Association of cytokine gene polymorphisms with peripheral neuropathy susceptibility in people living with HIV in Greece.

Relatively little research has been done in recent years to understand what leads to the unceasingly high rates of HIV sensory neuropathy despite successful antiretroviral treatment. In vivo and in vitro studies demonstrate neuronal damage induced by HIV and increasingly identified ART neurotoxicity involving mitochondrial dysfunction and innate immune system activation in peripheral nerves, ultimately all pathways resulting in enhanced pro-inflammatory cytokine secretion. Furthermore, many infectious/autoimmune/malignant diseases are influenced by the production-profile of pro-inflammatory and anti-inflammatory cytokines, due to inter-individual allelic polymorphism within cytokine gene regulatory regions. Associations of cytokine gene polymorphisms are investigated with the aim of identifying potential genetic markers for susceptibility to HIV peripheral neuropathy including ART-dependent toxic neuropathy. One hundred seventy-one people living with HIV in Northern Greece, divided into two sub-groups according to the presence/absence of peripheral neuropathy, were studied over a 5-year period. Diagnosis was based on the Brief Peripheral Neuropathy Screening. Cytokine genotyping was performed by sequence-specific primer-polymerase chain reaction. Present study findings identify age as an important risk factor (p < 0.01) and support the idea that cytokine gene polymorphisms are at least involved in HIV peripheral-neuropathy pathogenesis. Specifically, carriers of IL1a-889/rs1800587 TT genotype and IL4-1098/rs2243250 GG genotype disclosed greater relative risk for developing HIV peripheral neuropathy (OR: 2.9 and 7.7 respectively), while conversely, carriers of IL2+166/rs2069763 TT genotype yielded lower probability (OR: 3.1), all however, with marginal statistical significance. The latter, if confirmed in a larger Greek population cohort, may offer in the future novel genetic markers to identify susceptibility, while it remains significant that further ethnicity-oriented studies continue to be conducted in a similar pursuit.

The STAT signaling profile at the single cell level reveals novel insights in the association of FOXP3+ T regulatory cells with recurrent spontaneous abortions before and after lymphocyte immunotherapy.

Foxp3+ T regulatory cell (Tregs) are central in the pathobiology of recurrent spontaneous abortions (RSA). Signal transducer and activator of transcription (STAT) proteins instruct Treg differentiation and polarization, but the STAT signaling architecture of Tregs in RSA and its modifications by lymphocyte immunotherapy (LIT) are yet unknown. By using single-cell phospho-specific flow cytometry we show that the STAT signaling biosignature of Tregs in women with RSA was characterized by marked downregulation of the IFNα/pSTAT1&5, IL-6/pSTAT1&3 and IL-2/pSTAT5 signaling nodes compared to age-matched fertile females. LIT partially restored all of these signaling axes in Tregs only in women who achieved pregnancy after treatment. Both the pretreatment biosignature of Tregs and its modulations by LIT were associated with therapeutic success. We conclude that STAT signaling pathways in Tregs are actively involved in the pathophysiology of RSA and may serve as a predictive tool for selecting patients who may benefit from LIT.

The Impact of Methylprednisolone Pulses during Relapses of Multiple Sclerosis on the Kinetics of Anti-Interferon-Beta Antibodies.

BACKGROUND/AIMS: We assessed the, hitherto unknown, impact of intravenous methylprednisolone (ivMP) pulses during relapses of multiple sclerosis (MS) on the kinetics of anti-interferon-beta neutralizing antibodies (Nabs) and binding antibodies (Babs). METHODS: Babs (ELISA) and Nabs (antiviral cytopathic effect assay) titers were evaluated before, immediately after and at 1 month following ivMP in 60 MS patients. RESULTS: ivMP reduces Nabs and Babs titers for at least 1 month. Baseline titers determine Nabs and Babs seronegativity at the end of ivMP. Clinical response to ivMP tends to be better in Nabs(+) patients. CONCLUSION: Sampling for Nabs/Babs should be avoided during or shortly after ivMP to avoid transient positive or negative results that may obscure the decision to switch treatment.

Thyrotropin receptor autoantibodies and early miscarriages in patients with Hashimoto thyroiditis: a case-control study.

We have previously hypothesized that early miscarriage in women with Hashimoto thyroiditis might be the result of a cross-reactivity process, in which blocking autoantibodies against thyrotropin receptor (TSHr-Ab) antagonize hCG action on its receptor on the corpus luteum. To test this hypothesis from the clinical perspective, we investigated the presence of TSHr-Ab in Hashimoto thyroiditis patients with apparently unexplained, first-trimester recurrent miscarriages compared to that in Hashimoto thyroiditis patients with documented normal fertility. A total of 86 subjects (43 cases and 43 age-matched controls) were finally included in a case-control study. No difference in the prevalence of TSHr-Ab positivity was detected between cases and controls (Fisher's exact test, p value = 1.00). In patients with recurrent miscarriages, TSHr-Ab concentrations did not predict the number of miscarriages (univariate linear regression, p value = 0.08). These results were robust in sensitivity analyses, including only cases with full investigation or those with three or more miscarriages. We conclude that no role could be advocated for TSHr-Ab in the aetiology of recurrent miscarriages in women with Hashimoto thyroiditis.

Epidemiology of HIV-associated peripheral neuropathy in people living with human immunodeficiency virus infection in Greece.

BACKGROUND: Peripheral neuropathy is among the most common complications among people with HIV with prevalence rates varying widely among studies (10-58%). OBJECTIVE: This study aims to assess the prevalence of HIV-associated peripheral neuropathy among HIV-positive people in Northern Greece monitored during the last 5-year period and investigate possible correlations with antiretroviral therapy, disease staging, and potential risk factors, as there is no prior epidemiological record in Greek patients. METHODS: Four hundred twenty patients were divided into a group with peripheral neuropathy (n = 269), and those without (n = 151). Peripheral neuropathy was assessed with a validated Peripheral Neuropathy Screening tool. Statistical analyses were performed with SPSS, were two-tailed, and p-value was set at 0.05. RESULTS: The incidence of peripheral neuropathy was estimated at 35.9%. Age was found to correlate with higher odds of developing HIV-peripheral neuropathy, rising by 4%/year. Females encountered 77% higher probability to develop peripheral neuropathy. Stage 3 of the disease associated with higher occurrence of peripheral neuropathy (96% as compared to stage-1 patients). Among patients with peripheral neuropathy, the duration of antiretroviral therapy was found to be longer than in those without. CONCLUSIONS: Peripheral neuropathy remains one of the most common complications regardless of the antiretroviral-therapy type, indicating the involvement of other risk factors in its occurrence, such as the stage of the disease, age and gender. Therefore, the treating physician should screen patients as early and frequently as possible upon HIV-diagnosis to prevent the progression of this debilitating condition so that prolonged life-expectancy is accompanied by a good quality of life.

Sleep apnea syndrome, inflammation and oxidative stress in hemodialysis patients.

INTRODUCTION: Sleep apnea syndrome (SAS) is an established cardiovascular risk factor in the general population related to inflammation and oxidative stress and is very common among hemodialysis patients. Cardiovascular disease and its complications is the main cause of death among hemodialysis patients. The aim of the present study was to investigate the role of SAS in the promotion of inflammation and oxidative stress and thus in the augmentation of cardiovascular risk in hemodialysis patients. METHODS: Thirty-seven hemodialysis patients underwent an overnight full polysomnography study. The following morning blood samples were obtained and TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6), MPO (myeloperoxidase), and oxLDL (oxidized low density lipoprotein) were measured. FINDINGS: We investigated the correlation of patients' markers of inflammation and oxidative stress with their sleep parameters (total sleep time, AHI, apnea/hypopnea index; RDI, respiratory disturbance index; DI, desaturation index, mean and minimum SpO2 and percentage of sleep time with SpO2 < 90%). TNF-α correlated positively with BMI (r = 0.510, P < 0.0001) and total sleep time (r = 0.370, P = 0.027). IL-6 correlated positively with age (r = 0.363, P = 0.027), AHI (r = 0.385, P = 0.018), DI (r = 0.336, P = 0.042) and percentage of sleep time with SpO2 < 90% (r = 0.415, P = 0.012) and negatively with mean SpO2 (r = -0.364, P = 0.027). Myeloperoxidase correlated positively with AHI (r = 0.385, P = 0.018), DI (r = 0.380, P = 0.02) and percentage of sleep time with SpO2 < 90% (r = 0.388, P = 0.019). Finally, oxLDL correlated positively with BMI (r = 0.443, P = 0.007), AHI (r = 0.395, P = 0.015), RDI (r = 0.328, P = 0.048) and total sleep time with SpO2 <90% (r = 0.389, P = 0.019). CONCLUSIONS: These results indicate that, in hemodialysis patients, the severity of SAS and nocturnal hypoxia correlated positively with markers of inflammation and oxidative stress.

IL-10 and TGF-beta1 gene polymorphismsin Greek patients with recurrent aphthous stomatitis

Background: Recurrent aphthous stomatitis (RAS) is one of the most frequent inflammatory disorders of theoral mucosa. Cytokines, which play an important role in RAS pathogenesis, participate directly or indirectly innormal, immunological and inflammatory processes and are secreted from cells belonging to innate and adaptiveimmunity as a consequence of microbial and antigenic stimuli. Gene polymorphisms in specific cytokines maypredispose to RAS development. The aim of this study was the investigation and association of IL-10 and TGF-β1gene polymorphisms with RAS.Material and Methods: Study’s cohort consisted of 60 Greek patients diagnosed with RAS, including 40 patientswith minor, 10 patients with major and 10 with herpetiform aphthous ulcers. Forty age- and sex-matched controlsubjects were included in this study. DNA was extracted from whole blood samples of all patients and sequencespecific primers (SSP)-based polymerase chain reaction (PCR) was used for genotyping. Gene polymorphisms forcytokines IL-10 at loci -592 and -819 and for TGF-β1 at codon 10 were detected.Results: Significant differences between patients with minor RAS and healthy controls were recorded for IL-10genotypes distribution at position -592 (p=0.042) and -819 (p=0.045) with predominance of C/A and C/T genotypes in RAS patients, respectively. Also, in patients with minor and herpetiform aphthous ulcerations, heterozygousTGF-β1 genotype C/T at codon 10 was associated with increased risk of RAS (p=0.044 and p=0.020, respectively).Conclusions: These data provide evidence that genetic predisposition for RAS and possibly its specific clinical variants is related with the presence of gene polymorphisms for specific cytokines, including IL-10 and TGF-β1, which,in turn, may vary according to geographic origin and genetic background. (AU)

HLA and asthma phenotypes/endotypes: a review.

Asthma is a complex chronic inflammatory disease of the airways caused by the interaction of genetic susceptibility with environmental influences. Genome-wide association studies (GWAS) represent the most powerful approach for asthma, that have identified several genes (e.g., IL18R1, IL33, SMAD3, ORMDL3, HLA-DQ and IL2RB loci). HLA super-locus is a genomic region in the chromosomal position 6p21. Since no gene can be considered as an asthma gene, able to reflect the complex etiology and the heterogeneity of the disease the terms 'phenotype' and more recently 'endotype' have been used. This review, according to literature availability, focuses on the relationship between human leukocyte antigens (HLA) region specifically the HLA class II genes and different asthma phenotypes/endotypes, such as allergic asthma/Th2 associated, occupational and aspirin-sensitive asthma. The most common HLA haplotypes in the different asthma phenotypes are HLA-DRB1in allergic asthma, HLA-DQB1in occupational asthma and HLA-DPB1 in aspirin-sensitive asthma. However, it is difficult to study the role of class II genes in vivo because of the heterogeneity of human population, the complexity of MHC, and the strong linkage disequilibrium among different class II genes. Despite the variation and the inconsistency of the HLA haplotypes and alleles in different types of asthma, the association between HLA class II genes and asthma has been demonstrated in the majority of studies.

Peripheral corneal ulceration associated with rheumatoid arthritis.

PATIENT: Female, 60 FINAL DIAGNOSIS: Corneal ulceration Symptoms: Blurred vision Medication: Abatacept Clinical Procedure: - Specialty: Ophthalmology. OBJECTIVE: Management of emergency care. BACKGROUND: To report a case of a patient with rheumatoid arthritis (RA) and associated peripheral corneal ulceration. CASE REPORT: A 60-year-old woman with RA diagnosed 15 years ago, under immunosuppressive therapy (IV abatacept 250 mg/month), demonstrated blurring of vision in her RE (right eye). Visual acuity was 6/10 in the RE and 10/10 in the LE. Slit lamp examination revealed a paracentral superior corneal melt in the RE. Anterior chamber reaction was 2+. Laboratory investigations revealed positive anti-Ro and anti-La, anti-Extractable Nuclear Antigens (anti-ENA, ELISA), while anti-Sm, anti-Rnp, anti-Jo1 and anti-Scl70 were found negative. IgG and IgA serum immunoglobulins were found elevated, but IgE and IgM were within normal levels. Further evaluation for the underlying disease revealed highly elevated rheumatoid factor and C-reactive protein. The patient, who had been receiving anti-TNF during the last 6 months, underwent treatment with topical tobramycin and lubricants and oral prednisone 60 mg/day with tapering doses, to which methotrexate p.os. 15 mg/week was added. The condition improved within a few days after the initiation of prednisone treatment. Re-epithelization occurred 1 week after the onset of the immunosuppressive treatment. Only punctate fluorescein dye uptake was detected in the margins of the lesion. CONCLUSIONS: The effective control of the underlying disease and early diagnosis of the dry eye syndrome in RA patients may prevent serious corneal complications such as corneal ulceration. The initiation of treatment with steroids and immunosuppresants was found to halt the progression of keratolysis, and assisted re-epithelization.

Genotype and allele frequencies of heme oxygenase-1 promoter region in a Greek cohort.

BACKGROUND: Heme oxygenase-1 (HO-1) is an enzyme, which catabolizes heme into carbon monoxide, biliverdin and free iron. The induction of this enzyme is an important cytoprotective mechanism, which occurs as an adaptive and beneficial response to a wide variety of oxidant stimuli. HO-1 inducibility is mainly modulated by a (GT)(n) polymorphism in the promoter region, and has been shown that short (S) repeats are associated with greater up-regulation of HO-1, compared with long (L) repeats. METHODS: In the present study, 250 healthy Greek individuals have been screened in order to estimate the frequencies of (GT)(n) alleles in the HO-1 gene. RESULTS: Nineteen different alleles, ranging from 17 to 39 repeats, with (GT)(23) and (GT)(30) being the most common ones, were identified. CONCLUSION: The possible role of this polymorphism in disease states is discussed.

Are educators at high risk of sub-fertility? A multicenter study.

PROBLEM: A high percentage of women schoolteachers having fertility problems were observed by three independent teams. METHOD: Expected percentage of educators was calculated in 4650 sub-fertile women and 2,062,891 women at reproductive age. To explore the possibility that schoolteachers' contact with childhood viral infections results in alterations of peripheral blood natural killer (NK) cells, a multiple linear regression analysis for profession, age, difficulty to conceive, number of abortions/implantation failures (predictor variables) was performed in childless educators (210) and housewives (184). RESULTS: The difference between observed and expected percentage of sub-fertile schoolteachers was statistically significant (17.6% vs 6.86%, P < 0.0001). The mean percentage of PB NK cells was slightly higher in educators compared to housewives (12.48% vs 11.56%, P = 0.10), and the multiple linear regression analysis revealed that the profession (schoolteacher or not) was the only predictive variable for higher NK% values (P = 0.044). CONCLUSION: Teachers' sub-fertility appears as an 'occupational disease'. Τhe possibility that results from their exposure to childhood viral infections has to be further explored.

HLA Class II alleles and the presence of circulating Epstein-Barr virus DNA in Greek patients with nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Nasopharyngeal carcinoma (NPC) represents a seldom malignancy in most developed countries. Nevertheless, NPC receives an endemic form in concrete racial entities. The aims of this study were to detect the presence of Epstein-Barr virus DNA (EBV-DNA) in peripheral blood of NPC patients, to molecularly define human leukocyte antigens (HLA) DRB1*, DQA1* and DQB1* allele frequencies, and, finally, to determine whether the genetic predisposition of an individual to NPC depends on the liability to EBV infection. PATIENTS AND METHODS: A total of 101 patients of Hellenic origin and nationality, with histologically proven NPC, participated in this study. EBV-DNA detection was also applied in 66 patients with EBV-related malignancies (Hodgkin's [HL] and non-Hodgkin's lymphoma [NHL]) and infectious mononucleosis (IM), as well as in 80 healthy EBV-seropositive controls. RESULTS: 81% of the NPC patients, 77.8% with HL, 72.2% with NHL, and 66.7% with IM were EBV-DNA positive, whereas the EBV genome was detected only in 15% of the healthy controls. These differences were statistically significant in all cases. Analysis of HLA class II antigens showed decreased frequency of the DRB1*07 (p = 0.003), DQA1*0103 (p = 0.002), and DQA1*0201 (p = 0.003) alleles among NPC patients. A significant association between the HLA-DR/DQ alleles and the presence of EBV-DNA in peripheral whole blood was not established. CONCLUSION: Circulating EBV-DNA and specific HLA class II alleles may predispose to or protect from NPC. However, the results of this study suggest that the genetic predisposition of an individual to NPC is independent of the liability to EBV infection.