The Genetic Landscape of Systemic Rheumatic Diseases: A Comprehensive Multigene-Panel Study Identifying Key Gene Polymorphisms.

Systemic rheumatic diseases, including conditions such as rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, and systemic lupus erythematosus, represent a complex array of autoimmune disorders characterized by chronic inflammation and diverse clinical manifestations. This study focuses on unraveling the genetic underpinnings of these diseases by examining polymorphisms in key genes related to their pathology. Utilizing a comprehensive genetic analysis, we have documented the involvement of these genetic variations in the pathogenesis of rheumatic diseases. Our study has identified several key polymorphisms with notable implications in rheumatic diseases. Polymorphism at chr11_112020916 within the IL-18 gene was prevalent across various conditions with a potential protective effect. Concurrently, the same IL18R1 gene polymorphism located at chr2_103010912, coding for the IL-18 receptor, was observed in most rheumatic conditions, reinforcing its potential protective role. Additionally, a further polymorphism in IL18R1 at chr2_103013408 seems to have a protective influence against the rheumatic diseases under investigation. In the context of emerging genes involved in rheumatic diseases, like PARK2, a significant polymorphism at chr6_161990516 was consistently identified across different conditions, exhibiting protective characteristics in these pathological contexts. The findings underscore the complexity of the genetic landscape in rheumatic autoimmune disorders and pave the way for a deeper understanding of their etiology and the possible development of more targeted and effective therapeutic strategies.

Latent Potential of Multifunctional Selenium Nanoparticles in Neurological Diseases and Altered Gut Microbiota.

Neurological diseases remain a major concern due to the high world mortality rate and the absence of appropriate therapies to cross the blood-brain barrier (BBB). Therefore, the major focus is on the development of such strategies that not only enhance the efficacy of drugs but also increase their permeability in the BBB. Currently, nano-scale materials seem to be an appropriate approach to treating neurological diseases based on their drug-loading capacity, reduced toxicity, targeted delivery, and enhanced therapeutic effect. Selenium (Se) is an essential micronutrient and has been of remarkable interest owing to its essential role in the physiological activity of the nervous system, i.e., signal transmission, memory, coordination, and locomotor activity. A deficiency of Se leads to various neurological diseases such as Parkinson's disease, epilepsy, and Alzheimer's disease. Therefore, owing to the neuroprotective role of Se (selenium) nanoparticles (SeNPs) are of particular interest to treat neurological diseases. To date, many studies investigate the role of altered microbiota with neurological diseases; thus, the current review focused not only on the recent advancement in the field of nanotechnology, considering SeNPs to cure neurological diseases, but also on investigating the potential role of SeNPs in altered microbiota.

Antibodies against HSV-1 and Curli Show the Highest Correlation in Parkinson's Disease Patients in Comparison to Healthy Controls.

Parkinson's disease (PD) is a neurodegenerative disorder involving the accumulation of alpha-synuclein (α-syn)/Lewy bodies in the brain and -enteric nervous system. The etiology of the disease is not well understood, but bacterial and viral infections may contribute to the pathogenesis of PD. It has been suggested that the gastrointestinal (GI) complications observed in PD patients may arise from bacterial dysbiosis, leading to curli/α-syn deposits in the enteric nervous system. Enteric bacteria secrete curli, a functional amyloid peptide involved in adhesion to surfaces, cell invasion, and biofilm formation. However, these bacterial amyloids can initiate additional α-syn deposits through immune system activation and cross-seeding. In this study, we investigate the humoral response against α-syn, curli peptides, and various bacterial and viral immunogen peptides in PD patients, and compare them with those in healthy controls (HCs). Polyclonal IgG antibodies (Abs) were detected against peptides derived from α-syn (α-syn100−114), curli (Curli133−141), Porphyromonas gingivalis Pg (RgpA800−812, Kpg328−339), Aggregatibacter actinomycetemcomitans (LtxA1429−445, LtxA264−80), Mycobacterium avium subsp. paratuberculosis (MAP3865c125−133, MAP1,4-a-gbp157−173 and MAP_402718−32), Epstein−Barr virus (EBNA1400−413, BOLF1305−320), and Herpes Simplex virus 1 (UI4222−36), as investigated by indirect ELISA of 51 serum samples from PD and 58 sex and age-matched HCs. Significant differences in OD (optical density) values and Abs positivity between PD patients and HCs were observed for Kpg (82.3% vs. 10.3%), followed by RgpA (60.7% vs. 24.1%), curli (51% vs. 22.4%), and UI42 (43.1% vs. 25.8%) in PD, compared to HCs sera (p < 0.001). No significant difference was found in the ODs obtained from other tested peptides in PD patients, compared to HCs. Significant positive correlations between OD values obtained by ELISA were observed for UI42 and curli (r = 0.811, p < 0.0001), Kpg and RgpA (r = 0.659, p < 0.0001), followed by LtxA1 and LtxA2 (r = 0.653, p < 0.0001). The correlation between the HY scale (Hoehn and Yahr Scale) and LtxA1 (r = 0.306, p < 0.028) and HY and Kpg (r = 0.290, p < 0.038) were significantly positive. This study reports a significantly increased humoral response against curli, Pg, and HSV-1 in PD patients, implying that they could be important factors in the pathogenesis of the disease. In addition, the high positive correlation between UI42 and curli may suggest the involvement of HSV-1 in GI dysbiosis. Therefore, the role of each individual pathogen and curli in PD needs to be further investigated.

HERV-K Envelope Protein Induces Long-Lasting Production of Autoantibodies in T1DM Patients at Onset in Comparison to ZNT8 Autoantibodies.

Human endogenous retroviruses (HERVs) have been thought of as silent passengers within our genomes, but their reactivation has been linked with several autoimmune diseases, including type 1 diabetes (T1DM). In order to evaluate the potential role of HERVs, in addition to the recognized role of HERV-W, we focused on the debated role of the HERV-K family in T1DM. Therefore, we performed a serological evaluation of IgG antibodies against HERV-K Env epitope (HERV-K Env19−37) in comparison to an important ß-cellular autoimmunity biomarker, ZnT8, from plasma samples of Sardinian children at the onset of T1DM, different T1DM groups (1−5 and 6−12 years since diagnosis), and healthy controls (HCs), by an indirect enzyme-linked immunosorbent assay (ELISA). A significant antibody response was observed against HERV-K Env19−37 (p < 0.0001) in T1DM patients compared to HCs, and significantly higher IgG responses were detected in the group at the onset compared to the other T1DM groups and HCs. Unlike the trend of the ß-cellular autoimmunity autoantibodies, for HERV-K Env antibodies we observed positive values that persist over time up to 5 years since the onset of T1DM. Our results add new evidence about the presence of antibodies against HERV-K in T1DM, but further investigations are necessary to relate these results with the established role of HERVs, considering the contrasting results for HERV-K.

Oral Microbiota as Novel Biomarkers for Colorectal Cancer Screening.

Alterations of the gut microbiome in cases of colorectal cancer (CRC) hint at the involvement of host-microbe interactions in the onset and progression of CRC and also, possibly, provide novel ways to detect and prevent CRC early. The aim of the present study was to evaluate whether the oral and fecal microbiomes of an individual can be suitable for CRC screening. Oral and fecal samples (n = 80) were gathered in Taleghani hospital, affiliated with Shahid Beheshti University of Medical Sciences, Tehran-Iran, from CRC stage 0 and I patients and healthy controls (HCs), who were screened for the first time. Microbial metagenomics assays were performed for studying microbiota profiles in all oral and fecal samples gathered. An abundance of top bacterial genera from both types of specimens (fecal and saliva samples) revealed a distinction between CRC patients and HCs. In saliva samples, the α diversity index was different between the microbiome of HCs and CRC patients, while ß diversity showed a densely clustered microbiome in the HCs but a more dispersed pattern in CRC cases. The α and ß diversity of fecal microbiota between HCs and CRC patients showed no statistically significant differences. Bifidobacterium was identified as a potential bacterial biomarker in CRC saliva samples, while Fusobacterium, Dialister, Catonella, Tennerella, Eubacterium-brachy-group, and Fretibacterium were ideal to distinguish HCs from CRC patients. One of the reasons for the heterogeneity of CRC may be the gastrointestinal (GI) tract microbiota, which can also cause systematic resistance to CRC. Moreover, an evaluation of saliva microbiota might offer a suitable screening test for the early detection of this malignancy, providing more accurate results than its fecal counterpart.

Humoral Response to Microbial Biomarkers in Rheumatoid Arthritis Patients.

BACKGROUND/OBJECTIVE: Chronic humoral immune response against multiple microbial antigens may play a crucial role in the etiopathogenesis of rheumatoid arthritis (RA). We aimed to assess the prevalence and magnitude of antibody response against various bacterial and viral immunogen peptides in the sera of RA patients compared with the general population. METHODS: Polyclonal IgG antibodies (Abs) specific for peptides derived from Porphyromonas gingivalis (RgpA, Kpg), Aggregatibacter actinomycetemcomitans (LtxA1, LtxA2), Mycobacterium avium subsp. paratuberculosis (MAP4027), Epstein-Barr virus (EBNA1, EBVBOLF), and human endogenous retrovirus (HERV-W env-su) were detected by ELISA in serum samples from 148 consecutive RA patients and 148 sex and age-matched healthy controls (HCs). In addition, the presence of a relationship between the positivity and the titer of antibodies and RA descriptors was explored by bivariate correlation analysis. RESULTS: RA patients exhibit a higher prevalence of humoral immune response against all tested peptides compared to HCs with a statically significant difference for MAP4027 (30.4% vs. 10.1%), BOLF (25.7% vs. 8.1%), RgpA (24.3% vs. 9.4%), HERV W-env (20.3% vs. 9.4%), and EBNA1 (18.9% vs. 9.4%) peptides. Fifty-three (35.8%) out of 148 RA serum and 93 (62.8%) out of 148 HCs were negative for all pathogen-derived peptides. There was a significant correlation between OD values obtained by ELISA test against all peptides (p < 0.0001). We also found an increased titer and prevalence of Abs against LtxA1 and LtxA2 in seropositive vs. seronegative RF (p = 0.019, p = 0.018). CONCLUSION: This study demonstrates a significantly increased humoral response against multiple pathogens in patients with RA and implies that they could be an important factor in the pathogenesis of the disease. Therefore, the role of each individual pathogen in RA needs to be further investigated.

Antibiotic resistance pattern of Bacteroides fragilis isolated from clinical and colorectal specimens.

BACKGROUND: Bacteroides fragilis is a part of the normal gastrointestinal flora, but it is also the most common anaerobic bacteria causing the infection. It is highly resistant to antibiotics and contains abundant antibiotic resistance mechanisms. METHODS: The antibiotic resistance pattern of 78 isolates of B. fragilis (22 strains from clinical samples and 56 strains from the colorectal tissue) was investigated using agar dilution method. The gene encoding Bacteroides fargilis toxin bft, and antibiotic resistance genes were targeted by PCR assay. RESULTS: The highest rate of resistance was observed for penicillin G (100%) followed by tetracycline (74.4%), clindamycin (41%) and cefoxitin (38.5%). Only a single isolate showed resistance to imipenem which contained cfiA and IS1186 genes. All isolates were susceptible to metronidazole. Accordingly, tetQ (87.2%), cepA (73.1%) and ermF (64.1%) were the most abundant antibiotic-resistant genes identified in this study. MIC values for penicillin, cefoxitin and clindamycin were significantly different among isolates with the cepA, cfxA and ermF in compare with those lacking such genes. In addition, 22.7 and 17.8% of clinical and GIT isolates had the bft gene, respectively. CONCLUSIONS: The finding of this study shows that metronidazole is highly in vitro active agent against all of B. fragilis isolates and remain the first-line antimicrobial for empirical therapy.

Role of Infections in the Pathogenesis of Rheumatoid Arthritis: Focus on Mycobacteria.

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by chronic erosive polyarthritis. A complex interaction between a favorable genetic background, and the presence of a specific immune response against a broad-spectrum of environmental factors seems to play a role in determining susceptibility to RA. Among different pathogens, mycobacteria (including Mycobacterium avium subspecies paratuberculosis, MAP), and Epstein-Barr virus (EBV), have extensively been proposed to promote specific cellular and humoral response in susceptible individuals, by activating pathways linked to RA development. In this review, we discuss the available experimental and clinical evidence on the interplay between mycobacterial and EBV infections, and the development of the immune dysregulation in RA.

Toxigenic and non-toxigenic patterns I, II and III and biofilm-forming ability in Bacteroides fragilis strains isolated from patients diagnosed with colorectal cancer.

BACKGROUND: Enterotoxigenic Bacteroides fragilis (ETBF) associated with the initiation and progression of colorectal cancer (CRC) has been alarmingly reported all over the world. In this study, simultaneous investigation of toxigenic and non-toxigenic patterns I, II and III and biofilm formation ability of Bacteroides fragilis isolated from patients with colorectal cancer was performed. METHODS: Thirty-one patients diagnosed with CRC and thirty-one control subjects were recruited in this study. Specimens were cultured on BBE and BBA culture media. Classical phenotypic identification tests and PCR was performed to verify Bacteroides fragilis presence. Also, biofilm-forming ability and expression of bft gene were assessed under biofilm and planktonic forms. RESULTS: A total of 68 B.fragilis was isolated from all colorectal tissue, of which 13 isolates (19.1%) (11 isolates from CRC and 2 from normal tissue) were positive for bft gene. The abundance patterns of I, II and III were as follow in descending order; pattern I > pattern III > pattern II in CRC subjects and pattern II > pattern III > pattern I in normal tissues. Also, pattern I showed higher biofilm formation ability compared to other patterns. Toxin expression was significantly reduced in biofilm form comparing with planktonic form. CONCLUSIONS: Based on our findings, there was a difference between the abundance of patterns I, II, and III and biofilm formation in isolates obtained from CRC and normal tissues. Biofilm formation ability and toxin encoding gene (bft) are two main virulence factors in B. fragilis pathogenicity which require more investigation to treat B. fragilis infections effectively.

Multiple Myeloma or Brucellosis: A Case Report.

BACKGROUND: Brucellosis, a major health problem in developing countries, is a multisystem infection with a broad spectrum of clinical manifestations. Hematological complications, ranging from an intravascular coagulopathy to mild homeostasis disorders (such as gammopathy), have been reported in brucella infection. These signs and symptoms may lead to misdiagnosis of brucellosis with other hematological diseases. CASE: A 65-year-old male whose occupation was shepherding was referred to our hospital as a known case of multiple myeloma with continuous fever, muscle weakness, and night sweating after taking 2 courses of chemotherapy. The laboratory diagnosis of multiple myeloma had been based on the observation of a high percent of plasma cells in the bone marrow aspiration. At follow- up, the result of patient's fever workup, with 2 sets of blood cultures, was positive for Brucella melitensis. Isolated brucella was confirmed as B. melitensis by 16S rRNA sequencing. Brucellosis serologic test was performed by agglutination test and positive results were obtained. The patient was discharged with the cessation of fever and general improvement after the end of the parental treatment phase of brucella bacteremia. CONCLUSIONS: Brucella infection may cause a severe disease, mimicking a primary hematological disease, which could complicate the correct diagnosis. In brucellosis cases, due to the wide range of symptoms, in addition to cultivation and serological methods, molecular methods should also be used to prevent inappropriate diagnosis and additional costs.

Detection of Nocardia, Streptomyces and Rhodococcus from bronchoalveolar lavage specimens of patients with HIV by Multiplex PCR Assay.

BACKGROUND: Nocardia, Streptomyces and Rhodococcus are life threatening opportunistic pathogens under immunodeficiency conditions, particularly among patients infected with HIV. Rapid and accurate detection of these infections can improve immune health quality, patient management and appropriate treatment. The aim of this study was to design a novel multiplex-PCR assay for rapid diagnosis of these three organisms directly from bronchoalveolar lavage (BAL) specimens of patients infected with HIV. METHODS: The genus specific primers were designed for direct-detection of Nocardia, Streptomyces and Rhodococcus in a single tube multiplex PCR. This PCR specifically amplified the target genes from pure cultures. It subsequently was applied on BAL specimens of 29 HIV positive patients that had previously been culture negative for actinomycete bacteria, of which Nocardia, Streptomyces and Rhodococcus are members. RESULTS: Of 29 respiratory clinical specimens, there were positive for Nocardia spp. and one was positive for Streptomyces spp using the multiplex PCR assay. The sequencing of the PCR products identified the species as Nocardia cyriacigeorgica (n=2), Nocardia farcinica and Streptomyces albus. CONCLUSION: This novel multiplex PCR assay yielded reliable results for accurate identification of Nocardia, Streptomyces and Rhodococcus from BAL while the results of bacterial culture were negative.

Enterotoxigenic Bacteroides fragilis: A Possible Etiological Candidate for Bacterially-Induced Colorectal Precancerous and Cancerous Lesions.

Enterotoxigenic Bacteroides fragilis (ETBF) produces Bacteroides fragilis toxin (BFT), which is associated with acute diarrheal, inflammatory bowel disease, and colorectal cancer (CRC). In experimental models, ETBF has been shown to contribute to colon carcinogenesis. The present study was conducted to investigate mucosal colonization of ETBF in the colon to find a possible association between the presence of ETBF and precancerous and cancerous lesions. The mucosal biopsies of involved sites were obtained from 68 patients with precancerous and cancerous lesions and 52 healthy controls (HC). The samples were cultured on Bacteroides Bile Esculin agar. Then, specific primers were designed to detect B. fragilis and bft gene using quantitative real-time PCR, and the possible links of ETBF with clinicopathological characteristics was evaluated. Also real-time PCR was performed to detect the bft gene subtypes. Bacteroides fragilis was detected in 51% of the patients and 48% of HCs cultures. The 16SrRNA gene was found to be present in 63 and 81% of the patients and HCs' samples, respectively. Moreover, the bft gene was detected in 47 and 3.8% of the patients and HCs, respectively. Also, B. fragilis was significantly more abundant in the patients' samples compared to those of HCs. In the patient group, higher odds ratio (OR) of ETBF was significantly associated with serrated lesions and adenoma with low-grade dysplasia. The bft1 gene was the most prevalent subtype of bft gene, followed by the bft2 gene. This was the first study in Iran to demonstrate increased positivity of ETBF in patients with precancerous and cancerous lesions. In this study, the bft gene was found to be associated with CRC, especially in the patients with precancerous lesions and initial carcinogenic lesions. Moreover, the results suggest that mucosal BFT exposure is common and could be a risk factor and a screening marker for developing CRC.

Evidence of Interruption of the comM Gene in a Large Series of Clinical Isolates of Multidrug-Resistant Acinetobacter baumannii.

Recent studies have recognized the ATPase-encoding comM gene as a hot spot for the integration of Acinetobacter baumannii resistance islands (RIs). Despite the circulation of high numbers of multidrug-resistant A. baumannii (MDR-AB) isolates in Middle East countries, no information is available about the interruption of comM and subsequent transposition into comM in isolates belonging to the global clones (GC) GC1, GC2, or GC3. In this study 401 A. baumannii isolates from hospitals in Tehran, Iran, were included. The resistance profile was determined by disc diffusion against 22 antibiotics. PCR was used to assess the GC type, presence of the comM gene, and the boundary junctions (J1 and J2) of RIs. Most of the MDR-AB isolates (384 of 388; 98%) and more than half of the susceptible A. baumannii isolates (9 of 13; 69%) had interrupted comM gene-carrying integrative elements. Among the isolates tested, 57 belonged to GC1, 86 to GC2, and 8 to GC3. A set of 250 isolates showed distinct patterns of allele-specific PCR for ompA, csuE, and blaOXA-51-like genes. All but 2 of the GC1 isolates and 2 of the GC2 isolates contained interrupted comM genes. Four A. baumannii isolates harbored intact comM, but were multiply resistant to antibiotics. This study demonstrated that the comM gene is targeted by transposons in Iranian MDR-AB isolates belonging to different GCs. The data also showed that the carriage of interrupted comM is not exclusive to MDR isolates of A. baumannii.