Maintained clinical response of infliximab treatment in ankylosing spondylitis: A 6-year long-term study

ObjectivesTo investigate the efficacy, safety and drug discontinuation in patients with ankylosing spondylitis treated with infliximab, as well as the drug survival over a period of 6 years.MethodsForty patients with ankylosing spondylitis treated with infliximab were included in this open label study. All patients fulfilled the New York revised criteria for ankylosing spondylitis. Infliximab was given intravenously (5 mg/kg/body weight) at weeks 0, 2, 6 and every 8 weeks thereafter for a period of 6 years. Data concerning infliximab efficacy, tolerability, adverse events and drug discontinuation, were recorded. Clinical improvement according to the Bath Ankylosing Spondylitis Disease Activity Index 50% and the Ankylosing Spondylitis Assessment Study Group 20% and 40% were also recorded.ResultsA significant improvement in the Bath Ankylosing Spondylitis Disease Activity Index and Ankylosing Spondylitis Assessment Study Group scores was noted in the first year which sustained through the sixth year of treatment. More specifically, after the sixth year of treatment, Bath Ankylosing Spondylitis Disease Activity Index 50% was achieved by 65% of patients (26/40), Ankylosing Spondylitis Assessment Study Group 20% by 72.5% (29/40) and Ankylosing Spondylitis Assessment Study Group 40% was reached by 70% (28/40) of patients. Clinical improvement was associated with the reduction of acute phase reactants, such as C-reactive protein levels. After the first and the second year of treatment, the survival rate of infliximab reached 95%, after the third year it was 80%, while after the fourth year it was 72.5%, which was maintained throughout the fifth and sixth year of therapy. Five patients were increased the dose of infliximab and three of them had shortened the interval infusion. Overall, 11 patients were withdrawn during the observational period, three because of adverse events, two because of lack of efficacy, while six were lost from follow-up.ConclusionInfliximab was effective, safe and well-tolerated in patients with ankylosing spondylitis. The clinical response was maintained for a period of 6 years, with high infliximab survival rate, reaching the percentage of 72.5%.     

Particle size distribution of airborne microorganisms and pathogens during an Intense African dust event in the eastern Mediterranean

BACKGROUND: The distribution of microorganisms, and especially pathogens, over airborne particles of different sizes has been ignored to a large extent, but it could have significant implications regarding the dispersion of these microorganisms across the planet, thus affecting human health. OBJECTIVES: We examined the microbial quality of the aerosols over the eastern Mediterranean region during an African storm to determine the size distribution of microorganisms in the air. METHODS: We used a five-stage cascade impactor for bioaerosol collection in a coastal city on the eastern Mediterranean Sea during a north African dust storm. Bacterial communities associated with aerosol particles of six different size ranges were characterized following molecular culture-independent methods, regardless of the cell culturability (analysis of 16S rRNA genes). RESULTS: All 16S rDNA clone libraries were diverse, including sequences commonly found in soil and marine ecosystems. Spore-forming bacteria such as Firmicutes dominated large particle sizes (> 3.3 microm), whereas clones affiliated with Actinobacteria (found commonly in soil) and Bacteroidetes (widely distributed in the environment) gradually increased their abundance in aerosol particles of reduced size (< 3.3 microm). A large portion of the clones detected at respiratory particle sizes (< 3.3 microm) were phylogenetic neighbors to human pathogens that have been linked to several diseases. CONCLUSIONS: The presence of aerosolized bacteria in small size particles may have significant implications to human health via intercontinental transportation of pathogens.     

Evaluation of FAK and Src Expression in Human Benign and Malignant Thyroid Lesions

Focal Adhesion Kinase (FAK) and Src have been reported to regulate tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate by immunohistochemistry the clinical significance of FAK and Src expression in 108 patients with benign and malignant thyroid lesions. Total FAK expression provided a distinct discrimination between malignant and benign (p = 0.00001), as well as between papillary carcinoma and hyperplastic nodules thyroid lesions (p = 0.00005), being also associated with follicular cells’ proliferative capacity (p = 0.0003). In malignant thyroid lesions, total FAK expression was associated with tumor size (p = 0.0455), and presence of capsular (p = 0.0102) and lymphatic (p = 0.0173) invasion. Total Src expression was borderline increased in cases of papillary carcinoma compared to hyperplastic nodules (p = 0.0993), being also correlated with tumor size (p = 0.0169). FAK and Src expression was ascribed to a significant extent to the phosphorylated forms of the enzymes, which provided a better discrimination between malignant and benign thyroid lesions. The current data revealed that FAK and to a lesser extent Src expression could be considered of clinical utility in thyroid neoplasia with potential use as therapeutic targets.     

Early non-invasive detection of fetal Y chromosome sequences in maternal plasma using multiplex PCR

ObjectiveClinical indications for fetal sex determination include risk of X-linked disorders, a family history of conditions associated with ambiguous development of the external genitalia, and some fetal ultrasound findings. It is usually performed in the first trimester from fetal material obtained through CVS and is associated with an approximately 1% risk of miscarriage. Ultrasound fetal sex determination is often performed after 11 weeks of gestation. This study aims to validate a reliable method for non-invasive prenatal diagnosis of fetal gender using maternal plasma cell-free fetal DNA (cffDNA) for fetal sex assessment in the first trimester of pregnancy and test its clinical utility in the diagnosis of potentially affected pregnancies in carriers of X-linked disorders.Study designIn the validation study, blood samples from 100 pregnant women at 6–11 weeks of gestation were analysed. In the clinical study, 17 pregnancies at risk of having an affected fetus were tested. 7 ml of maternal blood in EDTA were obtained and cffDNA was extracted using a commercially available kit. DNA was enzymatically digested using a methylation sensitive endonuclease (AciI) to remove maternal unmethylated sequences of the RASSF1A gene. A multiplex PCR was performed for the simultaneous amplification of target sequences of SRY and DYS14 from chromosome Y, along with RASSF1A and ACTB sequences. Amplification of these loci indicates fetal gender, confirms the presence of cffDNA and allows assessment of digestion efficiency.ResultsAfter establishing the appropriate experimental conditions, validation studies were successful in all 100 cases tested with no false negative or false positive results. Y chromosome-specific sequences were detected in 68 samples, and 32 cases were diagnosed as female based on the amplification of RASFF1A sequences only, in the absence of ACTB. In the clinical studies, fetal sex was correctly diagnosed in 16 pregnancies, and one case was reported as inconclusive.ConclusionsFetal sex assessment by detecting Y chromosome sequences in maternal blood can be routinely used from the 6th week of gestation. Reliable fetal sex determination from maternal blood in the 1st trimester of gestation can avoid conventional invasive methods of prenatal diagnosis.     

Variants of the elastin (ELN) gene and susceptibility to intracranial aneurysm: a synthesis of genetic association studies using a genetic model-free approach

Background: The presence of an intracranial aneurysm (IA) is thought to have a genetic origin. The genetic association studies (GAS) that investigated the association between IA and elastin gene (ELN) variants have produced contradictory or inconclusive results. Materials and methods: In order to decrease the uncertainty of estimated genetic risk effects, a meta-analysis of published GAS-related variants in the ELN gene (ELN INT20 1315T > C, EX20 1264G > A, INT23 1501 + 24T > C and INT4 196 + 71G > A) with susceptibility to IA was conducted using a genetic model-free approach. The risk effects were estimated using the generalized odds ratio (ORG) metric. Results: The analysis showed significant association for the INT20 1315T > C variant [ORG = 0.66 (0.45–0.95)], indicating a protection effect. For the variants EX20 1264G > A, INT23 1501 + 24T > C and INT4 196 + 71G > A, no statistically significant association with IAs was found. Conclusion: There is evidence that the ELN variant INT20 1315T > C is implicated in the development of IA; however, the results should be interpreted with caution since the number of published studies is limited.     

A family with Hoyeraal–Hreidarsson syndrome and four variants in two genes of the telomerase core complex

We describe an African American family with Hoyeraal–Hreidarrson syndrome (HHS) in which 2 TERT mutations (causing P530L and A880T amino acid changes) and two in the DKC1 variants (G486R and A487A) were segregating. Both genes are associated with dyskeratosis congenita and HHS. It was important to determine the importance of these mutations in disease pathogenesis to counsel family members. From genetic analysis of family members, telomere length and X‐inactivation studies we concluded that compound heterozygosity for the TERT mutations was the major cause of HHS and the DKC1 G486R variant is a rare African variant unlikely to cause disease. Pediatr Blood Cancer 2013; 60: E4–E6. © 2013 Wiley Periodicals, Inc.     

Severe reactions after the intake of soy drink in birch pollen-allergic children sensitized to Gly m 4

Aim: To study the connection between reaction to soy milk and IgE sensitization to Gly m 4. Methods: Four subjects who experienced unforeseen and severe symptoms after the ingestion of soymilk were studied. Results: All children were birch pollen allergic, had high IgE responses to the PR‐10 proteins from birch and soybean, Bet v 1 and Gly m 4. All reactions took place after the ingestion of soymilk during the peak pollen season. Conclusion: This is the first time soybean‐dependant pollen‐food cross‐reaction has been reported in children experiencing reactions during the birch pollen season. These findings may well be helpful to doctors in identifying individuals at risk of severe reactions upon the ingestion of soymilk, and we foresee an increase in the number of similar cases as soy drinks are promoted for health purposes.     

Programmed death 1 and B and T lymphocyte attenuator immunoreceptors and their association with malignant T‐lymphoproliferative disorders: brief review

Malignant T‐cell lymphoproliferative diseases are relatively rare. T cells are activated through the T‐cell receptor with the aid of costimulating molecules that can be either excitatory or inhibitory. Such pathways have been also implicated in mechanisms of malignant T‐cell lymphoproliferative diseases' persistence and relapse by circumventing immune responses. To date, three major immunoinhibitory molecules have been recognized, namely programmed cell death‐1 (PD‐1), B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte antigen 4 (CTLA‐4). Although CTLA‐4 is considered the ‘gatekeeper’ of immune tolerance, PD‐1 negatively regulates immune responses broadly, whereas BTLA activation has been shown to inhibit CD8+ cancer‐specific T cells. Both PD‐1 and BTLA downregulate proximal T‐cell receptor signalling cascade and are involved in immune evasion of leukaemias and lymphomas, even after allogeneic stem cell transplantation. These immunoregulatory molecules can have seemingly a synergistic effect on weakening the immune response of patients with haematological malignancies, and their manipulation represents a very active field of preclinical as well as clinical interest. Copyright © 2013 John Wiley & Sons, Ltd.