub-lethal dose of a combination insecticide during early embryogenesis influences the normal patterning of mesoderm resulting in incomplete closure of ventral body wall of chicks of domestic hen.

Pesticide exposure to the non target groups especially during embryonic development has quite often resulted in congenital malformations. A commercially available combination insecticide (Ci, 50% chlorpyrifos and 5% cypermethrin) is known to induce ventral body wall defects (VBWDs) wherein abdominal viscera protrude out of the ventral body wall. Herein, an attempt was made to understand the mechanistic insight into Ci induced VBWDs. For this, before incubation, the chick embryos were dosed with the test chemical and then at different developmental stages of incubation, they were monitored for the changes in the expression of certain genes, which are indispensable for the ventral body wall closure since they regulate the cell fate, proliferation and survival. Concurrently, histopathological changes during the embryonic development were examined to corroborate the above observations. The results of mRNA profiling revealed a significant downregulation of Shh on day 4 and upregulation on day 10, while bmp4, Pitx2, E-cadherin, Wnt11, Wnt6, Pxn, MyoD1, Caspase-3, AHR, Cyp3A4, showed a significant upregulation on day 4 and/or on day 10. N-cadherin, fgf8, bmp1 showed no significant changes. The possible means by which these skewed expression patterns of regulatory molecules culminated into the VBWD are discussed.

Annealing Temperature Dependent Structural and Optical Properties of RF Sputtered ZnO Thin Films.

This work investigates the effect of annealing temperature on structural and optical properties of ZnO thin films grown over Si 100 and glass substrates using RF sputtering technique. Annealing temperature has been varied from 300 °C to 600 °C in steps of 100, and different microstructural parameters such as grain size, dislocation density, lattice constant, stress and strain have been evaluated. The structural and surface morphological characterization has been done using X-ray Diffraction (XRD) and Scanning Electron Microscope (SEM). XRD analysis reveals that the peak intensity of 002 crystallographic orientation increases with increased annealing temperature. Optical characterization of deposited films have been done using UV-Vis-NIR spectroscopy and photoluminescence spectrometer. An increase in optical bandgap of deposited ZnO thin films with increasing annealing temperature has been observed. The average optical transmittance was found to be more than 85% for all deposited films. Photoluminiscense spectra (PL) suggest that the crystalline quality of deposited film has increased at higher annealing temperature.

Analysis of autosomal dominant spinocerebellar ataxia type 1 in an extended family of central India.

BACKGROUND: Spinocerebeller ataxia type 1 (SCA1) is a specific type of ataxia among a group of inherited diseases of the central nervous system. In SCA1, genetic defects lead to impairment of specific nerve fibers carrying messages to and from the brain, resulting in the degeneration of the cerebellum, the coordination center of the brain. We investigated 24 members of an extended family in Gwalior city, India, some of which were earlier clinically diagnosed to be suffering from yet unconfirmed type of SCA neurodegenerative disorder. MATERIALS AND METHODS: All the family members from each age group were screened clinically and the characteristics of those resembling with ataxia were recorded for diagnosis by MRI. The confirmed patients of the family were genetically tested by PCR based molecular testing to identify the type of SCA (i.e., SCA 1, 2, 3, 4, 6 or 7). Family tree of the disease inheritance was constructed by pedigree based method. RESULT AND CONCLUSION: We found the clinical (symptoms and MRI) and genetic (Pedigree and PCR) results to be correlated. The PCR result revealed the disease to be of SCA 1 type being inherited in the family.