Efficacy and safety of a novel pegylated interferon alpha-2a in Egyptian patients with genotype 4 chronic hepatitis C

BACKGROUND:

Hepatitis C virus (HCV) genotype 4 is a common infection in Egypt and is the leading cause of liver disease.

OBJECTIVE:

To study the efficacy and safety of a novel 20 kD pegylated interferon alpha-2a derived from Hansenula polymorpha in combination with ribavirin for the treatment of Egyptian patients with genotype 4 chronic hepatitis C (CHC).

METHODS:

One hundred seven patients with genotype 4 CHC were involved in the present study. Liver biopsy was performed in all patients. All patients received a fixed weekly dose of 160 μg of a novel pegylated interferon in combination with ribavirin in standard and adjusted doses. Serum HCV RNA levels were assessed by a real-time sensitive polymerase chain reaction assay at four, 12, 48 and 72 weeks after the start of therapy. Patients demonstrating an early virological response (EVR) completed a 48-week course of treatment.

RESULTS:

The overall sustained virological response (SVR) was 60.7%. The SVR in patients with a rapid virological response was significantly higher (91.7%) than in patients with complete EVR (67.74%) (P=0.033) and partial EVR (56.14%) (P=0.003). SVR was also significantly higher in patients with a low degree of liver fibrosis according to Metavir score (F1 and F2) (67.57%) compared with those with a high degree of liver fibrosis (F3 and F4) (45.45%) (P=0.017). The baseline viral load had no impact on SVR in the present series nor were any serious adverse events reported.

CONCLUSION:

The novel pegylated interferon alpha-2a assessed in the present study was effective for the treatment of patients with genotype 4 CHC, and was safe and well tolerated.     

Upregulation of interferon-alpha and RANTES in the cervix of HIV-1-seronegative women with high-risk behavior

OBJECTIVE: The expression of innate immune molecules associated with potential blocking activity of HIV-1 propagation was analyzed in the cervical tissue of a group of African HIV-1 IgG-negative commercial sex workers (CSWs) with an HIV-1-encountering risk behavior. METHODS: Cervical biopsies from the superior portion of the ectocervix were assessed for innate immune molecules and evaluated in situ by computerized image analysis at the single-cell level. RESULTS: A higher expression of interferon-alpha (IFNalpha) and RANTES was detected in CSWs and HIV-1-infected individuals as compared to low-risk HIV-1-uninfected controls (Neg Ctrls). Most (>90%) of RANTES-expressing cells were CD8 cells as determined by confocal microscopy. In contrast, the expression of leukemia inhibitory factor (LIF) and secretory leukocyte protease inhibitor (SLPI) was comparable between the groups. The expression of beta-defensin 2 was highest in HIV-1-infected individuals. CONCLUSIONS: Induction of IFNalpha and RANTES expression in cervical mucosa may contribute to protection of sexual HIV-1 transmission in subjects with a higher risk behavior.     

Abundant Expression of HIV Target Cells and C-Type Lectin Receptors in the Foreskin Tissue of Young Kenyan Men

A biological explanation for the reduction in HIV-1 (HIV) acquisition after male circumcision may be that removal of the foreskin reduces the number of target cells for HIV. The expression of potential HIV target cells and C-type lectin receptors in foreskin tissue of men at risk of HIV infection were thus analyzed. Thirty-three foreskin tissue samples, stratified by Herpes simplex virus type 2 status, were obtained from a randomized, controlled trial conducted in Kenya. The samples were analyzed by confocal in situ imaging microscopy and mRNA quantification by quantitative RT-qPCR. The presence and location of T cells (CD3⁺CD4⁺), Langerhans cells (CD1a⁺Langerin/CD207⁺), macrophages (CD68⁺ or CD14⁺), and submucosal dendritic cells (CD123⁺BDCA-2⁺ or CD11c⁺DC-SIGN⁺) were defined. C-type lectin receptor expressing cells were detected in both the epithelium and submucosa, and distinct lymphoid aggregates densely populated with CD3⁺CD4⁺ T cells were identified in the submucosa. Although the presence of lymphoid aggregates and mRNA expression of selected markers varied between study subjects, Herpes simplex virus type 2 serostatus was not the major determinant for the detected differences. The detection of abundant and superficially present potential HIV target cells and submucosal lymphoid aggregates in foreskin mucosa from a highly relevant HIV risk group demonstrate a possible anatomical explanation that may contribute to the protective effect of male circumcision on HIV transmission.Randomized, controlled trials in Africa have shown that male circumcision reduces HIV-1 (HIV) acquisition in men by approximately 60%.^1,2,3 Circumcision is now recommended as a component of HIV prevention strategies, particularly in countries with endemic, generalized HIV epidemics. One of the biological explanations for the reduction in HIV acquisition could be that removal of the foreskin reduces the number of target cells for HIV.In uncircumcised men, the foreskin is retracted over the shaft during intercourse, exposing the inner mucosa to genital secretions of the partner. Genital secretions contain HIV particles, and higher viral loads of HIV in blood and semen correlate with increased risk of transmission to the sexual partner.⁴ After intercourse, the subpreputial penile moistness in uncircumcised men may also increase the risk of HIV acquisition,⁵ whereas the relative dryness in the absence of this pocket-formed area in circumcised men is a less optimal environment for HIV viability. Furthermore, the foreskin tissue is vulnerable to trauma during intercourse, providing a portal for virus entry. Inflammatory conditions of the foreskin, including sexually transmitted diseases (STDs), may also act as cofactors for HIV transmission³ (reviewed in Gray et al⁶). Even though the unkeratinized urethral meatus may still be vulnerable to HIV after circumcision, this surface area is much smaller relative to the foreskin.Many subpopulations of mononuclear phagocytes have been defined in skin and mucosal tissue based on surface markers.⁷ Among these, dendritic cells (DCs) and C-type lectin receptor (CLR) expressing CD68⁺ macrophages are likely initial target cells for HIV in the genital tract mucosa, in addition to CD4⁺ T lymphocytes.^8,9,10,11 Foreskin mucosa has indeed a high density of such cells under the lightly keratinized surface.¹² Langerhans cells (LCs) are characterized based on the expression of Langerin/CD207 (Langerin), an endocytic CLR that localizes to and forms Birbeck granules. These cells also express CD1a, a HLA-class I-like molecule that presents glycolipids.¹³ In the stratified squamous epithelium of skin and genital mucosa, the LCs overlie interstitial or submucosal DCs. So-called myeloid or conventional DCs in many tissues are often identified on the basis of high expression of HLA-DR antigen-presenting molecules and the CD11c integrin. Dermal or submucosal DCs also express pattern recognition receptors such as DC-SIGN and mannose receptor (MR). HIV has been found to bind to the CLRs Langerin, DC-SIGN, and MR, in addition to the classical HIV receptors CD4 and CCR5, which can be expressed by the same cells.Previous studies have defined target cell populations in foreskin tissue of relevance for HIV transmission.^{12,14,15,16,17,18,19} To improve the biological understanding of the decreased HIV acquisition rates after male circumcision, we have here extended previous studies with a more detailed phenotypic characterization of both potential HIV target cells as well as CLRs in foreskin tissue. We selected a highly relevant study group by obtaining cryopreserved tissue samples representing young men of high risk for HIV infection participating in the Kenyan circumcision clinical trial.² Presence of STDs was carefully controlled for because the distribution and expression of phenotypic markers of mucosal cell populations is highly affected by inflammatory activity in the tissue. This also allowed a comparison between immune markers in asymptomatic Herpes simplex virus type 2 (HSV-2) seropositive versus seronegative men.     

Optimization of a self antigen for presentation of multiple epitopes in cancer immunity

T cells recognizing self antigens expressed by cancer cells are prevalent in the immune repertoire. However, activation of these autoreactive T cells is limited by weak signals that are incapable of fully priming naive T cells, creating a state of tolerance or ignorance. Even if T cell activation occurs, immunity can be further restricted by a dominant response directed at only a single epitope. Enhanced antigen presentation of multiple epitopes was investigated as a strategy to overcome these barriers. Specific point mutations that create altered peptide ligands were introduced into the gene encoding a nonimmunogenic tissue self antigen expressed by melanoma, tyrosinase-related protein-1 (Tyrp1). Deficient asparagine-linked glycosylation, which was caused by additional mutations, produced altered protein trafficking and fate that increased antigen processing. Immunization of mice with mutated Tyrp1 DNA elicited cross-reactive CD8(+) T cell responses against multiple nonmutated epitopes of syngeneic Tyrp1 and against melanoma cells. These multi-specific anti-Tyrp1 CD8(+) T cell responses led to rejection of poorly immunogenic melanoma and prolonged survival when immunization was started after tumor challenge. These studies demonstrate how rationally designed DNA vaccines directed against self antigens for enhanced antigen processing and presentation reveal novel self epitopes and elicit multi-specific T cell responses to nonimmunogenic, nonmutated self antigens, enhancing immunity against cancer self antigens.     

A novel explanation for the cause of atrial fibrillation seen in atherosclerotic coronary artery disease: “Downstream inflammation” hypothesis

Atrial fibrillation is a frequent arrhythmia, and atherosclerotic coronary artery disease remains as the most common etiological factor underlying atrial fibrillation, along with systemic hypertension. The relationship between uncomplicated coronary artery disease and atrial fibrillation is not explained satisfactorily. Inflammation is now recognized as an important pathogenetic mechanism for both disorders. We hypothesise that inflammation originated from atherosclerotic coronary arteries may disseminate downstream to atrial tissue and initiate or stabilize atrial fibrillation. Studies conducted with drugs bearing anti-inflammatory properties such as hydroxymethylglutaryl coenzyme A inhibitors decrease frequency of both conditions. Such a relationship may become a novel therapeutic target to prevent this arrhythmia or decrease the frequency of paroxysms.     

Rheumatoid arthritis is an autoimmune disease triggered by Proteus urinary tract infection

Rheumatoid arthritis (RA) is a chronic and disabling polyarthritic disease, which affects mainly women in middle and old age. Extensive evidence based on the results of various microbial, immunological and molecular studies from different parts of the world, shows that a strong link exists between Proteus mirabilis microbes and RA. We propose that sub-clinical Proteus urinary tract infections are the main triggering factors and that the presence of molecular mimicry and cross-reactivity between these bacteria and RA-targeted tissue antigens assists in the perpetuation of the disease process through production of cytopathic auto-antibodies. Patients with RA especially during the early stages of the disease could benefit from Proteus anti-bacterial measures involving the use of antibiotics, vegetarian diets and high intake of water and fruit juices such as cranberry juice in addition to the currently employed treatments.     

Amount,not strength of recollection,drives hippocampal activity: A problem for apparent word familiarity‐related hippocampal activation

The role of the hippocampus in recollection and familiarity remains debated. Using functional magnetic resonance imaging (fMRI), we explored whether hippocampal activity is modulated by increasing recollection confidence, increasing amount of recalled information, or both. We also investigated whether any hippocampal differences between recollection and familiarity relate to processing differences or amount of information in memory. Across two fMRI tasks, we separately compared brain responses to levels of confidence for cued word recall and word familiarity, respectively. Contrary to previous beliefs, increasing confidence/accuracy of cued recall of studied words did not increase hippocampal activity, when unconfounded by amount recollected. In contrast, additional recollection (i.e., recollecting more information than the word alone) increased hippocampal activity, although its accuracy matched that of word recall alone. Unlike cued word recall, increasing word familiarity accuracy did increase hippocampal activity linearly, although at an uncorrected level. This finding occurred although cued word recall and familiarity memory seemed matched with respect to information in memory. The detailed characteristics of these effects do not prove that word familiarity is exceptional in having hippocampal neural correlates. They suggest instead that participants fail to identify some aspects of recollection, misreporting it as familiarity, a problem with word‐like items that have strong and recallable semantic associates.     

A three-dimensional scapular motion analysis in patients with arthroscopic anterior capsulolabral repair of the shoulder: The effect of scapular stabilization taping

BackgroundThe aim of this study was to investigate the scapular kinematics during dynamic humeral movements in patients with arthroscopic anterior capsulolabral repair of the shoulder along with the potential biomechanical corrective effects of scapular stabilization taping.MethodsTwenty patients with unilateral traumatic anterior shoulder instability and arthroscopic anterior capsulolabral repair participated in the study. Dynamic shoulder kinematics were assessed during the scapular plane shoulder elevation for both the operated and non operated shoulders and also under two conditions: no-taping and taping. Statistical analysis to compare sides and conditions was performed with analysis of variance models.ResultsThe scapula was more internally rotated position in operated shoulders than in non operated shoulders. Furthermore, the scapula was less internally rotated and more downwardly rotated at 120° of elevation in the taping condition.ConclusionsOperated shoulders demonstrated kinematics alterations when compared to non operated shoulders underwent arthroscopic anterior capsulolabral repair. Additionally, changes in the scapular orientation with the taping was very small but followed a pattern, which would be suggested to be an orientation that potentially produce more scapular stability and to increase stress on the inferior glenohumeral ligament.     

Correlating serum micrornas and clinical parameters in amyotrophic lateral sclerosis

Introduction: Amyotrophic lateral sclerosis (ALS) is a debilitating neurologic disorder with poor survival rates and no clear biomarkers for disease diagnosis and prognosis. Methods: We compared serum microRNA (miRNA) expression from patients with ALS with healthy controls and patients with multiple sclerosis and Alzheimer disease. We also correlated miRNA expression in cross‐sectional and longitudinal cohorts of ALS patients with clinical parameters. Results: We identified 7 miRNAs (miR‐192‐5p, miR‐192‐3p, miR‐1, miR‐133a‐3p, miR‐133b, miR‐144‐5p, miR‐19a‐3p) that were upregulated and 6 miRNAs (miR‐320c, miR‐320a, let‐7d‐3p, miR‐425‐5p, miR‐320b, miR‐139‐5p) that were downregulated in patients with ALS compared with healthy controls, patients with Alzheimer disease, and patients with multiple sclerosis. Changes in 4 miRNAs (miR‐136‐3p, miR‐30b‐5p, miR‐331‐3p, miR‐496) correlated positively and change in 1 miRNA (miR‐2110) correlated negatively with changes in clinical parameters in longitudinal analysis. Discussion: Our findings identified serum miRNAs that can serve as biomarkers for ALS diagnosis and progression. Muscle Nerve 58 : 261–269, 2018