Publications by authors named "Ranjan Gupta"

152 Publications

Comparison of two dose escalation strategies of methotrexate in active rheumatoid arthritis: a multicentre, parallel group, randomised controlled trial.

Ann Rheum Dis 2021 Jun 10. Epub 2021 Jun 10.

Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Objectives: There are no head-to-head trials of different dose escalation strategies of methotrexate (MTX) in RA. We compared the efficacy, safety and tolerability of 'usual' (5 mg every 4 weeks) versus 'fast' (5 mg every 2 weeks) escalation of oral MTX.

Methods: This multicentre, open-label (assessor blinded) RCT included patients 18-55 years of age having active RA with disease duration <5 years, and not on DMARDs. Patients were randomized 1:1 into usual or fast escalation groups, both groups starting MTX at 15 mg/week till a maximum of 25 mg/week. Primary outcome was EULAR good response at 16 weeks, secondary outcomes were ΔDAS28 and adverse effects (AE). Analyses were intention-to-treat.

Results: 178 patients with mean DAS28-CRP of 5.4(1.1) were randomized to usual (n=89) or fast escalation groups (n=89). At 16 weeks, there was no difference in good EULAR response in the usual (28.1%) or fast escalation (22.5%) groups (p=0.8). There was no difference in mean ΔDAS28-CRP at 8 weeks (-0.9, -0.8, p=0.72) or 16 weeks (-1.3, -1.3, p=0.98). Even at 24 weeks (extended follow-up), responses were similar. There were no inter-group differences in ΔHAQ, or MTX-polyglutamates 1-3 levels at 8 or 16 weeks. Gastrointestinal AE were higher in the fast escalation group over initial 8 weeks (27%, 40%, p=0.048), but not over 16 weeks. There was no difference in cytopenias, transaminitis, or drug discontinuation/dose reduction between the groups. No serious AE were seen.

Conclusion: A faster MTX escalation strategy in RA was not more efficacious over 16-24 weeks, and did not significantly increase AE, except higher gastrointestinal AE initially.

Trial Registration Number: CTRI/2018/12/016549.
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http://dx.doi.org/10.1136/annrheumdis-2021-220512DOI Listing
June 2021

Modern Principles in the Acute Surgical Management of Open Distal Tibial Fractures.

J Am Acad Orthop Surg 2021 Jun;29(11):e536-e547

From the Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD (Shafiq), the Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY (Hacquebord), and the Department of Orthopaedic Surgery, University of California, School of Medicine, Los Angeles, CA (Wright and Gupta).

Over the past two decades, management of open distal tibial fractures has evolved such that a staged approach, with external fixation and débridement during the index procedure, followed by definitive fixation and wound closure at a later date, is often considered the standard of care. Although definitive treatment of these complex injuries is often done by a multidisciplinary team of surgeons well versed in periarticular fracture repair and soft-tissue coverage in the distal extremity, the on-call orthopaedic surgeon doing the index procedure must understand the principles and rationale of the staged treatment algorithm to avoid compromising definitive treatment options and ensure the best possible patient outcome. The mechanism of injury, neurovascular status, size and location of soft-tissue injury, fracture pattern, and concomitant injuries in the polytraumatized patient should direct the treatment plan and anticipated outcomes. This review focuses on evaluation and management of these complex injuries with an emphasis on early aggressive débridement, principles of initial fracture fixation, and modern options for soft-tissue coverage, including local and free tissue transfer.
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http://dx.doi.org/10.5435/JAAOS-D-20-00502DOI Listing
June 2021

Indian SLE Inception cohort for Research (INSPIRE): the design of a multi-institutional cohort.

Rheumatol Int 2021 05 12;41(5):887-894. Epub 2021 Jan 12.

Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Systemic lupus erythematosus (SLE) cohorts across the world have allowed better understanding of SLE, including its bimodal mortality, and the impact of social factors and ethnicity on outcomes. The representation of patients from South Asia has been poor in the existing SLE cohorts across the world. Hence, we planned to initiate an inception cohort to understand the diversity of lupus in India. Indian SLE Inception cohort for REsearch (INSPIRE), planned over 5 years is a multi-centric cohort of adult and childhood lupus patients of Indian origin, fulfilling the SLICC-2012 classification criteria, with an aim to provide cross-sectional information on demography, ethnicity, socio-economic status, standard disease variables, quality of life, and prospective information on new events like hospitalization, infections, pregnancies, changes in disease activity, and damage. One of the other deliverables of this project is the establishment of a biorepository. The instruments to be used for each variable and outcome were finalized, and a web-enabled case report form was prepared to encompass SLEDAI, BILAG, SLICC damage scores, and Lupus quality-of-life index.Ten centers located in different geographic areas of India would enroll patients who are seen for the first time after the start of the study. In the first 8 months, 476 patients (63 children, 36 males) have been enrolled with a median disease duration of 10 (IQR 4-17) months and mucocutaneous features being the most prevalent clinical manifestations. INSPIRE is the first prospective Indian SLE cohort to study the diversity of Indian patients.
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http://dx.doi.org/10.1007/s00296-020-04766-3DOI Listing
May 2021

OGG1 DNA Repair Gene Polymorphism As a Biomarker of Oxidative and Genotoxic DNA Damage.

Iran Biomed J 2021 01 31;25(1):47-53. Epub 2020 Aug 31.

Department of Biochemistry, Kurukshetra University Kurukshetra, Haryana 136119, India.

Background: Single nucleotide polymorphisms in 8-oxoguanine DNA glycosylase-1 (OGG1) gene modulates DNA repair capacity and functions as one of the first lines of protective mechanisms against 8-hydroxy-2'-deoxyguanosine (8-OHdG) mutagenicity. OGG1-Cys326 gene polymorphism may decrease DNA repair function, causing oxidative stress due to higher oxidative DNA damage. The main purpose of this study was to examine the link of oxidative and genotoxic DNA damage with DNA repair OGG1 gene polymorphism, in charcoal workers exposed to polyaromatic hydrocarbons.

Methods: Urinary 8-OHdG excretion (a biomarker of oxidative DNA damage) was determined in both exposed and control populations. Genotyping of OGG1 DNA repair gene in the blood samples of subjects was carried out by PCR-RFLP method.

Results: The 8-OHdG urinary concentration was significantly higher (p < 0.05) in the exposed (geometric mean 12.33 ± 3.78) than in the unexposed (geometric mean 7.36 ± 2.29) population. DNA damage, as measured by 8-OHdG and tail moment content, was found to be significantly higher in OGG1 homozygous mutants (mt/mt; 18.81 ± 3.34; 6.04 ± 0.52) as compared to wild-type genotypes (wt/wt; 10.34 ± 2.25; 5.19 ± 2.50) and heterozygous (wt/mt) mutants (12.82 ± 2.81; 6.04 ± 0.93) in the exposed group.

Conclusion: We found a significant association of OGG1 heterozygous (wt/mt) and homozygous (mt/mt) variants with oxidative and genotoxic damage, suggesting that these polymorphisms may modulate the effects of polycyclic aromatic hydrocarbons exposure in occupational workers.
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http://dx.doi.org/10.29252/ibj.25.1.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748119PMC
January 2021

Impact of the COVID-19 pandemic on patients with systemic lupus erythematosus: Observations from an Indian inception cohort.

Lupus 2021 Jan 6;30(1):158-164. Epub 2020 Oct 6.

Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Introduction: The ongoing pandemic of COVID-19 has led to severe disruption of healthcare services worldwide. We conducted this study to assess the impact of COVID-19 pandemic on the management of Systemic Lupus Erythematosus (SLE) patients who were enrolled in the nation-wide inception cohort.

Methods: A questionnaire was administered to the SLE patients enrolled in the inception cohort. Questions related to the effect on disease activity, preventive measures adopted against COVID-19, the incidence of COVID-19, hardships faced in getting access to health care professionals and availability of medicines, adherence, fear of COVID-19 and the potential benefits of being part of the registry.

Results: A total of 1040 (90% females) patients completed the questionnaire. The mean age was 27.5 ± 19.1 years and the mean disease duration was 1.25 years. Twenty-Four (2.3%) patients had developed fever (>1 day) during this period, including one patient with additional symptoms of diarrhoea and anosmia, however, none of the patients developed COVID-19 infection. 262 patients (25.2%) reported financial difficulty during this period and patients reported an average excess expenditure of at least 2255.45 INR ($30) per month. 378 patients (36%) reported problems in getting their prescribed medicines due to lockdown. Of these, 167 (40%) patients needed to change their medication schedule due to this non-availability. Almost 54% of patients missed their scheduled follow up visits during the lockdown period and 37% of patients were unable to get their investigations done due to closure of laboratories and hospitals. 266 patients (25.5%) reported worsening of various symptoms of SLE during this period. Almost 61% patients felt confident that being associated with the inception cohort had helped them in managing their disease better during this period of lockdown as they received help in the form of timely and frequent telephonic consults, assistance in making the medicines available, and regular counselling resulting in abetment of their fears and anxieties.

Conclusion: The current COVID-19 pandemic has made a huge impact on our SLE patients. Patients faced difficulty in the availability of medicines, missed the doses of medicines, had financial constraints, and spent more money on health during the pandemic.
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http://dx.doi.org/10.1177/0961203320962855DOI Listing
January 2021

Dedifferentiated liposarcoma of the scrotum. Case report and literature review.

J Surg Case Rep 2020 Sep 17;2020(9):rjaa342. Epub 2020 Sep 17.

Department of Surgery, Bronxcare Health System, Bronx, NY 10457, United States.

Malignant paratesticular and spermatic cord tumors are rare and often misdiagnosed preoperatively due to clinical presentations similar to other benign scrotal mass etiologies. Only a few cases regarding giant, paratesticular liposarcomas (>10 cm) have been reported. We report a unique case of an aggressive giant dedifferentiated liposarcoma of the scrotum with osteosarcoma features in a 70-year-old patient who initially presented with indolent scrotal swelling. A CT scan showed a large, complex, solid and cystic mass (12.0 x 15.5 x 19.0 cm) in the right scrotum. With a concern of a complex hydrocele, the patient was taken to the operating room for a scrotal approach to excise the hydrocele, but the spermatic cord was not traced to any discernible testicle as the entire mass was indurated and multilocular, and was excised. Pathology revealed a dedifferentiated liposarcoma, with MDM2 amplification. The patient's course was complicated due to metastatic disease.
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http://dx.doi.org/10.1093/jscr/rjaa342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497061PMC
September 2020

Human motor endplate remodeling after traumatic nerve injury.

J Neurosurg 2020 Sep 18:1-8. Epub 2020 Sep 18.

4Reeve-Irvine Research Center, University of California, Irvine, California.

Objective: Current management of traumatic peripheral nerve injuries is variable with operative decisions based on assumptions that irreversible degeneration of the human motor endplate (MEP) follows prolonged denervation and precludes reinnervation. However, the mechanism and time course of MEP changes after human peripheral nerve injury have not been investigated. Consequently, there are no objective measures by which to determine the probability of spontaneous recovery and the optimal timing of surgical intervention. To improve guidance for such decisions, the aim of this study was to characterize morphological changes at the human MEP following traumatic nerve injury.

Methods: A prospective cohort (here analyzed retrospectively) of 18 patients with traumatic brachial plexus and axillary nerve injuries underwent biopsy of denervated muscles from the upper extremity from 3 days to 6 years after injury. Muscle specimens were processed for H & E staining and immunohistochemistry, with visualization via confocal and two-photon excitation microscopy.

Results: Immunohistochemical analysis demonstrated varying degrees of fragmentation and acetylcholine receptor dispersion in denervated muscles. Comparison of denervated muscles at different times postinjury revealed progressively increasing degeneration. Linear regression analysis of 3D reconstructions revealed significant linear decreases in MEP volume (R = -0.92, R2 = 0.85, p = 0.001) and surface area (R = -0.75, R2 = 0.56, p = 0.032) as deltoid muscle denervation time increased. Surprisingly, innervated and structurally intact MEPs persisted in denervated muscle specimens from multiple patients 6 or more months after nerve injury, including 2 patients who had presented > 3 years after nerve injury.

Conclusions: This study details novel and critically important data about the morphology and temporal sequence of events involved in human MEP degradation after traumatic nerve injuries. Surprisingly, human MEPs not only persisted, but also retained their structures beyond the assumed 6-month window for therapeutic surgical intervention based on previous clinical studies. Preoperative muscle biopsy in patients being considered for nerve transfer may be a useful prognostic tool to determine MEP viability in denervated muscle, with surviving MEPs also being targets for adjuvant therapy.
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http://dx.doi.org/10.3171/2020.8.JNS201461DOI Listing
September 2020

Dopamine transporter availability in alcohol and opioid dependent subjects - a Tc-TRODAT-1SPECT imaging and genetic association study.

Psychiatry Res Neuroimaging 2020 Sep 10;305:111187. Epub 2020 Sep 10.

Laboratory of Cyto-Molecular Genetics, Department of Anatomy, AIIMS, New Delhi 110029, India. Electronic address:

Drug dependence associated with increased dopamine neurotransmission and neuroplastic changes is influenced by Dopamine transporters (DAT) which are modulated by genetic and epigenetic factors. This study assesses DAT availability in relation to the 40bp DAT1 VNTR (genetic) and DAT1 promoter methylation (epigenetic) changes in patients with alcohol dependence (AD) and opioid dependence (OD). A total of 60 subjects (n=20 each of AD, OD and controls) were recruited. SPECT/CT imaging using Tc-TRODAT-1 was performed for measuring striatal DAT availability and DNA screened to check DAT1promoter methylation and 40bp VNTR polymorphism. SPECT/CT imaging revealed significant decrease in DAT availability in the striatum and putamen and significant increase in DAT1 promoter methylation in AD compared to control and OD. The 40bp VNTR distribution was similar in all three groups with 10repeat and 9repeat alleles being the most common. The AD individuals with DAT1promoter methylation showed significantly lower TRODAT-1 uptake compared to the ones with no methylation. AD individuals homozygous for the 10repeat VNTR also showed reduced DAT availability. This is the first imaging study using Tc-TRODAT-1 from India documenting significantly reduced striatal DAT availability, increased DAT methylation and frequency of 10repeat individuals associated with decreased DAT availability in AD.
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http://dx.doi.org/10.1016/j.pscychresns.2020.111187DOI Listing
September 2020

Authors' Response to Letter to the Editor.

Spine J 2020 09;20(9):1524

University of California Irvine, Irvine, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.spinee.2020.05.544DOI Listing
September 2020

A Call to Arms: Emergency Hand and Upper-Extremity Operations During the COVID-19 Pandemic.

J Hand Surg Glob Online 2020 Jul 29;2(4):175-181. Epub 2020 May 29.

Department of Plastic Surgery, University of California, Irvine, Orange, CA.

Purpose: Limited data exist regarding volumetric trends and management of upper-extremity emergencies during periods of social restriction and duress, such as the coronavirus disease 2019 pandemic. We sought to study the effect of shelter-in-place orders on emergent operative upper-extremity surgery.

Methods: All patients undergoing emergent and time-sensitive operations to the finger(s), hand, wrist, and forearm were tracked over an equal number of days before and after shelter-in-place orders at 2 geographically distinct Level I trauma centers. Surgical volume and resources, patient demographics, and injury patterns were compared before and after official shelter-in-place orders.

Results: A total of 58 patients underwent time-sensitive or emergent operations. Mean patient age was 42 years; mean injury severity score was 9 and median American Society of Anesthesiologist score was 2. There was a 40% increase in volume after shelter-in-place orders, averaging 1.4 cases/d. Indications for surgery included high-energy closed fracture (60%), traumatic nerve injury (19%), severe soft tissue infection (15%), and revascularization of the arm, hand, or digit(s) (15%). High-risk behavior, defined as lawlessness, assault, and high-speed auto accidents, was associated with a significantly greater proportion of operations after shelter-in-place orders (40% vs 12.5%; < .05). Each institution dedicated an average of 3 inpatient beds and one intensive care unit-capable bed to upper-extremity care daily. Resources used included an average of 115 minutes of daily operating room time and 8 operating room staff or personnel per case.

Conclusions: Hand and upper-extremity operative volume increased after shelter-in-place orders at 2 major Level I trauma centers across the country, demanding considerable hospital resources. The rise in volume was associated with an increase in high-risk behavior.

Type Of Study/level Of Evidence: Therapeutic IV.
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http://dx.doi.org/10.1016/j.jhsg.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256509PMC
July 2020

Urinary soluble CD163 is a good biomarker for renal disease activity in lupus nephritis.

Clin Rheumatol 2021 Mar 18;40(3):941-948. Epub 2020 Aug 18.

Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India.

Objectives: Activated macrophages expressing CD163 (M2) are the most abundant macrophage subtype in renal biopsies from lupus nephritis (LN) patients. We studied the role of proteolytically cleaved soluble CD163 (sCD163) as a biomarker of LN disease activity.

Methods: SLE patients were classified as active LN (AN), inactive disease (ID), and active non-renal disease (ANR). Urine and plasma samples were collected at baseline from all patients and at 3 monthly follow-up from AN patients. sCD163 was measured by ELISA. Urine values were normalized to urinary creatinine excretion and expressed as pg/mg. Urine samples from 25 healthy controls (HC) and 20 rheumatoid arthritis patients served as disease controls (DC).

Results: Among the 122 patients studied (114 females, 57 AN, 42 ID, 23 ANR), baseline median urinary sCD163 in the AN group (114.01 pg/mg) was significantly higher (p < 0.001) as compared with ID (10.34 pg/mg), ANR (3.82 pg/mg), HC (0 pg/mg), and DC (7.56 pg/mg) groups and showed modest correlation with renal SLEDAI (r = 0.47; p < 0.001). Urinary sCD163 performed the best on receiver operating characteristics (ROC) analysis (AUC = 0.76) at baseline to differentiate between AN and ANR as compared with plasma sCD163, anti-ds DNA antibodies, and C3 and C4. In follow-up study, urinary sCD163 decreased significantly (p < 0.001) in AN patients at 3 (22.07 pg/mg), 6 (12.7 pg/mg), 9 (11.09 pg/mg), and 12 months (7.2 pg/mg). In 4 patients who had either relapse or developed CKD, urinary sCD163 levels correlated with the changing disease activity.

Conclusions: Urinary sCD163 is a good biomarker of LN disease activity. Key Points • Urinary sCD163 levels are raised in patients with active lupus nephritis and correlate with renal SLEDAI. • Urinary sCD163 levels fall after treatment and may be helpful in monitoring response to therapy in lupus nephritis.
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http://dx.doi.org/10.1007/s10067-020-05343-6DOI Listing
March 2021

Urinary C3d is elevated in patients with active Lupus nephritis and a fall in its level after 3 months predicts response at 6 months on follow up.

Lupus 2020 Nov 17;29(13):1800-1806. Epub 2020 Aug 17.

Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Introduction: Complement activation is central to the pathogenesis of lupus nephritis (LN). Low serum complement C3 and C4, are traditionally used as markers of lupus disease activity in general and LN in particular. In this study we prospectively measured plasma and urine C3d and C4d, degradation products of C3 and C4 corrected to creatinine in a cohort of biopsy proven LN in a longitudinal fashion for its correlation with disease activity.

Methods: Twenty eight biopsy proven active lupus nephritis (AN) were recruited along with four inactive nephritis (IN) and 10 healthy controls (HC). Plasma and urine were collected at baseline, prior to induction treatment and 3 months later. Clinical measures of disease activity, Systemic lupus erythematosus disease activity index 2000 (SLEDAI 2K), renal SLEDAI, serum C3, C4 and antibodies to ds DNA, urine protein and creatinine excretion (UP/UC) were collected. Plasma and urine C3d and C4d were measured using ELISA and normalized to spot urine creatinine value.

Results: Twenty eight AN of median age of 26.5 (20-31.50) years and disease duration of 3 (0.7-5) years were enrolled. The median urinary C3d/creatinine before treatment was 388.20 (48.98-1296) ng/mg which fell significantly to 62.69 (28.04-502.4) ng/mg at 3 months followup (p-0.01). The baseline values for the active renal disease was significantly different from IN group (9.9 (4.5-46.53 ng/mg) p-0.00). Treatment responders (partial and complete) at 6 months showed a significant fall in urinary C3d at 3 months whereas non responders had a non significant change in value. There was a significant correlation of urine C3d/creatinine with SLEDAI2K (r-0.433, p-0.00), renal SLEDAI (r-0.356, p-0.00), UP/UC ratio (r-0.489, p-<0.0001) but no significant correlation with C3 or C4. There was a significant fall in the median values of plasma C3d from 791.1 (516.0.00-1550.43) µg/ml to 338.52 (211.35-525.82) (p-0.00) µg/ml at the end of 3 months. The values showed a significant correlation with SLEDAI 2K, renal SLEDAI, UP/UC along with a significant negative correlation with C3 and C4.

Conclusion: Urinary C3d/creatinine levels and plasma C3d levels can be used as biomarker of disease activity and treatment response.
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http://dx.doi.org/10.1177/0961203320950019DOI Listing
November 2020

Reliable cerebrospinal fluid cytology reporting over an extended period: Is it possible by adding formol saline and ethylenediaminetetraacetic acid as cell preservative?

Diagn Cytopathol 2020 Aug 13;48(8):745-751. Epub 2020 May 13.

Department of Pathology, Chacha Nehru Bal Chikitsalaya, Delhi, India.

Background: Reporting cerebrospinal fluid (CSF) cytology within a narrow time frame is crucial as it is often indicated in critically ill patients and moreover, the cells in CSF are highly labile and tend to decline rapidly on standing. However, due to various logistic issues, delay in reporting is inevitable at times, especially if ancillary tools are required. In this study, we examine the effect of using formol saline and ethylenediaminetetraacetic acid (EDTA) as a preservative on the cellular composition of CSF at 18, 24, and 48 hours of preservation.

Methods: Thirty CSF specimens were examined within 2 hours of collection and this reading was recorded as time zero reading. The CSF specimens were then divided in three tubes with: (a) preservative:CSF ratio of 1:1; (b) preservative:CSF ratio of 1:5; and (c) no preservative. Total and differential leucocyte counts and immunocytochemistry were performed on the three specimens at 18, 24, and 48 hours and were compared with the readings at 0 hour.

Results: Preserved CSF (in the ratio of 1:5) showed no significant decrease in the number of cells at 18 hours (P = .4), 24 hours (P = .3), and 48 hours (P = .1). Cellularity decreased by 8.5%, 22%, and 40% at 18, 24, and 48 hours, respectively. Cell morphology and antigenicity were well preserved at all the three time intervals.

Conclusion: Formol saline and EDTA, when mixed with the CSF in the ratio of 1:5, can preserve significant cellularity for up to 24 hours.
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http://dx.doi.org/10.1002/dc.24471DOI Listing
August 2020

Pharmacovigilance of biosimilars - Why is it different from generics and innovator biologics?

Authors:
Ranjan Gupta

J Postgrad Med 2020 Apr-Jun;66(2):116

Assistant Professor, Department of Rheumatology, All India Institute of Medical Sciences, New Delhi, India.

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http://dx.doi.org/10.4103/jpgm.JPGM_651_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239406PMC
June 2020

The Opioid Epidemic: Risk Evaluation and Management Strategies for Prescribing Opioids.

Instr Course Lect 2020 ;69:405-414

Abuse of opioids has had and continues to have a devastating impact on public health and safety in the United States, and the use of opioids has increased dramatically in the last two decades. The purpose of this chapter is to examine the roots of this tragic state of affairs and what may be done about it moving forward. The authors review the medical-legal risks physicians face when prescribing pain relieving medications for their patients. Strategies are offered for staying out of trouble while providing quality pain management for patients.
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February 2020

Examination of the human motor endplate after brachial plexus injury with two-photon microscopy.

Muscle Nerve 2020 03 24;61(3):390-395. Epub 2019 Dec 24.

Department of Orthopaedic Surgery, University of California, Irvine, California.

Introduction: After traumatic nerve injury, neuromuscular junction remodeling plays a key role in determining functional outcomes. Immunohistochemical analyses of denervated muscle biopsies may provide valuable prognostic data regarding clinical outcomes to supplement electrodiagnostic studies.

Methods: We performed biopsies on nonfunctioning deltoid muscles in two patients after gunshot wounds and visualized the neuromuscular junctions using two-photon microscopy with immunohistochemistry.

Results: Although the nerves in both patients showed evidence of acute Wallerian degeneration, some of the motor endplates were intact but exhibited significantly decreased surface area and volume. Both patients exhibited substantial recovery of motor function over several weeks postinjury.

Discussion: Two-photon microscopic assessment of neuromuscular junction integrity and motor endplate morphometry in muscle biopsies provided evidence of partial sparing of muscle innervation. This finding supported the clinical judgment that eventual recovery would occur. With further study, this technique may help to guide operative decisionmaking after traumatic nerve injuries.
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http://dx.doi.org/10.1002/mus.26778DOI Listing
March 2020

Establishing validity of the fundamentals of spinal surgery (FOSS) simulator as a teaching tool for orthopedic and neurosurgical trainees.

Spine J 2020 04 18;20(4):580-589. Epub 2019 Nov 18.

Departments of Orthopedic Surgery, Biomedical Engineering, and Anatomy and Neurobiology, Neuroscience Research Facility, University of California, Irvine, CA, USA. Electronic address:

Background Context: Pedicle screw placement is a demanding surgical skill as a spine surgeon can face challenges including variations in pedicle morphology and spinal deformities. Available CT simulators for spine pedicle placement can be very costly and hands-on cadaver courses are limited by specimen availability and are not readily accessible.

Purpose: To conduct validation of a simulated training device for essential spine surgery skills.

Design: Cross-sectional, empirical study of physician performance on a surgical simulator model.

Sample: Spine attending physicians and residents from four different academic institutions across the United States.

Outcome Measures: Performance metrics on two surgical simulator tasks.

Methods: After IRB approval, an inexpensive ($30) simulator was developed to test two main psychomotor tasks (1) creation of the pedicle screw path with a standard gearshift probe without cortical breaks and (2) the ability to palpate for the presence or absence of cortical breaches as well as determine the location of wall defects. Orthopedic and neurosurgery residents (N=72) as well as spine attending surgeons (N=26) participated from four different institutions. To test construct validity, performance metrics were compared between participants of different training status through one-way analysis of variance and linear regression analysis, with significance set at p<.05.

Results: Spine attending surgeons consistently scored higher than the residents, in the screw trajectory task with triangular base (p=.0027) and defect probing task (p=.0035). In defect probing, performance improved with linear trend by number of residency training years with approaching significance (p=.0721). In that task, independent of institutional affiliation, PGY-2 residents correctly identified an average of 1.25±0.43 fewer locations compared with attending physicians (p=.0049). More than 80% of the spine attendings reported they would use the simulator for training purposes.

Conclusions: This low-cost fundamentals of spine surgery simulator detected differences in performances between spine attending surgeons and surgical residents. Programs should consider implementing a simulator such as fundamentals of spine surgery to assess and develop pedicle screw placement ability outside of the operating room.
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http://dx.doi.org/10.1016/j.spinee.2019.11.008DOI Listing
April 2020

Understanding and Treating Iatrogenic Nerve Injuries in Shoulder Surgery.

J Am Acad Orthop Surg 2020 Mar;28(5):e185-e192

From the Department of Orthopaedic Surgery, University of California, Irvine, CA (Dr. Gupta and Dr. Patel), the Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT (Dr. Mazzocca), and the Department of Orthopaedic Surgery, Rothman Institute, New York, NY (Dr. Romeo).

As surgical techniques and technology continue to advance in shoulder surgery along with the increased use of regional anesthesia, it is important to remember that iatrogenic nerve injuries remain a possible complication. Iatrogenic nerve injuries associated with shoulder surgery lead to patient disability and distress, increased healthcare costs, and possibly additional procedures. To obtain the best possible outcome for the patient after the nerve injury has been discovered, a timely appreciation of the management options is necessary rather than expectant management. Early recognition, appropriate neurodiagnostic testing, and prompt treatment or referral are mandatory for optimal outcomes.
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http://dx.doi.org/10.5435/JAAOS-D-18-00608DOI Listing
March 2020

A multibiomarker approach to evaluate the effect of polyaromatic hydrocarbon exposure on oxidative and genotoxic damage in tandoor workers.

Toxicol Ind Health 2019 Jul;35(7):486-496

1 Department of Biochemistry, Kurukshetra University Kurukshetra, Haryana, India.

We conducted a cohort study of tandoor workers to evaluate the relationship between the biomarkers of oxidative and genotoxic damage and exposure to polyaromatic hydrocarbons. A series of oxidative and genotoxic damage biomarkers, including urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA) content, and tail moment (TM) by comet assay, was studied. A total of 76 tandoor workers and 79 demographically matched healthy individuals as controls were included. Our results showed that the tandoor workers had significantly higher urinary levels of 1-hydroxypyrene, urinary 8-OHdG, MDA content, and TM compared with the control population. The concentration of all these biomarkers increased with age in the control population as well as tandoor workers. In tandoor workers, significant variation in MDA, 8-oxodG (8-oxo-2'-deoxyguanosine) and TM concentration was detected between smokers (5.08 ± 1.72 nmol/mL, 16.01 ± 4.94 ng/mg creatinine, and 5.87 ± 0.98 µm, respectively) and nonsmokers (3.84 ± 0.98 nmol/mL, 13.74 ± 3.60 ng/mg creatinine, and 5.32 ± 0.69 µm, respectively). A similar pattern was obtained for the control population. We did not obtain significant variations for alcoholics and tobacco chewers. A significant increase in all these three biomarkers was observed with the increase in the period of work exposure in tandoor workers. Multivariate regression analysis also revealed that urinary 8-oxodG, MDA, and TM were statistically significantly related to age and period of work exposure. Overall, the present study showed that the exposure to wood smoke in tandoor workers under occupational conditions led to increased DNA damage because of oxidative stress and genotoxicity. These biomarkers, therefore, are good indices to assess oxidative DNA damage in these workers exposed to occupational genotoxicants. It is also necessary to make preventive changes in work conditions and lifestyle, which will help these occupational workers to lead a healthy life.
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http://dx.doi.org/10.1177/0748233719862728DOI Listing
July 2019

Antigenotoxic effects of morin against lead induced genomic damage in cultured human peripheral blood lymphocytes.

J Food Biochem 2019 07 30;43(7):e12883. Epub 2019 Apr 30.

Department of Biotechnology, Kurukshetra University, Kurukshetra, India.

Lead (Pb) is a well-known carcinogenic heavy metal. Exposure to Pb induces DNA damage by enhancing the generation of reactive oxygen species (ROS). One of the possible ways to shield DNA from this damage is to supply antioxidants that can remove free radicals generated by genotoxicants. Hence, the current study was designed to evaluate the antigenotoxic potential of a flavonoid compound; morin against Pb-induced genomic damage on cultured human peripheral blood lymphocytes (PBL). The effect of Pb or morin or their combination was evaluated on the DNA damage using comet and sister chromatid exchange (SCE) assays. The results indicated a significant (p < 0.05) increase in the SCE frequency and various comet parameters in a dose-dependent manner upon treatment with lead as compared to control in cultured PBL. Supplementation of morin along with Pb effectively negated DNA damage as measured by SCE frequency and comet parameters. PRACTICAL APPLICATIONS: Results of our current study suggest that the DNA damage induced by genotoxicants can be overcome by co-treatment with natural antioxidants, found in dietary supplements such as vegetables and fruits.
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http://dx.doi.org/10.1111/jfbc.12883DOI Listing
July 2019

Pharmacological Attenuation of Electrical Effects in a Model of Compression Neuropathy.

J Bone Joint Surg Am 2019 Mar;101(6):523-530

Department of Orthopaedics and Rehabilitation, Center for Orthopaedic Research and Translational Science, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania.

Background: Peripheral nerve compression and entrapment can be debilitating. Using a validated animal model of peripheral nerve compression, we examined the utility of 2 drugs approved for other uses in humans, 4-aminopyridine (4-AP) and erythropoietin (EPO), as treatments for surgically induced ischemia and as adjuvants to surgical decompression.

Methods: Peripheral nerve compression was induced in wild-type mice by placing an inert silicone sleeve around the sciatic nerve. Decompression surgery was performed at 6 weeks with mice receiving 4-AP, EPO, or saline solution either during and after compression or only after decompression. A nerve conduction study and morphometric analyses were performed to compare the extent of the injury and the efficacy of the therapies, and the findings were subjected to statistical analysis.

Results: During peripheral nerve compression, there was a progressive decline in nerve conduction velocity compared with that in sham-treatment animals, in which nerve conduction velocity remained normal (∼55 m/s). Mice treated with 4-AP or EPO during the compression phase had significantly smaller declines in nerve conduction velocity and increased plateau nerve conduction velocities compared with untreated controls (animals that received saline solution). Histomorphometric analyses of newly decompressed nerves (i.e., nerves that underwent decompression on the day that the mouse was sacrificed) revealed that both treated groups had significantly greater proportions of large (>5-µm) axons than the untreated controls. Following surgical decompression, all animals recovered to a normal baseline nerve conduction velocity by day 15; however, treatment significantly accelerated improvement (in both the 4-AP and the EPO group), even when it was only started after decompression. Histomorphometric analyses at 7 and 15 days following surgical decompression revealed significantly increased myelin thickness and significantly greater proportions of large axons among the treated animals.

Conclusions: Both the 4-AP and the EPO-treated group demonstrated improvements in tissue architectural and electrodiagnostic measurements, both during and after peripheral nerve compression, compared with untreated mice.

Clinical Relevance: Peripheral nerve decompression is one of the most commonly performed procedures in orthopaedic surgery. We believe that there is reason for some optimism about the translation of our findings to the clinical setting. Our findings in this murine model suggest that 4-AP and EPO may lessen the effects of nerve entrapment and that the use of these agents after decompression may speed and perhaps otherwise optimize recovery after surgery.
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http://dx.doi.org/10.2106/JBJS.18.00162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738556PMC
March 2019

Perioperative Management of the Orthopaedic Patient and Alcohol Use, Abuse, and Withdrawal.

J Am Acad Orthop Surg 2019 Mar;27(6):e249-e257

From the UC Irvine Department of Orthopaedic Surgery, Irvine, CA (Dr. Lim and Dr. Gupta), the Department of Orthopaedic Trauma, Saint Alphonsus Health System, Boise, ID (Dr. Zamorano), and the Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA (Dr. Haghverdian).

Alcohol is one of most commonly abused substances in the United States, and it has contributed to a growing epidemic of medical ailments, including cirrhosis, neurologic and psychosocial disorders, impairment to fertility, and cancer. Moreover, acute and chronic alcohol use represent a significant risk factor for orthopaedic injury and postoperative complications. Yet, relatively little is known about the clinical implications of alcohol abuse in common orthopaedic procedures. Acute withdrawal from alcohol is potentially fatal, particularly in the orthopaedic inpatient whose abstinence is mandated by the hospital setting. The aim of this review is to address the screening, diagnostic, and therapeutic tools available to appropriately manage acute alcohol withdrawal in the orthopaedic inpatient. The influence of chronic alcohol consumption on bone metabolism, fracture healing, and surgical fixation will also be reviewed because this information may guide surgical decision making.
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http://dx.doi.org/10.5435/JAAOS-D-17-00708DOI Listing
March 2019

Antioxidative Effects of Piperine against Cadmium-Induced Oxidative Stress in Cultured Human Peripheral Blood Lymphocytes.

J Diet Suppl 2020 9;17(1):41-52. Epub 2018 Oct 9.

Biotechnology Department, Kurukshetra University, Kurukshetra, India.

Cadmium (Cd) has a remarkable property of generating oxidative stress. It upregulates the level of reactive oxygen species, which generates damage to lipids, proteins, and DNA The level of oxidative stress by Cd is observed by inhibitory effects of antioxidant enzymes such as catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase. Piperine is one of the plant-derived alkaloids isolated from and . It diminishes the level of oxidative damage by quenching the free radicals and reactive oxygen species and inhibiting the lipid peroxidation. It is well known to induce stress proteins, including metallothionein (MT), a metal-binding protein and heat shock protein (HSP70). In the present work, antioxidative effects of piperine have been studied against Cd-induced oxidative stress. We observed its ameliorative effects using various biomarkers, such as comet and lipid peroxidation (LPA) assays in cultured human peripheral blood lymphocytes from healthy individuals. Piperine at 35 and 50 µM concentrations significantly reduces the tail moment and peroxidation of lipids. We also explored the relationship of gene polymorphism on oxidative and antioxidative effects of Cd and piperine, respectively. At selected concentration, we observed a decrease in the mean value of tail moment and lipid peroxidation level. However, the overall effect was statistically nonsignificant ( > .05).
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http://dx.doi.org/10.1080/19390211.2018.1481485DOI Listing
September 2020

In Vitro Studies on Ameliorative Effects of Limonene on Cadmium-Induced Genotoxicity in Cultured Human Peripheral Blood Lymphocytes.

Appl Biochem Biotechnol 2019 Apr 19;187(4):1384-1397. Epub 2018 Sep 19.

Department of Microbiology, Kurukshetra University, Haryana, Kurukshetra, India.

Cadmium (Cd) is a non-redox metal that can indirectly cause oxidative stress by depleting cellular levels of glutathione. It is well-known for the generating reactive oxygen species (ROS) such as hydroxyl radicals, superoxide anions, nitric oxide, and hydrogen peroxide. The latter inactivates antioxidant enzymes and induces lipid peroxidation and DNA damage in cells. In our study, we have investigated the ameliorative effect of limonene against Cd-induced genotoxicity using various biomarkers such as sister chromatid exchange (SCE), comet, and lipid peroxidation (LPA) assays in cultured human peripheral blood lymphocytes (PBL) from healthy individuals. It is a naturally occurring flavonoid, found in essential oil of citrus fruits. Limonene at 20-μM and 100-μM concentrations had significantly (P < 0.05 and P < 0.01) reduced the SCE frequency, tail moment, and peroxidation of lipids. Ameliorative effect of limonene was also determined by measuring the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT). We found a significant increase (P < 0.05) in the enzyme activity after limonene treatment. We also studied the effect of GSTP1 gene polymorphism on Cd-induced genotoxicity and antigenotoxic potential of limonene. We found a significant decrease (P < 0.05) in SCE frequency, tail moment, and lipid peroxidation after limonene treatment compared to Cd. However, we did not observe any significant relationship (P > 0.05) between GSTP1 polymorphism and Cd, limonene genotoxicity and antigenotoxicity, respectively.
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http://dx.doi.org/10.1007/s12010-018-2881-5DOI Listing
April 2019

Lessons From Leprosy: Peripheral Neuropathies and Deformities in Chronic Demyelinating Diseases.

J Hand Surg Am 2019 May 1;44(5):411-415. Epub 2018 Sep 1.

Peripheral Nerve Research Lab, Gillespie Neuroscience Research Facility, Irvine, Orange, CA; Department of Orthopaedic Surgery, University of California, Irvine, Orange, CA. Electronic address:

In light of the World Health Organization's push to accelerate progress toward a leprosy-free world by 2020, it is fitting to look back on the evolution of progress in treating lepromatous neuropathy and limb deformities. To date, no surgeon has had as great an impact on the understanding and treatment of this disease as Dr Paul Brand. Before Dr Brand's accomplishments, few surgeons participated in the management of the deformed leprous patient. By challenging conventional beliefs, Dr Brand revealed that many of the deformities associated with leprosy were in fact caused by nerve damage and subsequent limb anesthesia. His pioneering work centered on tendon transfers to provide hand and foot mobility to leprous patients, revolutionizing the surgical management of this patient population and restoring functionality to the lives of otherwise stigmatized and functionally handicapped individuals. In the process, he provided us with the surgical principles and techniques that we still apply today. Because of its predilection for the peripheral nervous system, leprosy also provides an excellent opportunity to investigate mechanisms of demyelination and chronic nerve degeneration in nonacute peripheral neuropathies. Processes underlying demyelination of infectious, traumatic, and genetic etiologies overlap and precede the onset of acute neuronal derangement. Glial pathology has been shown to be a common pathological element in leprosy, Charcot-Marie-Tooth type I, multiple sclerosis, and chronic nerve compression injury. The aim of this article is to provide an overview of lepromatous neuropathy with its subsequent deformities as it relates to the pathophysiology, surgical management, and potential therapeutic targets of other modern peripheral neuropathies.
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http://dx.doi.org/10.1016/j.jhsa.2018.07.007DOI Listing
May 2019

A rare case of endobronchial mucoepidermoid carcinoma of the lung presenting as non-resolving pneumonia.

Respir Med Case Rep 2018 24;25:154-157. Epub 2018 Aug 24.

Division of Pulmonary and Critical Care Medicine, Bronx Care Health System, Affiliated with Icahn School of Medicine at Mount Sinai, 1650 Grand Concourse, Bronx, NY, 10457, USA.

Background: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor, and MECs of the lung are rare, accounting for 0.1-0.2% of malignant lung tumors. Pulmonary MECs are commonly found in the segmental or lobar bronchi, rarely presenting as endobronchial lesions.

Case Presentation: Here we describe the case of a 21-year-old female with no comorbid conditions who presented at the emergency room with a cough, yellow phlegm, pleuritic chest pain, and a subjective fever. These symptoms had been present for approximately one week prior to the patient's arrival at the hospital. A chest X-ray revealed right lower lobe alveolar infiltrate and computed tomography of the chest showed dense consolidation of the right lower lobe with ovoid intraluminal density in the right main stem bronchus. Upon fiber optic bronchoscopy, an endobronchial lesion was found in the right main stem sparing the right upper lobe uptake. Endobronchial biopsy results was consistent with MEC of the lung. The patient underwent a bilobectomy with complete resection of the tumor.

Conclusion: Endobronchial MEC is a rare type of salivary gland tumor. Patients with low-grade MECs have a good prognosis, whereas those with high-grade MECs, which are aggressive and associated with metastatic disease, have a poor prognosis. However, early identification and surgical resection can result in a good prognosis.
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http://dx.doi.org/10.1016/j.rmcr.2018.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115606PMC
August 2018

NMR-Based Serum Metabolomics Reveals Reprogramming of Lipid Dysregulation Following Cyclophosphamide-Based Induction Therapy in Lupus Nephritis.

J Proteome Res 2018 07 18;17(7):2440-2448. Epub 2018 Jun 18.

Department of Clinical Immunology , SGPGIMS , Lucknow 226014 , India.

Lupus nephritis (LN) is a major cause of morbidity and mortality in lupus. Renal biopsy is the gold standard for classification of nephritis, but because of its impracticality, new approaches for improving patient prognostication and monitoring treatment efficacy are needed. We aimed to evaluate the potential of metabolic profiling in identifying biomarkers to distinguish disease and monitor treatment efficacy in patients with LN. Serum samples from patients with LN ( n = 18) were profiled on NMR-based metabolomics platforms at diagnosis and after 6 months of treatment. LN patients had a different metabolomic fingerprint as compared with healthy controls, with increased lipoproteins and lipids and reduced acetate and amino acids. Using multivariate statistical analysis, we found that the metabolic changes observed in naïve LN patients at diagnosis displayed a variation in the opposite direction upon responding to treatment. Increased levels of lipid metabolites including low- and very-low-density lipoproteins (LDL/VLDL) in LN patients significantly decreased after 6 months of treatment, whereas the serum levels of acetate increased. These levels correlated significantly with SLE Disease Activity Index (SLEDAI 2K), renal SLEDAI, and serum C3 and C4 levels. The result presented in this pilot longitudinal study revealed the reprogramming of metabolome in LN patients on immunosuppressive therapy using NMR-based metabolomics, and thus this approach may be used to monitor the response to treatment.
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http://dx.doi.org/10.1021/acs.jproteome.8b00192DOI Listing
July 2018

Shielding effect of anethole against arsenic induced genotoxicity in cultured human peripheral blood lymphocytes and effect of GSTO1 polymorphism.

3 Biotech 2018 May 30;8(5):232. Epub 2018 Apr 30.

3Department of Microbiology, Kurukshetra University, Kurukshetra, Haryana 136119 India.

Chronic exposure of inorganic arsenic compounds is responsible for the manifestation of various tumours as well as other diseases. The principal mechanism behind arsenic toxicity is the induction of a strong oxidative stress with production of free radicals in cells. The present study was aimed to explore the shielding effect of anethole against oxidative damage induced by arsenic in cultured human peripheral blood lymphocytes and the effect of GSTO1 polymorphism. Sister chromatid exchange (SCE) frequency, comet tail moment and lipid peroxidation levels were used as biomarkers to assess the oxidative damage. Heparinised venous blood was collected from healthy individuals and treated with sodium arsenite (50 µM) in the presence of anethole (25 and 50 µM) for the analysis of shielding effect of anethole. For the genotyping of GSTO1, PCR RFLP method was adopted. A significant dose-dependent increase in the frequency of SCEs, tail moment and lipid peroxidation levels, was observed when lymphocytes were treated with sodium arsenite. Anethole in combination with sodium arsenite has shown a dose-dependent significant decrease in the frequency of SCEs, tail moment and lipid peroxidation levels. Genetic polymorphism of GSTO1 was found to effect individual susceptibility towards arsenic-mediated genotoxicity and was found insignificant when antigenotoxic effect of anethole was considered. GSTO1 mutant genotypes were found to have significant higher genotoxicity of sodium arsenite as compared to wild-type genotype. The results of the present study suggest ameliorative effects of anethole against arsenic-mediated genotoxic damage in cultured human peripheral blood lymphocytes. A significant effect of GSTO1 polymorphism was observed on genotoxicity of sodium arsenite.
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http://dx.doi.org/10.1007/s13205-018-1263-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928012PMC
May 2018

Laparoscopic management of an internal hernia in a pregnant woman with Roux-en-Y gastric bypass.

BMJ Case Rep 2018 Apr 19;2018. Epub 2018 Apr 19.

General Surgery, Bronx-Lebanon Hospital Center, Bronx, New York, USA.

Management of abdominal pain in a pregnant patient with a history of Roux-en-Y gastric bypass presents unique challenges. A misdiagnosis or delay in management can result in lethal maternal-fetal outcomes. We present a 30-year-old woman at 21 weeks of pregnancy presented with abdominal pain. She had a history of laparoscopic Roux-en-Y gastric bypass performed 3 years earlier. The clinical examination was remarkable for epigastric pain and tenderness. The vital signs and laboratory examinations were unremarkable. The CT scan was suggestive of an internal hernia. On an exploratory laparoscopy, the distal common small bowel was found to be herniating through the jejunojejunostomy mesenteric defect, causing intestinal obstruction with dilatation of the Roux limb and the biliopancreatic limb. The internal hernia was reduced, and no bowel resection was required. The mesenteric defect was closed with 3-0 silk sutures in a continuous fashion. The patient was discharged after 3 days and delivered a healthy baby at 40 weeks of gestation.
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http://dx.doi.org/10.1136/bcr-2017-221979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911130PMC
April 2018