Role of altered IL-33/ST2 immune axis in the immunobiology of Guillain-Barré syndrome.

BACKGROUND: The IL-33/ST2 immune axis plays crucial roles in infection and immunity. A dysregulated IL-33/ST2 axis can induce autoimmune reaction and inflammatory responses. Guillain-Barré syndrome (GBS) is an acute peripheral neuropathy, mostly caused by post-infection autoimmunity. The role of IL-33/ST2 axis is not known in GBS. This study aimed to explore the role of IL-33/ST2 axis in GBS. METHODS: Three single nucleotide polymorphisms (SNPs) of Il33 gene (rs16924159, rs7044343, rs1342336) and three SNPs of Il1rl1 gene (rs10192157, rs1041973, rs10206753) coding for suppressor of tumorigenicity 2 (ST2) were genotyped in 179 GBS patients and 186 healthy controls by TaqMan Allelic Discrimination Assay. Plasma levels of IL-33 and sST2 were measured in a subset of GBS patients (n = 80) and healthy controls (n = 80) by ELISA. RESULTS: The frequencies of CC genotype of rs10192157 (p = 0.043) and TT genotype of rs10206753 (p = 0.036) SNPs of Il1rl1 gene differed significantly between GBS patients and healthy controls. Gene-gene interaction between Il33 and Il1rl1 genes also conferred significant risk for GBS. In addition, the plasma sST2 levels were significantly elevated in GBS patients compared to healthy subjects (24,934.31 ± 1.81 pg/ml vs. 12,518.97 ± 1.51 pg/ml, p < 0.001). Plasma sST2 levels showed a significant correlation with the disability scores at the peak of neurological deficit in GBS patients. CONCLUSIONS: The IL-33/ST2 axis is suggested to influence the immunopathogenesis of GBS. Genetic variants of Il1rl1 gene might serve as a risk determinant of GBS and plasma sST2 levels might emerge as a biomarker of severity of GBS, if replicated further by other studies.

Variations within Toll-like receptor (TLR) and TLR signaling pathway-related genes and their synergistic effects on the risk of Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is the commonest post-infectious polyradiculopathy. Although genetic background of the host seems to play an important role in the susceptibility to GBS, genes conferring major risk are not yet known. Dysregulation of Toll-like receptor (TLR) molecules exacerbates immune-inflammatory responses and the genetic variations within TLR pathway-related genes contribute to differential risk to infection. The aim of this study was to delineate the impact of genetic variations within TLR2, TLR3, and TLR4 genes as well as TLR signaling pathway-related genes such as MyD88, TRIF, TRAF3, TRAF6, IRF3, NFκß1, and IκBα on risk of developing GBS. Fourteen polymorphisms located within TLR2 (rs3804099, rs111200466), TLR3 (rs3775290, rs3775291), TLR4 (rs1927911, rs11536891), MyD88 (rs7744, rs4988453), TRIF (rs8120), TRAF3 (rs12147254), TRAF6 (rs4755453), IRF3 (rs2304204), NFκß1 (rs28362491), and IκBα (rs696) genes were genotyped in 150 GBS patients and 150 healthy subjects either by PCR-RFLP or TaqMan Allelic Discrimination Assay. Genotypes of two polymorphic variants, Del/Del of rs111200466 insertion and deletion (INDEL) polymorphism of TLR2 gene and TT of rs3775290 single nucleotide polymorphism (SNP) of TLR3 gene had significantly higher frequencies among GBS patients, while the frequencies of TT genotype of rs3804099 SNP of TLR2 gene and TT genotype of rs11536891 SNP of TLR4 gene were significantly higher in controls. Gene-gene interaction study by Multifactor Dimensionality Reduction analysis also suggested a significant combined effect of TLR2, and NFκß1 genes on the risk of GBS. The SNPs in the IκBα and IRF3 genes correlated with severity of GBS. The genes encoding TLRs and TLR signaling pathway-related molecules could serve as crucial genetic markers of susceptibility and severity of GBS.

What Factors Influence Union and Refracture of Congenital Pseudarthrosis of the Tibia? A Multicenter Long-term Study.

OBJECTIVE: To identify factors influencing union of congenital pseudarthrosis of the tibia (CPT), refractures, and integrity of the tibia at maturity. METHODS: Data of 119 children operated for Crawford-type IV CPT and followed-up till skeletal maturity were analyzed. Logistic regression and recursive partitioning analyses were used to test associations between several variables and the outcome. RESULTS: Primary union occurred in 86% of children. At maturity, 69% remained soundly united. The odds ratio for failure of primary union was 3.89 (95% confidence interval, 1.05-14.40; P=0.042) when bone morphogenetic protein was used, and children who had a combination of the Ilizarov technique and intramedullary nailing were at risk for unsound union at maturity (odds ratio, 6.19; 95% confidence interval, 1.24-30.83; P=0.026). No other association reached statistical significance. On recursive partitioning, use of the Ilizarov technique, transfixing the ankle and subtalar joints, use of cortical graft and not operating on the fibula were associated with a better outcome; use of bone morphogenetic protein and combining intramedullary nailing with the Ilizarov technique were associated with poor results. CONCLUSIONS: A larger sample is needed to confirm which factors truly influence the outcome of CPT. This may be feasible if data are collected prospectively through a multicenter registry.

The Shreveport Myeloma Experience: Survival, Risk Factors and Other Malignancies in the Age of Stem Cell Transplantation.

BACKGROUND: The overall prognosis of multiple myeloma has improved significantly over the last 15 years. We wondered whether the overall improvement would also be seen in unselected patients in an academic center in Northwest Louisiana with a high proportion of minority patients, and if second malignant neoplasms are relevant for our patients. MATERIALS AND METHODS: Between 1998 and 2009, 215 patients were treated for multiple myeloma at our center and had complete follow-up until May 2013. RESULTS: The mean survival of patients with multiple myeloma increased from 3.25 to 5.34 years, which is comparable to patients treated at larger centers. No prognostic difference was observed in the subgroups of myeloma patients. Among 215 patients followed for the development of secondary cancers, 16 already had a preexisting or concomitant malignancy (7.4%) and 10 developed secondary cancers. Our data indicate a significant background of histologically unrelated cancers and a cumulative incidence of new cancers of about 20% after 10 years of follow-up. Based on SEER data, preexisting or secondary cancers were not statistically increased in our population. CONCLUSIONS: The use of autologous transplantation and the introduction of new agents resulted in a significant improvement in the prognosis of multiple myeloma. Other cancers are not statistically increased before or after multiple myeloma is diagnosed and are not prognostically relevant.

Re-examining Psychometric Properties of Fertility Problem Inventory: A Clinic-Based Study from India.

Background: The fertility problem inventory (FPI) is one of the most widely used measures that tap the diverse psychological problems faced by infertile couples. Research on translated versions of FPI has also reflected its high clinical significance. Aim: This research aimed to explore the psychometric properties and the clinical validity of the original 46-item FPI in an Indian sample. Setting and Design: This cross-sectional study was conducted in a tertiary hospital setup of a medical college. Materials and Methods: The original FPI was translated and pilot tested. The translated FPI was taken by 205 consenting infertile patients (113 women and 92 men). The psychometric properties of FPI were thus explored. Statistical Analysis: Exploratory factor analysis with minimum residual method of extraction followed by oblimin rotation was performed. Perceived Stress Scale was used to establish the convergent validity of the newly developed FPI-Kannada version (FPI-K). A cut-off score for the FPI-K was obtained separately for males and females using ROC analysis in which hamilton anxiety scale was used as the gold standard. Results: Only 32 items of the original FPI had factor loadings above 0.3 and overall six factors explained these items with a cumulative percentage variation of 32%. Overall Cronbach's alpha for FPI-K was 0.671 and it had a good convergent validity. Conclusions: The new FPI-K had 6 sub-domains and the clinical utility of same is discussed.

Impact of Antecedent Infections on the Antibodies against Gangliosides and Ganglioside Complexes in Guillain-Barré Syndrome: A Correlative Study.

Background and Aims: Guillain-Barré Syndrome (GBS), an immune-mediated neuropathy, is characterized by antibodies against gangliosides/ganglioside complexes (GSCs) of peripheral nerves. Antecedent infections have been reported to induce antibodies that cross-react with the host gangliosides and thereby have a pivotal role in conferring an increased risk for developing GBS. Data pertaining to the impact of various antecedent infections, particularly those prevalent in tropical countries like India on the ganglioside/GSC antibodies is sparse. We aimed at exploring the association between six antecedent infections and the profile of ganglioside/GSC antibodies in GBS. Methods: Patients with GBS (n = 150) and healthy controls (n = 50) were examined for the serum profile of antibodies against GM1, GM2, GD1a, GD1b, GT1b, and GQ1b and their GSCs by ELISA. These antibodies were correlated with immunoreactivities against Campylobacter jejuni, Japanese encephalitis (JE), dengue, influenza, zika, and chikungunya infections. Results: The frequencies of antibodies against six single gangliosides (P < 0.001) and their GSCs (P = 0.039) were significantly higher in patients as compared to controls. Except for GT1b-antibody which was more frequent in axonal GBS, none of the other ganglioside/GSC antibodies correlated with the electrophysiological subtypes of GBS. Antecedent JE infection was significantly associated with increased frequency of antibodies against GD1a, GD1b, GT1b, and GQ1b. Antibodies against GSCs were not influenced by the antecedent infections. Interpretation: This study for the first time shows an association between antecedent JE infection and ganglioside antibodies in GBS. This finding reinforces the determining role of antecedent infections on ganglioside antibody responses and the subsequent immunological processes in GBS.

Development and validation of a Smartphone Impact Scale among healthcare professionals.

OBJECTIVES: Smartphone overuse is prevalent among healthcare professionals. There is no standard scale that can measure the impact of smartphone usage on healthcare professionals. This study aimed to develop and validate a tool, the Smartphone Impact Scale (SIS), that can effectively measure the use of smartphone among healthcare professionals. METHODS: We developed a generic instrument to study the impact of smartphone usage among healthcare professionals. A total of 1436 healthcare professionals from various regions of KSA participated in this study through an online questionnaire-based survey. The psychometric properties of the SIS were developed using content validity index (CVI), factor analysis, internal consistency, and test-retest reliability analysis. RESULTS: A 23-item scale was selected for reliability and validity analysis. The average CVI was found to be 0.824. The internal consistency with Cronbach's alpha value was 0.91, and test-retest reliability was 0.85. The Cronbach's alpha values for Factors 1 and 2 were 0.875 and 0.803, respectively. The confirmatory factor analysis indices were as follows: root mean square of approximation = 0.0710, comparative fit index = 0.861, Tucker-Lewis index = 0.845, and the coefficient of determination = 0.969. The correlation between two factors was 0.66. After factor analysis, we developed a final questionnaire with 23 items. CONCLUSIONS: Our SIS showed a three-factor structure and appropriate psychometric characteristics. Due to its adequate reliability and validity, SIS can be conveniently used to evaluate the impact of smartphone usage on healthcare professionals.

Exceptional response to cetuximab monotherapy in a patient with metastatic oropharyngeal squamous cell carcinoma: a molecular insight.

BACKGROUND: Metastatic head and neck squamous cell carcinoma (HNSCC) carries a very poor prognosis. A better understanding of the molecular driver of the disease and the identification of biomarkers of response remain paramount for an effective personalized therapy. CASE REPORT: We report an original case of a 56-year-old patient diagnosed with metastatic HNSCC to both kidneys, who experienced a long-lasting complete response to a single-agent cetuximab, a monoclonal antibody-targeting EGFR. Comprehensive multiplatform biomarker analysis of the tumor revealed the presence of phosphatidyl-inositol 3 kinase mutation, EGFR overexpression, and the absence of PD-1/PD-L1 expression. Since PI3K, a downstream effector of EGFR, is activated, the tumor regression may have occurred mainly through a cetuximab-induced immune-mediated response, rather than EGFR signal blockade. It is plausible that this effect was enhanced by the lack of PD-1 and PD-L1 expression. CONCLUSION: Our case proposes that the absence of PD-1 and PD-L1 expression in conjunction with EGFR overexpression may correlate with better response to cetuximab in HNSCC. This hypothesis needs to be examined through a large clinical trial.

Distress in Infertile Males in Manipal-India: A Clinic Based Study.

BACKGROUND: Being infertile comes as an overwhelming realization for couples trying to conceive. In consideration of rising rates of infertility worldwide, clinicians in India have also begun exploring this field for new possibilities, development and research. The purpose of this study was to estimate the proportion and predictors of infertility specific stress in males diagnosed with primary infertility. METHODS: This cross-sectional research was conducted in an assisted reproduction center, Manipal, India, on 300 infertile married males. The tools were "semi-structured questionnaire" compiled by the authors, "ICD-10 Classification of Mental and Behavioural Disorders (Clinical Descriptions and Diagnostic Guidelines) and" Psychological Evaluation Test for infertility. Multiple logistic regression analysis was carried out on data with p-value fixed as 0.05. RESULTS: The presence of stress was reported in 72% of male participants. The predictors of stress were nature and severity of their infertility diagnosis, sperm defects, urological condition and experience of corrective surgery undergone for it. Psychological stress in men was also predicted by present and past history of significant psychiatric morbidity and coping difficulties associated with it. CONCLUSION: The stress is both a common experience and at times a clinical condition associated with deteriorating mental and physical health in men seeking fertility treatments. As a prerequisite, Indian fertility clinics need to treat stress as an identifiable condition and devise ways of addressing it at all stages of assisted conception and reproductive treatments.

Occupational stress and health-related quality of life among public sector bank employees: A cross-sectional study in Mysore, Karnataka, India.

BACKGROUND: Occupational morbidities have been estimated to cause an economic loss up to 10-20% of the gross national product of a country. It is an important cause of occupational morbidity and decreased quality of life (QOL) for the workers. AIM: The aim of the present study is to assess the level of occupational stress and its association with the QOL among the public sector bank employees. MATERIALS AND METHODS: The present study was conducted among employees of public sector banks in Mysore district, Karnataka, India. A cross-sectional study design was used for the study. Job stress was measured by using occupational stress index (OSI) scale questionnaire and health-related QOL was measured using the short form 12 (SF-12) questionnaire. The sample size estimated for the study was 526 and cluster random sampling technique was used. Chi-square test was used to find the association between the study variables and level of stress. Multiple linear regression model was used to find the determinants of health-related QOL among the study subjects. RESULTS: The total number of the study subjects was 546 out of which 57% were males and 43% were females. The proportion of study subjects reporting to be current smokers was 4.2% and almost all study subjects reported occasional alcohol consumption. The mean physical component summary (PCS) score and mental component summary (MCS) using the original United States standardization were 47.90 and 48.30, respectively. The individuals with mild stress scored higher in both PCS and MCS than the individuals who had moderate to severe stress levels. There was significant association of health related quality of life with the age of the respondent,presence of at least one morbidity and level of stress with health-related QOL. CONCLUSION: This study has shown an association of occupational stress with the QOL. There is a need for interventions aimed at mitigating the occupational stress among employees of the banking sector.

Cisplatin, cetuximab, and radiation in locally advanced head and neck squamous cell cancer: a retrospective review.

Efficacy of cisplatin versus cetuximab with radiation in locally advanced head and neck cancer (LAHNC) was evaluated. A total of 96 patients with newly diagnosed LAHNC treated at our institution between 2006 and 2011 with concurrent radiation and cisplatin (group A, n = 45), cetuximab (group B, n = 24), or started with cisplatin but switched to cetuximab because of toxicity (group C, n = 27) were reviewed. Chi-square test, analysis of variance, and log-rank test were used for analysis. The three groups had similar baseline characteristics, except for median age, T stage, albumin levels, hemoglobin levels, performance status, and comorbidities. A complete response (CR) was seen in 77%, 17%, and 67% of patients (P < 0.001), respectively. There was no significant difference in median overall survival (OS) between groups A and C. The median OS for groups A and C was not reached (>65 months), even though it was significantly longer than median OS for group B (11.6 months; P ≤ 0.001). The 2-year OS in groups A and C is significantly higher than that in group B (70% for groups A and C, 22% for group B). There is no significant difference in progression-free survival (PFS) between groups A and C. The median PFS for these groups was not reached (>62 months), and is significantly longer than that for group B (4.3 months; P ≤ 0.001). The 2-year PFS of group A (67%) and group C (76%) was significantly longer than that of group B (20%). Cisplatin with radiation appears to be more efficacious even in suboptimal dosing than cetuximab with radiation in LAHNC but the two groups were not well matched.

Tolosa-hunt syndrome in double-hit lymphoma.

Tolosa-Hunt syndrome (THS) is a painful condition characterized by hemicranial pain, retroorbital pain, loss of vision, oculomotor nerve paralysis, and sensory loss in distribution of ophthalmic and maxillary division of trigeminal nerve. Lymphomas rarely involve cavernous sinus and simulate Tolosa-Hunt syndrome. Here we present a first case of double-hit B cell lymphoma (DHL) relapsing and masquerading as Tolosa-Hunt syndrome. The neurological findings were explained by a lymphomatous infiltration of the right Gasserian ganglion which preceded systemic relapse. As part of this report, the diagnostic criteria for Tolosa-Hunt syndrome and double-hit lymphoma are reviewed and updated treatment recommendations are presented.

Malignant Melanoma with Concurrent BRAF E586K and NRAS Q81K Mutations.

Cutaneous melanoma is an aggressive malignant tumor of melanocytes which accounts for 80% of skin cancer-related deaths. A number of driver mutations have been identified in melanoma, with the mutually exclusive BRAF V600E and NRAS Q61A mutations together accounting for roughly 70% of mutations. Simultaneous BRAF V600E and NRAS Q61A mutations in melanoma are rare, with evidence suggesting that up to 2.9% (2/69) of primary cutaneous melanomas carry both mutations. Here we describe a 42-year-old man with concurrent BRAF E586K and NRAS Q81K driver mutations. To our knowledge, this is the first description of these driver mutations occurring simultaneously in primary cutaneous melanoma.

Current and emerging pharmacotherapies for the treatment of relapsed small cell lung cancer.

Small cell lung cancer (SCLC) is a very aggressive cancer with poor outcome if left untreated, but it is also one of the most chemotherapy responsive cancers. Overall it has a very poor prognosis especially if it is chemotherapy resistant to first line treatment. Second line chemotherapy has not been very beneficial in SCLC as opposed to breast cancer and lymphoma. In the last few years topotecan is the only drug that has been approved by the food and drug administration (FDA) for the second line treatment of SCLC but in Japan another drug, amrubicin is approved. There are many combinations of different chemotherapies available in moderate to high intensity, in this difficult to treat patient to overcome the chemo resistance, but many of these studies are small or phase II trials. In this article we have reviewed single agent and multidrug regimens that were studied in both chemo sensitive and refractory setting, including the most recent clinical trials.