Cytotoxicity of WT1-reactive T cells against Wilms tumor: An implication for antigen-specific adoptive immunotherapy.

Introduction: T cells that recognize WT1 peptides have been shown to efficiently eliminate WT1-expressing tumor cells. This study was designed to investigate the feasibility of isolating WT1-reactive T cells from peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with Wilms tumor, and to assess the cytotoxicity mediated by these cells against Wilms tumor cells (WiTu cells). Methods: WT1-reactive T cells were enriched and isolated by stimulating PBMCs with a WT1 peptide pool and interferon-γ capture-based immunomagnetic separation (IMS). Using the lactate dehydrogenase release assay, the in vitro cytotoxicity of the isolated cells and standard chemotherapy was evaluated on WiTu cells. Results: Higher proportions of WT1-reactive T cells were isolated from patients with Wilms tumor compared to those isolated from HDs. WT1-reactive T cells produced > 50% specific lysis when co-cultured with WT1+ WiTu cells at the highest effector-to-target (E:T) ratio in this study (i.e., 5:1), compared to <23% when co-cultured with WT1- WiTu cells at the same ratio. WT1-reactive T cells showed anti-tumoral activity in a dose-dependent manner and mediated significantly greater cytotoxicity than the non-WT1-reactive fraction of PBMCs on WT1+ WiTu cells. The cytotoxicity of standard chemotherapy was significantly lower than that of WT1-reactive T cells when co-cultured with WT1+ WiTu cells at E:T ratios of 2:1 and 5:1. Conclusion: WT1-reactive T cells can be effectively enriched from the PBMCs of patients with Wilms tumor. Ex vivo generated WT1-reactive T cells might be considered an adoptive immunotherapeutic option for WT1+ Wilms tumors.

Medically important snakes and snakebite envenoming in Iran.

Snakebite is a relatively common health condition in Iran with a diverse snake fauna, especially in tropical southern and mountainous western areas of the country with a plethora of snake species. The list of medically important snakes, circumstances and effects of their bite, and necessary medical care require critical appraisal and should be updated regularly. This study aims to review and map the distributions of medically important snake species of Iran, re-evaluate their taxonomy, review their venomics, describe the clinical effects of envenoming, and discuss medical management and treatment, including the use of antivenom. Nearly 350 published articles and 26 textbooks with information on venomous and mildly venomous snake species and snakebites of Iran, were reviewed, many in Persian (Farsi) language, making them relatively inaccessible to an international readership. This has resulted in a revised updated list of Iran's medically important snake species, with taxonomic revisions of some, compilation of their morphological features, remapping of their geographical distributions, and description of species-specific clinical effects of envenoming. Moreover, the antivenom manufactured in Iran is discussed, together with treatment protocols that have been developed for the hospital management of envenomed patients.

Efficacy of adoptively transferred allogeneic CIK cells on colorectal cancer: Augmentative antitumoral effects of GvHD.

OBJECTIVE: A preclinical study was designed to evaluate the effects of adoptively transferred cytokine-induced killer (CIK) cells on colorectal adenocarcinoma. METHODS: Forty NOG mice bearing HT-29 xenograft tumors were developed and equally divided into 2 groups of treatment and control. The mice in the treatment group received cumulatively 40-60 × 106 CIK cells in four divided doses. RESULTS: Median tumor doubling times for HT-29 xenograft tumors in the treatment and control groups were found to be 8.98 and 4.32 days; respectively. The treatment resulted in tumor growth delay (TGD) of 52.5 %. CIK cell-induced log cell kill (LCK) was found to be 0.67, which implies reduction of 78.6 % of neoplastic colorectal cells. Median length of survival in the treated mice was significantly longer than controls (57 (41-63) vs 41 (31-57) days, P < 0.001). Mice in the treatment group experienced graft-versus-host disease (GvHD) from median of day 13th after the cell therapy. LCK and TGD significantly increased after emergence of GvHD. After necropsy, tumors of the treatment group contained high levels of human-originated CD3+, CD4+ and CD8+ cells and showed significantly lower mitotic counts (P < 0.001) and residual tumor scores (P = 0.005) than the controls (entirely negative for the mentioned CD markers). Ninety percent of the treated mice were found to be responding. CONCLUSIONS: Adoptive transfer of allogeneic CIK cells may be an efficient antitumoral therapy for colorectal cancer. Allogeneic CIK cell-mediated GvHD may contribute to amplification of graft-versus-tumor effects of the cellular therapy.

Spontaneous xenogeneic GvHD in Wilms' tumor Patient-Derived xenograft models and potential solutions.

Severely immunocompromised NOD.Cg-Prkdcscid Il2rgtm1Sug (NOG) mice are among the ideal animal recipients for generation of human cancer models. Transplantation of human solid tumors having abundant tumor-infiltrating lymphocytes (TILs) can induce xenogeneic graft-versus-host disease (xGvHD) following engraftment and expansion of the TILs inside the animal body. Wilms' tumor (WT) has not been recognized as a lymphocyte-predominant tumor. However, 3 consecutive generations of NOG mice bearing WT patient-derived xenografts (PDX) xenotransplanted from a single donor showed different degrees of inflammatory symptoms after transplantation before any therapeutic intervention. In the initial generation, dermatitis, auto-amputation of digits, weight loss, lymphadenopathy, hepatitis, and interstitial pneumonitis were observed. Despite antibiotic treatment, no response was noticed, and thus the animals were prematurely euthanized (day 47 posttransplantation). Laboratory and histopathologic evaluations revealed lymphoid infiltrates positively immunostained with anti-human CD3 and CD8 antibodies in the xenografts and primary tumor, whereas no microbial infection or lymphoproliferative disorder was found. Mice of the next generation that lived longer (91 days) developed sclerotic skin changes and more severe pneumonitis. Cutaneous symptoms were milder in the last generation. The xenografts of the last 2 generations also contained TILs, and lacked lymphoproliferative transformation. The systemic immunoinflammatory syndrome in the absence of microbial infection and posttransplant lymphoproliferative disorder was suggestive of xGvHD. While there are few reports of xGvHD in severely immunodeficient mice xenotransplanted from lymphodominant tumor xenografts, this report for the first time documented serial xGvHD in consecutive passages of WT PDX-bearing models and discussed potential solutions to prevent such an undesired complication.

Adoptive NK-cell transfer as a potential treatment paradigm for Wilms tumor: A preclinical study.

BACKGROUND: Natural killer (NK) cell therapy has been shown to be effective in the treatment of some cancers. However, the effects of this adoptive immunotherapy have not been investigated for Wilms tumor (WT). In this study, the effects of adoptive NK-cell transfer on a patient-derived xenograft (PDX) model of anaplastic WT were evaluated, and the impacts of cell source and ex vivo activation strategy on the therapeutic efficacy of NK-cell product were appraised. METHODS: NK cells were isolated from human peripheral blood mononuclear cells (NKPB ) and human cord blood (NKCB ), and were expanded and activated using a cytokine cocktail. Another group of NK cells (NKET ) was produced through activation with the exosomes extracted from previously challenged NKPB cells with WT. PDX-bearing mice were treated with clinically relevant doses of NKPB , NKCB , NKET , standard chemotherapy, and placebo (phosphate-buffered saline). RESULTS: PDX models treated with NKCB showed a better survival rate, though the difference among the study groups was not significant. Compared with the placebo control group, NKCB significantly improved the histopathologic response, NKPB significantly inhibited the proliferation of neoplastic cells, and NKET led to a significant decrease in the metastasis score (all p-values <.05). Standard chemotherapy provided the greatest tumor growth inhibition and the lowest mitotic count, though it did not show any significant advantage over NK-cell therapies in any of the outcome parameters in two-by-two comparisons. CONCLUSIONS: This study spotlights the efficacy of adoptive NK-cell transfer as a potential treatment candidate for high-risk WT.

Allogeneic adipose-derived mesenchymal stromal cell transplantation for refractory lupus nephritis: Results of a phase I clinical trial.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) are known for their immunomodulatory properties. This study was performed to analyse the effects of MSC transplantation on treatment-resistant lupus nephritis (LN). METHODS: In this phase I trial, nine biopsy-proven LN patients refractory to standard treatments underwent systemic infusion of 2 × 106 allogeneic adipose-derived (AD) MSCs/kg and were followed for 12 months post-intervention. RESULTS: The treatment protocol resulted in no major adverse events. Urine protein levels significantly decreased during the first month post-intervention (baseline vs. month 1 (median): 1800 vs. 1020, P = 0.008), followed by a gradual increase but remained significantly lower than baseline only up to the 3rd month. During the first 3 months post-intervention, complete renal response (proteinuria < 0.5 g/24 h) and partial response (proteinuria > 0.5 g/24 h, but > 50% decrease in proteinuria) were observed in 33.3% and 44.4% of the patients, respectively, though these rates declined thereafter. Median score of Systemic Lupus Erythematosus Disease Activity Index decreased significantly from 16 at the baseline to 6 at sixth months post-treatment (P = 0.007), though it slightly increased at the 12th month follow-up. CONCLUSIONS: Allogenic AD-MSC transplantation was associated with favourable safety and efficient to reduce urine protein excretion and disease activity; however, the maximum effect (greatest improvement in outcomes) was observed at 1 month based on the proteinuria, and 6 months post-intervention based on disease activity scores. A single dose of AD-MSCs may not be adequate to maintain long-term remission of refractory LN, and so, additional doses may be required.

First report of a confirmed case of Montivipera latifii (Latifi's viper) envenoming and a literature review of envenoming by Montivipera species.

Latifi's viper (Montivipera latifii), also known as Lar Valley or Damavandi viper, is endemic to Iran. It has rarely been recorded, as it occurs in a highly-protected national park. In this first clinical report of a confirmed bite by this species, a teenage girl was bitten on the chin, causing rapidly-progressive swelling of the face and oropharyngeal mucosa. At a local hospital, a misleading history given by the patient's relatives of a wasp sting and inadequate inspection of the bite wound misled the physicians from making the correct diagnosis, resulting in a considerable delay in the administration of antivenom. This allowed the development of partial obstruction of the upper airway causing respiratory distress. After transfer to a tertiary hospital, attempts at endotracheal intubation failed, necessitating tracheostomy, but this was not implemented early enough to prevent her developing respiratory failure and losing consciousness. After she was stabilized, snakebite envenoming was diagnosed by a clinical toxicologist who observed two fang puncture marks on her chin. This was later confirmed when a snake, identified as M. latifii, was discovered at the room where the bite had occurred. Her facial swelling and ecchymosis, attributable to envenoming, were effectively controlled by high-dose antivenom therapy. However, she did not recover consciousness, remaining in a vegetative state. About three weeks after the bite, she died as an indirect result of hypoxic brain damage complicated by septicemia. Prompt diagnosis, relief of upper airway obstruction and timely antivenom therapy might have prevented this tragic fatal outcome.

Comparative Analysis of the Effectiveness of Intra-Articular Injection of Platelet-Rich Plasma versus Hyaluronic Acid for Knee Osteoarthritis: Results of an Open-Label Trial.

BACKGROUND: Platelet-rich plasma (PRP), an autologous source of growth factors, and hyaluronic acid (HA) are among the minimally invasive treatments for knee osteoarthritis (OA). This trial was designed to compare the effectiveness of intra-articular injection of PRP with HA (as one of the standard treatments) on mild to moderate knee OA. METHODS: In this phase I open-label clinical trial, 10 patients underwent intra-articular PRP injection and 10 others received HA injection. At baseline (pre-injection) visit and 1, 3, 6, and 12 months post-injection, clinical assessments were performed using visual analogue scale (VAS) and Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Physical examinations of the knee, including crepitation and range of motion (ROM) were performed at each visit. The follow-up responses were compared with the baseline visit. RESULTS: The PRP treatment was ascertained to be safe and caused no adverse effects. Significant improvements in the majority of KOOS subscales and VAS were found throughout the entire 12-month follow-up, following the PRP injections. HA injection, however, caused only one month significant improvement in the majority of patient-reported outcomes. In the majority of visits, the extent of improvements in the scores of KOOS subscales, as well as the extent of reduction in VAS were significantly greater in PRP recipients, compared to HA recipients. The ROM in both groups slightly increased after interventions. The frequency of coarse crepitation, which was detected in 100% of the patients in both groups at the baseline visit, decreased significantly to fine crepitation at the first follow-up visit in 80% and 40% of the PRP and HA recipients, respectively. CONCLUSION: Intra-articular injection of PRP or HA alleviates symptoms and pain and improves functionality and physical examinations in patients with knee OA. However, PRP therapy produces greater and longer-lasting improvements in most of the outcome parameters compared to HA.

Extracellular Matrix Scaffold Using Decellularized Cartilage for Hyaline Cartilage Regeneration.

The repair of osteochondral defects is among the top ten medical needs of humans in the 21st centuries with many countries facing rapidly aging population involved with osteoarthritis as a major contributor to global disease burden. Tissue engineering methods have offered new windows of hope to treat such disorders and disabilities. Regenerative approaches to cartilage injuries require careful replication of the complex microenvironment of the native tissue. The decellularized hyaline cartilage derived from human allografts or xenografts is potentially an ideal scaffold, simulating the mechanical and biochemical properties, as well as biological microarchitecture of the hyaline cartilage. There have been many attempts to regenerate clinically viable hyaline cartilage tissue using decellularized cartilage-derived extracellular matrix with stem cell technology. This chapter describes the reproducible methods for hyaline cartilage decellularization and recellularization. In addition, quality control and characterization requirements of the product at each step, as well as the clinical applications of final product have been discussed.

Radiation-Free myeloablative allogeneic hematopoietic stem cell transplantation for adult acute lymphoblastic leukemia: A comparison of outcomes between patients with and without central nervous system involvement.

For patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), total body irradiation (TBI) has been particularly advocated as a part of the conditioning regimen in case of extramedullary involvement in sanctuary sites such as the central nervous system (CNS), to ensure greater tissue penetration. In resource-limited countries lacking TBI facilities; however, ALL patients undergo radiation-free myeloablative conditioning, though its impacts on post-HSCT outcomes of the patients with pre-HSCT CNS involvement have not been analyzed. In this 14-year series of 278 adult (> 18 y) ALL patients undergoing TBI-free busulfan/cyclophosphamide conditioning allo-HSCT, we found that the long-term probabilities of overall survival, disease free survival, relapse and non-relapse mortality were not significantly different between CNS-involved and CNS-spared patients. Moreover, there was no statistically significant difference in the incidence of post-HSCT CNS relapse between CNS-involved and CNS-spared patients. Pre-HSCT cranial radiation therapy (CRT) showed no significant preventive effect on the likelihood of post-HSCT CNS relapse. Through multivariable regression analysis, grade III-IV acute graft-versus-host disease (GvHD), extensive chronic GvHD and post-HSCT relapse were ascertained as independent determinants of mortality (Adj.R2 = 53.9 %, F(12,265) = 28.1, P < 0.001), while other parameters including Philadelphia translocation, pre-HSCT CNS involvement and CRT were found to have no independent effect. Although this study was not an attempt to compare TBI-based vs. non-TBI conditioning, the TBI-free myeloablative allo-HSCT was shown to be feasible and an option for adult ALL patients with CNS involvement, considering the comparable outcomes between patients with and without CNS involvement.

An outlook on antigen-specific adoptive immunotherapy for viral infections with a focus on COVID-19.

Although not a standard-of-care yet, adoptive immunotherapeutic approaches have gradually earned a place within the list of antiviral therapies for some of fatal and hard-to-treat viral diseases. To maintain robust antiviral immunity and to effectively target the viral particles and virally-infected cells, immune cells capable of recognizing the viral antigens are required. While conventional vaccination can induce these cells in vivo; another option is to prime and generate antigen-specific immune cells ex vivo. This approach has been successfully trialed for virulent opportunistic viral infections after bone marrow transplantation. Amid the crisis of SARS-CoV2 pandemic, which has been followed by the success of certain early-authorized vaccines; some institutions and companies have explored the effects of viral-specific adoptive cell transfers (ACTs) in trials, as alternative treatments. Aimed at outlining a perspective on antigen-specific adoptive immunotherapy for viral infections, this review article specifically provides an appraisal of ACT-based studies/trials on SARS-CoV2 infection.

Analysis of determinant factors of liver fibrosis progression in ex-thalassemic patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) potentially renders thalassemia patients disease-free with presumably cessation of associated complications. This study analyzes the liver fibrosis status and the determinants of its progression in ex-thalassemic patients. The liver fibrosis status of 108 pediatric transfusion-dependent ß-thalassemia major patients was evaluated before and one year after allo-HSCT using transient elastography (TE). All patients achieved normal hematopoiesis. In univariate analyses, not in all, but in patients developing significant post-HSCT iron overload or hepatic graft-versus-host disease (GvHD), as well as recipients of bone marrow stem cells (BMSC), significant TE increment occurred. In multivariable analyses, through a model with large effect size (Adj.R2 = 26%, F(3,104) = 13.53, P < 0.001), post-HSCT serum ferritin and hepatic GvHD were ascertained as independent determinants of significant TE increase, and the effect of stem cell graft source approached the level of significance. Excluding the patients with intermediate/high Lucarelli risk classes, the TE increase was significantly greater only in BMSC recipients (P = 0.033). Although the risk impact of allograft source on liver fibrosis progression requires further evaluation; hepatic status of ex-thalassemic patients can be preserved after HSCT, if hepatic GvHD is controlled and adequate post-transplantation iron depletion is ensured.

Analysis of effectiveness of Iranian snake antivenom on Viper venom induced effects including analysis of immunologic biomarkers in the Echis carinatus sochureki envenomed victims.

Snakebite is an important toxicologic emergency with the potential of triggering local and systemic inflammation. Antivenom has remained the mainstay of treatment for snakebite envenomation. In this study we sought to investigate the effectiveness of Iranian antivenom in a series of 44 viper envenomed patients through analysis of changes in clinical severity and the levels of inflammatory markers. Clinical envenomation severity assessed by snakebite severity score (SSS) and laboratory exams of the patients were recorded before (baseline visit) and after antivenom therapy. During 12-h antivenom therapy, the median (range) score of SSS significantly decreased from 3.5 (2-10) on admission to 1 (0-5) in the last visit (P < 0.001). Moreover, a significant decrease in prothrombin time and international normalized ratio was found (P = 0.006 and 0.008; respectively). Plasma concentrations of interleukin (IL) 1-ß, IL-6, IL-8, tumor necrosis factor α (TNF-α), complement hemolytic activity (CH50) were also measured in 10 severely Echis carinatus sochureki envenomed victims and 10 age and gender-matched healthy controls. Except IL-8, the baseline levels of IL-1ß, IL-6 and TNF-α in victims were significantly higher than healthy controls (P = 0.005, <0.001 and < 0.001, respectively). Moreover, the baseline level of CH50 was significantly lower in the patients compared to healthy controls (P < 0.001). After 12-h antivenom therapy, the plasma levels of IL-1ß, IL-6 and TNF-α significantly decreased (P = 0.032, 0.006 and 0.003, respectively), the levels of IL-8 remained relatively unchanged and the CH50 significantly increased (P = 0.011). Iranian snake antivenom was effective in treating viper bite envenomation as it reversed clinical venom effects and restored near normal underlying inflammatory status. This study is the first to ascertain and report the effectiveness of this antivenom in human subjects.

Efficacy analysis of hydroxychloroquine therapy in systemic lupus erythematosus: a study on disease activity and immunological biomarkers.

BACKGROUND: Hydroxychloroquine (HCQ) is a widely prescribed medication to patients with systemic lupus erythematosus (SLE), with potential anti-inflammatory effects. This study was performed to investigate the efficacy of HCQ therapy by serial assessment of disease activity and serum levels of proinflammatory cytokines in SLE patients. METHODS: In this prospective cohort study, 41 newly diagnosed SLE patients receiving 400 mg HCQ per day were included. Patients requiring statins and immunosuppressive drugs except prednisolone at doses lower than 10 mg/day were excluded. Outcome measures were assessed before commencement of HCQ therapy (baseline visit) as well as in two follow-up visits (1 and 2 months after beginning the HCQ therapy). Serum samples of 41 age-matched healthy donors were used as controls. RESULTS: Median levels of IL-1ß (p < 0.001), IL-6 (p = 0.001), and TNF-α (p < 0.001) were significantly higher, whereas, median CH50 level was significantly lower (p < 0.001) in SLE patients compared with controls. Two-month treatment with HCQ resulted in significant decrease in SLEDAI-2K (p < 0.001), anti-dsDNA (p < 0.001), IL-1ß (p = 0.003), IL-6 (p < 0.001) and TNF-α (p < 0.001) and a significant increase in CH50 levels (p = 0.012). The reductions in SLEDAI-2K and serum levels of IL-1ß and TNF-α were significantly greater in the first month compared with the reductions in the second month. CONCLUSION: HCQ therapy is effective on clinical improvement of SLE patients through interfering with inflammatory signaling pathways, reducing anti-DNA autoantibodies and normalizing the complement activity.

Outcome Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia Treated with Total Body Irradiation-Free Allogeneic Hematopoietic Stem Cell Transplantation: Comparison of Patients with and Without Central Nervous System Involvement.

Hematopoietic stem cell transplantation (HSCT) with a non-total body irradiation (TBI) conditioning regimen has proven feasible for treating patients with acute lymphoblastic leukemia (ALL). However, it is commonly believed that for extramedullary involvement of ALL in sanctuary sites, such as the central nervous system (CNS), TBI shall not be abandoned. In this study, the outcomes of pediatric ALL patients with CNS involvement (CNS+) and without CNS involvement (CNS-) treated with TBI-free allogeneic HSCT were retrospectively compared. The patients received a TBI-free busulfan plus cyclophosphamide conditioning regimen. Comparing CNS+ (n = 27) and CNS- (n = 134) patients, the 5-year probabilities of relapse (44.4% versus 41.8%; P = .799), disease-free survival (DFS; 48.1% versus 43.3%; P = .642) and overall survival (OS; 51.9% versus 47.0%; P = .646) were not significantly different. Although transplantation-related mortality (TRM) was higher in the CNS- patients, the difference between the 2 groups was not significant (3.7% versus 12.7%; P = .177). In multivariate analysis, there were no significant between-group differences in OS (P = .502), DFS (P = .424), relapse rate (P = .226), or TRM (P = .117). These findings suggest that HSCT using a non-TBI-containing conditioning regimen can lead to similar outcomes in pediatric ALL patients with and without CNS involvement. TBI-free allogeneic HSCT might be feasible and effective for CNS+ ALL patients.

Effectiveness of a clinical protocol implemented to standardize snakebite management in Iran: initial evaluation.

OBJECTIVE: This study was designed to evaluate the effectiveness of a new protocol implemented to standardize snakebite management in Iran. METHODS: In this study, 27 patients treated according to the new protocol in 2012 (P+) were compared with 22 patients treated according to the previous modality in the year before implementation of the protocol (P-) in Mashhad Medical Toxicology Centre (MTC). Demographic characteristics and treatment details of all patients were recorded prospectively. Envenomation severity of each victim was assessed according to snakebite severity score (SSS). RESULTS: After implementation of the protocol, a smaller percentage of patients received antivenom (AV) therapy (78% vs 95%; P=.079). In spite of no significant difference in baseline severity of envenomation between the 2 groups (SSS [mean±SD], 34.8±18.1 vs 35.5±17.4; P=.801), the P+ group received significantly fewer AV vials (8.4±6.8 vs 12.1±5.6 vials; P=.042) and had a significantly shorter length of hospital stay (2.2±1.5 vs 3.2±1.8 days; P=.027). Moreover, smaller proportion of P+ patients experienced recurrence of venom-induced effects; however, the difference was not significant (18.5% vs 36%; P=.159). The reduction in use of antiallergy treatments to prevent or treat acute hypersensitivity reactions approached statistical significance (41% vs 68%; P=.051). These findings denote a reduction in AV use of approximately 4 vials and a reduction in hospital stay of 1 day for each patient, which translates to approximately $196/patient in healthcare cost savings. CONCLUSIONS: Implementation of a snakebite management protocol at MTC reduced overall antivenom usage, use of antiallergy interventions, and length of hospital stay.

Snakebite management in Iran: Devising a protocol.

BACKGROUND: Snakebite in Iran has been a health concern. However, management of snakebite is not standardized and varies from center to center. This study is aimed at devising an evidence-based comprehensive protocol for snakebite management in Iran, to reduce unnecessary variations in practice. MATERIALS AND METHODS: A narrative search in electronic databases was performed. Fifty peer-reviewed articles, guidelines, and textbooks were reviewed and practical details were extracted. Our currently used protocol in the Mashhad Toxicology Center was supplemented with this information. Consequently an improved wide-range protocol was developed. The protocol was then discussed and amended within a focus group comprised of medical toxicologists and internal medicine specialists. The amended version was finally discussed with expert physicians specialized in different areas of medicine, to be optimized by supplementing other specific considerations. RESULTS: During a one-year process, the protocol was finalized. The final version of the protocol, which was designed in six steps, comprised of three components: A schematic algorithm, a severity grading scale, and instructions for supportive and adjunctive treatments. The algorithm pertains to both Viperidae and Elapidae snakebite envenomations and consists of a planned course of action and dosing of antivenom, based on the severity of the envenomation. CONCLUSION: Snakebite envenomation is a clinical toxicologic emergency, which needs to be treated in a timely and organized manner. Hence, a multi-aspect protocol was designed to improve the clinical outcomes, reduce unnecessary administration of antivenom, and help physicians make more proper clinical judgments.

High disease activity is associated with high disease damage in an Iranian inception cohort of patients with lupus nephritis.

OBJECTIVES: This paper aims to determine disease activity and damage in patients with lupus nephritis (LN) and to evaluate the correlation among these domains and sociodemographic features. METHODS: This study was carried out on 71 lupus patients who were candidate for kidney biopsy due to their clinical renal manifestations. Clinical and sociodemographic data were collected and the Systemic Lupus Erythaematosus Disease Activity Index (SLEDAI-2K updated version), European Consensus Lupus Activity Measurement (ECLAM) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) were assessed after 10 days of admission, the day prior to performing renal biopsy. RESULTS: Sixty-five females (91.5%) and six males (8.5%) were studied. Their age was 24 (21-32) yr and disease duration was 1.5 (0.8-4) yr (median [IQR]). SLEDAI-2K, ECLAM and SDI scores were 25.5±12.3, 6.21±2.45, 2.0±2.3 (mean±SD) respectively. A great relationship between SLEDAI-2K and ECLAM (r=0.827, p<0.001) was found. SDI was significantly associated with SLEDAI-2K (r=0.742, p<0.001) and ECLAM (r=0.699, p<0.001). Age, gender and disease duration had no significant impact on SLEDAI-2K and ECLAM, while SDI was significantly higher in subjects with longer disease duration particularly in those of more than 3 years. Patients with lower education attainment had less medication adherence and higher disease activity and damage. CONCLUSIONS: There is a highly significant correlation of high disease activity with cumulative damage in patients with LN, particularly in those with newly-onset disease. Considering that the first years of SLE are an active critical period which can lead to severe damage, this highlights the necessity of aggressive treatment, tight-organised follow-ups and more patient compliance with the physician orders.