Common variable immunodeficiency (CVID) is the most common clinical primary antibody deficiency, characterized by increased susceptibility to recurrent bacterial infections. Since Toll-like receptors (TLRs) play an important role in the maturation and differentiation of B-cells, TLRs' defect can be involved in the pathogenesis of CVID. Therefore, we evaluated the expression of TLR2 and TLR4 and their signaling pathway; also their association with autoimmunity, B-cell subtypes and response to pneumovax-23 were assessed in CVID patients. Sixteen CVID patients were enrolled in the study. Flow cytometry was used for assessing the protein expression of TLR2 and TLR4, and real-time PCR was used for gene expression of myeloid differentiation primary response 88 (MyD88) and toll interacting protein (Tollip). We found a higher protein expression of TLR2 in CVID patients which was associated with lower number of end stage B-cells and hyporesponse to pneumovax-23 vaccination. We showed a lower mRNA expression of MyD88 and an almost equal Tollip mRNA expression in CVID patients compared with controls. There was a profound association between MyD88 gene expression and autoimmunity in CVID patients. According to the presence of the lower number of end stage B-cells and poor vaccine response in CVID patients and their correlation with the higher expression of TLR2, we hypothesized that there is a functional defect in this receptor and/or its downstream in the peripheral blood mononuclear cells (PBMCs) of CVID patients.

For over 50 years, metronidazole and other nitro compounds such as nitazoxanide have been used as a therapy of choice against giardiasis and more and more frequently, resistance formation has been observed. Model systems allowing studies on biochemical aspects of resistance formation to nitro drugs are, however, scarce since resistant strains are often unstable in culture. In order to fill this gap, we have generated a stable metronidazole- and nitazoxanide-resistant Giardia lamblia WBC6 clone, the strain C4. Previous studies on strain C4 and the corresponding wild-type strain WBC6 revealed marked differences in the transcriptomes of both strains. Here, we present a physiological comparison between trophozoites of both strains with respect to their ultrastructure, whole cell activities such as oxygen consumption and resazurin reduction assays, key enzyme activities, and several metabolic key parameters such as NAD(P)+/NAD(P)H and ADP/ATP ratios and FAD contents. We show that nitro compound-resistant C4 trophozoites exhibit lower nitroreductase activities, lower oxygen consumption and resazurin reduction rates, lower ornithine-carbamyl-transferase activity, reduced FAD and NADP(H) pool sizes and higher ADP/ATP ratios than wildtype trophozoites. The present results suggest that resistance formation against nitro compounds is correlated with metabolic adaptations resulting in a reduction of the activities of FAD-dependent oxidoreductases.

The current picture of Clostridium difficile infection (CDI) is alarming with a mortality rate ranging between 3% and 15% and a CDI recurrence rate ranging from 12% to 40%. Despite the great efforts made over the past 10 years to face the CDI burden, there are still gray areas in our knowledge on CDI management. The traditional anti-CDI antimicrobials are not always adequate in addressing the current needs in CDI management. The aim of our review is to give an update on novel antimicrobials for the treatment of CDI, considering the currently available evidences on their efficacy, safety, molecular mechanism of action, and their probability to be successfully introduced into the clinical practice in the near future. We identified, through a PubMed search, 16 novel antimicrobial molecules under study for CDI treatment: cadazolid, surotomycin, ridinilazole, LFF571, ramoplanin, CRS3123, fusidic acid, nitazoxanide, rifampin, rifaximin, tigecycline, auranofin, NVB302, thuricin CD, lacticin 3147, and acyldepsipeptide antimicrobials. In comparison with the traditional anti-CDI antimicrobial treatment, some of the novel antimicrobials reviewed in this study offer several advantages, i.e., the favorable pharmacokinetic and pharmacodynamic profile, the narrow-spectrum activity against CD that implicates a low impact on the gut microbiota composition, the inhibitory activity on CD sporulation and toxins production. Among these novel antimicrobials, the most active compounds in reducing spore production are cadazolid, ridinilazole, CRS3123, ramoplanin and, potentially, the acyldepsipeptide antimicrobials. These antimicrobials may potentially reduce CD environment spread and persistence, thus reducing CDI healthcare-associated acquisition. However, some of them, i.e., surotomycin, fusidic acid, etc., will not be available due to lack of superiority versus standard of treatment. The most CD narrow-spectrum novel antimicrobials that allow to preserve microbiota integrity are cadazolid, ridinilazole, auranofin, and thuricin CD. In conclusion, the novel antimicrobial molecules under development for CDI have promising key features and advancements in comparison to the traditional anti-CDI antimicrobials. In the near future, some of these new molecules might be effective alternatives to fight CDI.

This study was performed to evaluate the visual, refractive, and aberration measurement results of 2 implants, including Intacs Intracorneal Ring Segments (ICRS) and phakic Toric Implantable Collamer Lens (TICL), in patients with moderate Keratoconus (KCN). In this retrospective cross-sectional study, 30 patients with KCN with a mean age of 29.83 years were included in 2 groups, including the Intacs Intracorneal Ring Segments (ICRS) group and the phakic Toric Implantable Collamer Lens (TICL) group. Preoperative data as well as 6-month, 1-, 2-, 3- and 4-year follow-up data after the operation were collected and analyzed with the SPSS software (ver. 23.0, SPSS, Inc., Chicago, IL), using the paired t-test, independent t-test, repeated measures Analysis of Variance (ANOVA), and one-way ANOVA. This study included 30 patients with KCN with a mean age of 29.83 years and range of 25 to 35 years, including 17 males with a mean age of 30.11 years and 13 female with a mean age of 29.25 years. Except for preoperative Uncorrected Distance Visual Acuity (UCDVA), Spherical Equivalent (SE) and astigmatism, there was a significant difference between the 2 groups regarding other variables. The TICL group had a significantly better UCDVA and Best Corrected Distance Visual Acuity (BCDVA) in all post-operative follow-ups, and SE and astigmatism values were significantly lower in all post-operative follow-ups when compared with the ICRS group. There was a significant reduction in corneal and total coma as well as internal trefoil aberrations (P<0.01, P<0.01, and P=0.014, respectively) in the ICRS group, and TICL led to a significant reduction in internal trefoil aberration with P<0.03. Comparison of the 2 groups revealed a significant difference in corneal spherical (P<0.01) and total coma (P=0.02) aberrations and no significant differences in other HOA. Both ICRS and TICL are useful in patients with moderate KCN. However, TICL appears to have more stable and predictable vision results.

Uncontrolled studies suggest a benefit of nitazoxanide for the treatment of norovirus gastroenteritis in immunocompromised individuals. Here, we report the use of nitazoxanide in a 13-year-old male kidney transplant recipient who developed intractable norovirus gastroenteritis. Reduction of immunosuppression was not possible due to refractory TCMR. Administration of oral immunoglobulin and switching from tacrolimus to sirolimus failed to produce a meaningful clinical response. Treatment with a 14-day course of nitazoxanide resulted in prompt resolution of diarrhea as well as clearance of norovirus from the stool despite intense immunosuppression. Nitazoxanide may be considered as an option for the treatment of intractable norovirus gastroenteritis in pediatric transplant patients when reduced immunosuppression is not feasible or other treatment options have failed. Further studies to evaluate the safety and effectiveness of nitazoxanide in immunocompromised children are needed.

Nitazoxanide (NTZ) is an FDA-approved anti-protozoal drug that inhibits several bacteria and viruses as well. However, its effect on poxviruses is unknown. Therefore, we investigated the impact of NTZ on vaccinia virus (VACV). We found that NTZ inhibits VACV production with an EC50 of ~2 μM, a potency comparable to that reported for several other viruses. The inhibitory block occurs early during the viral life cycle, prior to viral DNA replication. The mechanism of viral inhibition is likely not due to activation of intracellular innate immune pathways, such as protein kinase R (PKR) or interferon signaling, contrary to what has been suggested to mediate the effects of NTZ against some other viruses. Rather, our finding that addition of exogenous palmitate partially rescues VACV production from the inhibitory effect of NTZ suggests that NTZ impedes adaptations in cellular metabolism that are needed for efficient completion of the VACV replication cycle.