A target site for template-based design of measles virus entry inhibitors

Measles virus (MV) constitutes a principal cause of worldwide mortality, accounting for almost 1 million deaths annually. Although a live-attenuated vaccine protects against MV, vaccination efficiency of young infants is low because of interference by maternal antibodies. Parental concerns about vaccination safety further contribute to waning herd immunity in developed countries, resulting in recent MV outbreaks. The development of novel antivirals that close the vaccination gap in infants and silence viral outbreaks is thus highly desirable. We previously identified a microdomain in the MV fusion protein (F protein) that is structurally conserved in the paramyxovirus family and constitutes a promising target site for rationally designed antivirals. Here we report the template-based development of a small-molecule MV inhibitor, providing proof-of-concept for our approach. This lead compound specifically inhibits fusion and spread of live MV and MV glycoprotein-induced membrane fusion. The inhibitor induces negligible cytotoxicity and does not interfere with receptor binding or F protein biosynthesis or transport but prevents F protein-induced lipid mixing. Mutations in the postulated target site alter viral sensitivity to inhibition. In silico docking of the compound in this microdomain suggests a binding model that is experimentally corroborated by a structure-activity analysis of the compound and the inhibition profile of mutated F proteins. A second-generation compound designed on the basis of the interaction model shows a 200-fold increase in antiviral activity, creating the basis for novel MV therapeutics. This template-based design approach for MV may be applicable to other clinically relevant members of the paramyxovirus family.     

Dry eye in chronic stroke patients with hemiplegia: A cross-sectional study

ABSTRACT

Objective: Dry eye is reported to be associated with several neurological diseases. The aim of this study is to evaluate the patients with hemiplegia after stroke for dry eye and compare their results with a control group.

Materials and methods: Forty-five patients with hemiplegia and 45 individuals as the control group were included in the study. Tear function tests (Schirmer and tear breakup time) and a dry eye questionnaire for dry eye symptoms (ocular surface disease index) were performed and the results of the two groups were compared.

Results: Schirmer test results were significantly lower in the post-stroke hemiplegia group compared to the control group (11.3 ± 8.2 mm and 20.6 ± 11.6 mm, respectively, p < .001). Tear breakup time results were significantly lower in the post-stroke hemiplegia group compared to the control group (7.9 ± 3.1 s and 12.1 ± 4.3 s, respectively, p < .001). Ocular surface disease index scores were not significantly different between hemiplegia and control groups (21.6 ± 20.0 and 19.8 ± 13.9, respectively, p = .635). Schirmer scores lower than 10 mm (60% and 30%, p < .001) and tear breakup time results lower than 10 s (65.6% and 28.9%, p < .001) were also higher in the hemiplegia group compared to control group.

Conclusion: We found lower Schirmer test and tear breakup time results and similar OSDI scores in hemiplegia patients compared to controls. Hemiplegia patients may have dry eye without typical symptoms. This should be taken into consideration in the follow-up and rehabilitation of post-stroke hemiplegia patients.     

To what extent and why are COPD and Willis-Ekbom disease associated?

Aim

Willis-Ekbom disease (RLS/WED) is common in chronic obstructive pulmonary disease (COPD). Patients with RLS/WED have poorer quality of sleep and more fatigue and depressive symptoms. The prevalence of RLS/WED in patients with COPD has been reported to vary between 29.1 and 36.8 %. However, during exacerbation, the prevalence can increase up to 54 %. These rates are higher than those seen in general population. We have not enough knowledge regarding the association between RLS and COPD. In this study, we aimed to determine the frequency of RLS in patients with stable COPD without comorbid conditions. In addition, we also aimed to determine possible related causative factors.

Method

We included 80 COPD patients without comorbid conditions who presented to our outpatient clinic between April 2013 and September 2013 for RLS/WED evaluation. Three cases that have polyneuropathy and one case that refused undergoing electromyography (EMG) examination were excluded from the study. Demographic data, P-A chest X-rays, pulmonary function tests (PFT), biochemical parameters (including hemogram), and dyspnea scales were evaluated for each patient. In addition, the RLS/WED rating scale and Epworth Sleep Scale (ESS) were applied. Further, each patient diagnosed with RLS/WED underwent a detailed neurological examination (performed by a neurologist) and an EMG examination to rule out polyneuropathy.

Results

Out of 76 COPD cases included in our study, 26.3 % (n?=?20) were diagnosed with RLS/WED (mean age 60.4?±?7.5 years, 20 males). The cases with RLS/WED had significantly lower body mass index (BMI) than cases without RLS/WED (p?=?0.009). There were no significant differences between cases with and without RLS/WED with respect to PFT, dyspnea scales, and arterial blood gas values. However, ESS was significantly different (p?=?0.016). There were no significant differences in RLS/WED scores and mean hs-CRP levels between COPD stages (p?=?0.424; p?=?0.518, respectively), while ESS was significantly different (p?=?0.016). ESS was significantly higher in stage B COPD than in stages A and D (p?=?0.005, p?=?0.008, respectively). Based on our model, we found that exacerbations and iron binding capacity (UIBC) were predictive factors for RLS/WED (p?<?0.100)

Conclusion

RLS/WED is a common disease in cases with stable COPD. Despite our hypothesis suggesting that the prevalence of RLS/WED in COPD is related with systemic inflammation, we did not find a significant association between hs-CRP and COPD cases with RLS/WED. However, we did find that UIBC is a predictive factor for the development of RLS/WED. Nonetheless, further studies are needed to understand the relationships between UIBC, low BMI, and the development of RLS/WED in COPD.

     

Laparoscopic vs open complete mesocolic excision with central vascular ligation for right-sided colon cancer

Complete mesocolic excision (CME) is being performed more frequently and has recently become an established oncologic surgical method for right hemicolectomy. Despite its advantages, such as its association with early mobilization, a short hospital stay, early bowel movement, mild postoperative pain, and good cosmesis, CME is technically demanding and carries the risk of severe complications. This study aims to compare the clinical, pathological, and oncological results of open and laparoscopic right hemicolectomy with CME.The data of 76 patients who underwent right hemicolectomy with CME and high vascular ligation were reviewed retrospectively. The patients were divided into 2 groups according to whether the open or laparoscopic technique was used.Thirty-two patients underwent open right hemicolectomy, and 44 patients underwent laparoscopic right hemicolectomy. The 2 groups were similar in age, sex, American Society of Anesthesiologists class, abdominal surgical history, tumor localization, and operation time. No significant differences were found regarding the specimen length, tumor size, harvested lymph nodes, number of metastatic lymph nodes, or tumor grade. According to the Clavien–Dindo classification system, the laparoscopic group had significantly fewer complications than did the open group (11.4% vs 31.2%; P = .04). The open group had a longer postoperative hospital stay than did the laparoscopic hemicolectomy group (9.9 ± 4.7 vs 7.2 ± 3.1 days; P = .002). In addition, the groups were similar with respect to disease-free survival (P = .14) and overall survival (P = .06).The data in this study demonstrated that no differences exist between the open and laparoscopic techniques concerning pathological and oncological results. However, significantly fewer complications and a shorter length of hospital stay were observed in the laparoscopic group than in the open group. Laparoscopic right hemicolectomy with CME and central vascular ligation is a safe and feasible surgical procedure and should be considered the standard technique for right-sided colon cancer.     

Delirium and extrapyramidal symptoms due to a lithium-olanzapine combination therapy: a case report

We report an elderly patient who developed severe delirium and extrapyramidal signs after initiation of lithium-olanzapine combination. On hospital admission, serum levels of lithium were found to be 3.0 mM/L which were far above toxic level. Immediate discontinuation of both drugs resulted in complete resolution of most of the symptoms except for perioral dyskinesia which persisted for three more months. We critically discussed the differential diagnosis of lithium intoxication and assessed confounding factors which induce delirium and extrapyramidal signs related with combination therapy of lithium and olanzapine.     

Stature estimation based on hand length and foot length

This study was carried out to estimate the relationship between hand length, foot length and stature using multiple linear regression analyses based on a sample of male and female adult Turks residing in Adana. Measurements of hand length, foot length and stature were taken from 155 adult Turks (80 male, 75 female) aged 17-23 years. The participants were students of the Medical Faculty of Cukurova University. A multiple linear regression model was fitted to the observed data. Stature was taken as the response or dependent variable, hand length and foot length were taken as explanatory variables or regressors. All possible (simple and multiple) linear regression models for each of males, females and both genders together were tested for the best model. The multiple linear regression model for both genders together was found to be the best model with the highest values for the coefficients of determination R2 = 0.861 and R2adjusted = 0.859, and multiple correlation coefficient R = 0.928.     

Chemokine receptor CXCR4 expression in breast cancer as a potential predictive marker of isolated tumor cells in bone marrow

Interactions between the CXCR4 chemokine receptor in breast cancer cells and the ligand CXCL12/SDF-1α are thought to play an important role in breast cancer metastases. In this pilot study, CXCR4 expression along with other biomarkers including HER2-neu and EGFR, were measured in primary tumor samples of patients with operable breast cancer to test whether any of these biomarkers alone and in combination could indicate breast cancer with high likelihood of metastasizing to bone marrow. Cytokeratin (CK) positive cells in bone marrow were identified by flow-cytometry following enrichment with CK 7/8 antibody-coupled magnetic beads. Primary tumors (n = 18) were stained with specific antibodies for CXCR4, HER2-neu, EGFR, and PCNA using an indirect avidin–biotin horseradish peroxidase method. The majority of the patients had T2/T3 tumors (72%), or lymph node involvement (67%) as pathologic characteristics that were more indicative of high-risk breast cancer. High CXCR4 cytoplasmic expression was found in 7 of 18 patients (39%), whereas 6 of 18 patients (33%) were found to have CK positivity in bone marrow. The median number of CK⁺ cells was 236 (range, 20–847) per 5 × 10⁴ enriched BM cells. The presence of CK⁺ cells in bone marrow was found to be associated with increased expression of CXCR4 alone or in addition to EGFR and/or HER2-neu expression (P = 0.013, P = 0.005, and P = 0.025, respectively) in primary tumors. Furthermore, three patients with high CK positivity (>236 CK⁺ per 5 × 10⁴ enriched bone marrow cells) in bone marrow exclusively expressed high levels of CXCR4 with EGFR/HER2-neu (P = 0.001). Our data suggest that high CXCR4 expression in breast cancer may be a potential marker in predicting isolated tumor cells in bone marrow. CXCR4 coexpression with EGFR/HER2-neu might further predict a particular subset of patients with high CK positivity in bone marrow.