Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need. Objectives: To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets. Design: Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS. Methods and analysis: Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes. Discussion: The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.

Distinctive transcriptomic and epigenomic signatures of bone marrow-derived myeloid cells and microglia in CNS autoimmunity.

In the context of autoimmunity, myeloid cells of the central nervous system (CNS) constitute an ontogenically heterogeneous population that includes yolk sac-derived microglia and infiltrating bone marrow-derived cells (BMC). We previously identified a myeloid cell subset in the brain and spinal cord that expresses the surface markers CD88 and CD317 and is associated with the onset and persistence of clinical disease in the murine model of the human CNS autoimmune disorder, experimental autoimmune encephalomyelitis (EAE). We employed an experimental platform utilizing single-cell transcriptomic and epigenomic profiling of bone marrow-chimeric mice to categorically distinguish BMC from microglia during CNS autoimmunity. Analysis of gene expression and chromosomal accessibility identified CD88+CD317+ myeloid cells in the CNS of EAE mice as originating from BMC and microglia. Interestingly, each cell lineage exhibited overlapping and unique gene expression patterns and transcription factor motifs that allowed their segregation. Our observations will facilitate determining pathogenic contributions of BMC and microglia in CNS autoimmune disease. Ultimately, this agnostic characterization of myeloid cells will be required for devising disease stage-specific and tissue-specific interventions for CNS inflammatory and neurodegenerative disorders.

Biological Significance of Anti-SARS-CoV-2 Antibodies: Lessons Learned From Progressive Multifocal Leukoencephalopathy.

OBJECTIVE: To discuss the pathogenic and diagnostic relevance of cellular and humoral immune responses against severe acute respiratory syndrome novel coronavirus (SARS-COV-2) and pertinent observations made in progressive multifocal leukoencephalopathy (PML). METHODS: Review of pertinent literature. RESULTS: There is at least 1 precedent for an antibody response against a viral pathogen that fails to provide host protection in the absence of immune-competent CD4+ T cells. PML is an infection of the CNS caused by JC virus (JCV), which commonly occurs during treatment with the therapeutic monoclonal antibody natalizumab. In this context, the humoral immune response fails to prevent JCV reactivation, and elevated anti-JCV serum indices are associated with a higher PML incidence. The more relevant immune-competent cells in host defense against JCV appear to be T cells. T cell-mediated responses are also detectable in convalescing patients with SARS-COV-2 irrespective of the humoral immune response. CONCLUSION: Based on pathogenic lessons learned from PML under natalizumab therapy, we suggest the incorporation of functional assays that determine neutralizing properties of SARS-CoV-2-specific antibodies. In addition, we outline the potential role of T-cell detection assays in determining herd immunity in a given population or in studying therapeutic responses to vaccines.

Limitations of cell-lineage-specific non-dynamic gene recombination in CD11c.Cre+ITGA4fl/fl mice.

BACKGROUND: The Cre-lox system is a non-dynamic method of gene modification and characterization. Promoters thought to be relatively cell-specific are utilized for generation of cell-lineage-specific gene modifications. METHODS: CD11c.Cre+ITGA4fl/fl mice were generated to abolish the expression of ITGA (α4-integrin) in CD11c+ cells. Ex vivo flow cytometry studies were used to assess the expression of cellular surface markers in different lymphoid compartments and leukocytes subsets after Cre-mediated recombination. RESULTS: A significant reduction of α4-integrin expression among CD11c+- cells was achieved in CD11c.Cre+ITGA4fl/fl mice in primary and secondary lymphoid tissues. A similar reduction in the expression of α4-integrin was also observed in CD11c- cells. CONCLUSION: Cre-lox-mediated cell lineage-specific gene deletion is limited by the transient expression of recombination regulating sequences in hematopoietic cell lines. These methodological issues indicate the need to consider when to employ non-dynamic DNA recombination models in animal models of CNS autoimmunity. An experimental algorithm to address the biological complexities of non-dynamic gene recombination is provided.

Outcome of lesional epilepsy surgery: Report of the first comprehensive epilepsy program in Iran.

BACKGROUND: We investigated the utility of epilepsy surgery and postoperative outcome in patients with lesional epilepsy in Iran, a relatively resource-poor setting. METHODS: This prospective longitudinal study was conducted during 2007-2017 in Kashani Comprehensive Epilepsy Center, Isfahan, Iran. Patients with a diagnosis of intractable focal epilepsy, with MRI lesions, who underwent epilepsy surgery and were followed up ≥ 24 months, were included and evaluated for postoperative outcome. RESULTS: A total of 214 patients, with a mean age of 26.90 ± 9.82 years (59.8% men) were studied. Complex partial seizure was the most common type of seizure (85.9%), and 54.2% of the cases had auras. Temporal lobe lesions (75.2%) and mesial temporal sclerosis (48.1%) were the most frequent etiologies. With a mean follow-up of 62.17 ± 19.33 months, 81.8% of patients became seizure-free postoperatively. Anticonvulsants were reduced in 86% of the cases and discontinued in 40.7%. In keeping with previous studies, we found that seizure freedom rates were lower among patients with longer follow-up periods. CONCLUSIONS: We found high rates of seizure freedom after surgery in lesional epilepsy patients despite limited facilities and infrastructure; antiepileptic medications were successfully tapered in almost half of the patients. Considering the favorable outcome of epilepsy surgery in our series, we believe that it is a major treatment option, even in less resource-intensive settings, and should be encouraged. Strategies to allow larger scale utility of epilepsy surgery in such settings in the developing world and dissemination of such knowledge may be considered an urgent clinical need, given the established mortality and morbidity in refractory epilepsy.

Evaluation of dual pathology among drug-resistant epileptic patients with hippocampal sclerosis.

PURPOSE: Dual pathology (DP) is defined as simultaneous presence of hippocampal sclerosis (HS) and any other pathology in the brain. Since this is a less probed concept, we aimed to evaluate the frequency and characteristics of DP among drug-resistant epileptic patients with HS. METHODS: This is a cross-sectional study conducted during 2007-2016 in Kashani Comprehensive Epilepsy Center, Isfahan, Iran. Patients with diagnosis of drug-resistant epilepsy and HS were enrolled in the study, and demographic data, seizure semiology, EEG findings, and MRI findings were collected. We compared these variables between three groups of DP, unilateral HS, and bilateral HS. RESULTS: Of the 200 enrolled cases, 29 patients (14.5%) had DP and 21 patients (10.5%) had bilateral HS; the remaining patients had unilateral HS. The average age of patients with DP was 30.03, and 65.5% of them were male. Patients with DP had more EEG discharges from regional and multi-focal sites compared to unilateral HS (P value < 0.001). Also, complex partial seizure (CPS) was more commonly presented in patients with unilateral HS (96.8%). Comparison of disease characteristics between DP and bilateral HS showed no difference in most categories (P > 0.05). CONCLUSIONS: We found DP among 14.5% of our drug-resistant epileptic patients with HS. DP patients mostly presented with CPS and had high proportion of ictal and interictal EEG discharges from regional and multi-focal areas. Gliosis and focal cortical dysplasia were the most common pathologies among DP patients. Patients with DP showed a similar behavior to bilateral HS in many features.

Cutaneous anaplastic large cell lymphoma in a multiple sclerosis patient receiving Fingolimod.

BACKGROUND: Previous reports of cutaneous neoplastic lesions secondary to Fingolimod treatment among multiple sclerosis patients. OBJECTIVE: Reporting a case of cutaneous large cell lymphoma in a multiple sclerosis patient during Fingolimod treatment. METHOD: Case study. RESULT: Our patient developed CD30+ cutaneous large cell lymphoma two years after initiation of Fingolimod treatment and her symptoms regressed following the cessation of treatment. CONCLUSION: This report indicates that cutaneous lymphoid neoplasms should be considered a possible side effect among patients receiving Fingolimod.

Attitudes Toward Cancer and Cancer Patients in an Urban Iranian Population.

BACKGROUND: Because of the significant incidence and mortality of cancer in Iran, a Comprehensive National Cancer Control Program for the prevention and early detection of cancer was launched in 2007. However, cancer awareness and screening rates in Iran did not improve. This study aimed to evaluate public attitudes toward cancer and cancer patients in Iran. MATERIALS AND METHODS: We conducted a cross-sectional survey among 953 non-institutionalized individuals in Isfahan, Iran, from November 2014 to February 2015. We collected data on attitudes toward cancer in three domains (impossibility of recovery, cancer stereotypes, and discrimination), as well as questions on willingness to disclose a cancer diagnosis. RESULTS: Among all participants, 33.9% agreed that it is very difficult to regain one's health after a cancer diagnosis, 17.4% felt uncomfortable with a cancer patient, and 26.9% said that they would avoid marrying people whose family members had cancer. While 88.9% of study participants said that cancer patients deserve to be protected in society, 53.3% and 48.4% of participants agreed that they would not disclose a cancer diagnosis to neighbors and coworkers, respectively. CONCLUSION: Negative attitudes with respect to impossibility of recovery and discrimination toward cancer and cancer patients were common among urban Iranians. Most people would not disclose a cancer diagnosis to others in spite of advancements in cancer diagnosis and treatment, reflecting unfavorable attitudes toward cancer and cancer patients in society. Successful implementation of cancer awareness and prevention programs in Iran may require social changes based on adequate information on cancer and cancer patients. IMPLICATIONS FOR PRACTICE: Public attitudes toward cancer and cancer patients are an important factor affecting cancer control programs as well as quality of life and recovery of cancer patients. The issue has not been studied in Iran and the surrounding countries in the Middle East. This is the first report presented on the subject. These findings can be used by health policy makers, health managers, and clinicians for better practice.

A comparative study of transcutaneous interferential electrical stimulation plus behavioral therapy and behavioral therapy alone on constipation in postoperative Hirschsprung disease children.

PURPOSE: We assessed the effectiveness of transcutaneous interferential (IF) electrical stimulation on constipation in postoperative Hirschsprung's disease (HD) patients. METHODS: Thirty HD children (18 boys and 12 girls) with constipation who had no surgical complication were enrolled and then randomly divided into two treatment groups. The control group underwent only behavioral therapy comprising high fiber diet, hydration, toilet training and pelvic floor muscles exercises while; the IF group underwent behavioral therapy plus IF electrical stimulation. Patients underwent anorectal manometry before and 6months after the treatment. In addition, a complete bowel diary with data on the frequency of defecation per week, stool form and the number of fecal soiling episodes, a constipation score and a visual pain score were obtained from all patients before, after treatment and 6months later. RESULTS: Constipation symptoms were improved in 10 (66%) and 4 (26.6%) patients in IF and control groups, respectively at 6months of follow up (P<0.03). Frequency of defecation per week significantly increased after the treatment in the IF group compared with control group at the 6months of follow up (5.4±2.1 vs. 3.3±1.8 per week, respectively; P<0.009). In addition, mean pain score was significantly decreased in IF group compared with controls after treatment (P<0.05). CONCLUSION: IF electrical stimulation is an effective adjunct to behavioral therapy to overcome symptoms of constipation in postoperative HD patients.

Recurrent acute pancreatitis and cholangitis in a patient with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder associated with multiple cyst formation in the different organs. Development of pancreatic cyst in ADPKD is often asymptomatic and is associated with no complication. A 38-year-old man with ADPKD was presented with six episodes of acute pancreatitis and two episodes of cholangitis in a period of 12 months. Various imaging studies revealed multiple renal, hepatic and pancreatic cysts, mild ectasia of pancreatic duct, dilation of biliary system and absence of biliary stone. He was managed with conservative treatment for each attack. ADPKD should be considered as a potential risk factor for recurrent acute and/or chronic pancreatitis and cholangitis.