Milder Diseases Research Articles

Effectiveness of Brodalumab in Patients with Moderate-to-Severe Plaque Psoriasis Located in Difficult-to-Treat Areas.

Recent knowledge of psoriasis pathogenesis has led to the development of selective drugs. Among these, brodalumab is a monoclonal antibody targeting the interleukin (IL)-17A receptor approved for the treatment of moderate-to-severe plaque psoriasis. Biologics may be considered in patients with milder diseases in case of active psoriatic arthritis, severe impact on patient's quality of life, and involvement of sensitive and difficult-to-treat areas. These skin locations commonly require systemic drugs. Recently, psoriasis severity monitoring has also changed. Indeed, the clinical evaluation by means of specific efficacy scores was combined with serological evaluation by means of the assay of specific inflammatory biomarkers. An observational study enrolled patients affected by moderate-to-severe plaque psoriasis involving difficult-to-treat areas, undergoing treatment with brodalumab to evaluate the effectiveness and safety of brodalumab in patients with psoriasis affecting difficult-to-treat areas (scalp and palmoplantar regions). Secondary outcomes were the assessment of the development of serum markers of inflammation during the treatment period as well as the evaluation of the dermoscopic features of the affected sites to quantify disease activity and response to treatment. Twenty-five patients were included in the study. A statistically significant reduction from baseline in PASI, PSSI, ppPASI and DLQI values as early as week 24 was observed, with further improvement up to week 52. Plasma levels of MMP-3, VEGF-A, and hs-PCR decreased during treatment from week 0 to week 52. Our real-life experience suggests brodalumab as a valuable option for the management of psoriasis located in difficult-to-treat areas. Moreover, our study highlights that the use of brodalumab reduces the plasmatic levels of inflammatory biomarkers (MMP-3, VEGF-A and hs-PCR), showing how the drug modulates the skin inflammatory response by reducing systemic inflammation.

Clinical Profile and Diagnosis of Recurrent Cutaneous Leishmaniasis.

This case-control study compared the clinical profile, parasite load, polymerase chain reaction positivity, and response to therapy in patients with recurrent cutaneous leishmaniasis (RCL) with primary cutaneous leishmaniasis (CL). The RCL patients had milder diseases with lower parasite loads, a lower number of lesions, and more self-healing diseases than primary CL patients.

Attenuation and Degeneration of SARS-CoV-2 Despite Adaptive Evolution.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has followed similar trends as other RNA viruses, such as human immunodeficiency virus type 1 and the influenza A virus. Rapid initial diversification was followed by strong competition and a rapid succession of dominant variants. Host-initiated RNA editing has been the primary mechanism for introducing mutations. A significant number of mutations detrimental to viral replication have been quickly purged. Fixed mutations are mostly diversifying mutations selected for host adaptation and immune evasion, with the latter accounting for the majority of the mutations. However, immune evasion often comes at the cost of functionality, and thus, optimal functionality is still far from being accomplished. Instead, selection for antibody-escaping variants and accumulation of near-neutral mutations have led to suboptimal codon usage and reduced replicative capacity, as demonstrated in non-respiratory cell lines. Beneficial adaptation of the virus includes reduced infectivity in lung tissues and increased tropism for the upper airway, resulting in shorter incubation periods, milder diseases, and more efficient transmission between people.

Spike protein-independent attenuation of SARS-CoV-2 Omicron variant in laboratory mice.

Despite being more transmissible, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant only causes milder diseases in laboratory animals, often accompanied by a lower viral load compared with previous variants of concern. In this study, we report the structural basis for a robust interaction between the receptor-binding domain of the Omicron spike protein and mouse ACE2. We show that pseudovirus bearing the Omicron spike protein efficiently utilizes mouse ACE2 for entry. By comparing viral load and disease severity among laboratory mice infected by a natural Omicron variant or recombinant ancestral viruses bearing either the entire Omicron spike or only the N501Y/Q493R mutations in its spike, we find that mutations outside the spike protein in the Omicron variant may be responsible for the observed lower viral load. Together, our results imply that a post-entry block to the Omicron variant exists in laboratory mice.

Pathobiology of the Hepatic Glycogen Storage Diseases

The purpose of this study is to review the pathobiology of the hepatic glycogen storage diseases (GSD) and recent developments in their management. Increasingly, noninvasive mutation detection has replaced biological and tissue samples as the first line diagnostic method. For type 1 GSD, continuous subcutaneous monitoring has transformed patient monitoring. There is evidence that improved metabolic control can prevent complications such as adenoma formation and renal dysfunction. Improved understanding of the pathophysiology of hepatic adenomata may allow rationalization of their management. Hepatocellular carcinoma only develops in established adenomata, offering an option for prevention. For type 111 GSD, intrinsic liver disease and myopathy become the major clinical concerns after childhood. Type IV GSD is a heterogenous multisystemic disorder which often results in progressive liver and cardiac failure. Recombinant acid α-glucosidase may have a disease-modifying role, but experience remains limited. Types VI and IX GSD are milder diseases where supportive treatment usually results in an excellent long-term outcome. Current management of the hepatic GSDs has significantly improved their outcome and improved metabolic control can prevent many long-term complications.

Virulence of mixed fungal infections in honey bee brood

IntroductionHoney bees, Apis mellifera, have a diverse community of pathogens. Previous research has mostly focused on bacterial brood diseases of high virulence, but milder diseases caused by fungal pathogens have recently attracted more attention. This interest has been triggered by partial evidence that co-infection with multiple pathogens has the potential to accelerate honey bee mortality. In the present study we tested whether co-infection with closely related fungal brood-pathogen species that are either specialists or non-specialist results in higher host mortality than infections with a single specialist. We used a specially designed laboratory assay to expose honey bee larvae to controlled infections with spores of three Ascosphaera species: A. apis, the specialist pathogen that causes chalkbrood disease in honey bees, A. proliperda, a specialist pathogen that causes chalkbrood disease in solitary bees, and A. atra, a saprophytic fungus growing typically on pollen brood-provision masses of solitary bees.ResultsWe show for the first time that single infection with a pollen fungus A. atra may induce some mortality and that co-infection with A. atra and A. apis resulted in higher mortality of honey bees compared to single infections with A. apis. However, similar single and mixed infections with A. proliperda did not increase brood mortality.ConclusionOur results show that co-infection with a closely related fungal species can either increase or have no effect on host mortality, depending on the identity of the second species. Together with other studies suggesting that multiple interacting pathogens may be contributing to worldwide honey bee health declines, our results highlight the importance of studying effects of multiple infections, even when all interacting species are not known to be specialist pathogens.

The Shiga toxin genotype rather than the amount of Shiga toxin or the cytotoxicity of Shiga toxin in vitro correlates with the appearance of the hemolytic uremic syndrome

Shiga toxins (Stx) are believed to play a key role in the pathogenesis of diseases caused by Stx-producing Escherichia coli (STEC), including the potentially life-threatening hemolytic uremic syndrome (HUS). In this study, 201 STEC strains collected from patients and environmental sources were investigated with regard to the stx genotypes and pathogenicity. The stx 2 and stx 2c alleles were associated with high virulence and the ability to cause HUS, whereas stx 2d, stx 2e, stx 1, and stx 1c occurred in milder or asymptomatic infections. Quantification of Stx using an enzyme immunoassay and the Vero cell cytotoxicity assay showed no significant differences between the strains associated with HUS and those causing milder diseases. We hypothesize that the stx genotype and perhaps other yet unknown virulence factors rather than the amount of Stx or the in vitro cytotoxicity correlate with the development of HUS.

Suppression of immune-mediated liver injury after vaccination with attenuated pathogenic cells

Cell vaccination via immunization with attenuated pathogenic cells is an effective preventive method that has been successfully applied in several animal models of inflammatory or autoimmune diseases. Concanavalin A (Con A)-induced hepatitis (CIH) is a commonly used experimental model to study immune-mediated liver injury. Multiple cell types including T lymphocytes, macrophages and neutrophils have been found to be involved in the pathogenesis of CIH. In this study, we used attenuated spleen lymphocytes or peripheral blood lymphocytes as vaccines to investigate whether they could induce protective immune responses to prevent mice from developing CIH. We found that mice receiving such vaccination before CIH induction developed much milder diseases, exhibited a lower level of alanine aminotransferase (ALT) released into their plasma and had less inflammatory lesions in their livers. Such CIH-suppression is dose- and frequency-dependent. The suppressive effect was associated with inhibition of several major inflammatory mediators, pro-inflammatory cytokines and chemokines.

Current Trends in Plague Research: From Genomics to Virulence

Yersinia pestis is the causative agent of plague, which diverged from Yersinia pseudotuberculosis within the past 20,000 years. Although these two species share a high degree of homology at the DNA level (>90%), they differ radically in their pathogenicity and transmission. In this review, we briefly outline the known virulence factors that differentiate these two species and emphasize genetic studies that have been conducted comparing Y. pestis and Y. pseudotuberculosis. These comparisons have led to a better understanding of the genetic contributions to the differences in the virulence and pathogenicity between these two organisms and have generated information that can be applied in future diagnostic and vaccine development. Comparison of the genetic differences between Y. pestis and Y. pseudotuberculosis has also lent insight into the emergence of acute pathogens from organisms causing milder diseases.

Tuberculosis of the spine in the new millennium.

Tuberculosis of the spine is probably one of the earliest diseases to have affected the human race. Over the past few decades, the epidemiology, pathology, natural history and diagnostic methodology have been well studied. The multinational prospective study on the efficacy of conservative chemotherapy and surgical treatment coordinated by the Medical Research Council has just completed a final 15-year follow-up report. Although it appears from this study that conservative treatment is as effective as surgical intervention for earlier and milder diseases, there are still reservations on the effect of such treatment at much longer follow-ups and for more severe diseases. Further developments in diagnosis using molecular genetic techniques, more effective antibiotics and more aggressive surgical protocols in the next millennium may help in solving the problems of late severe deformity and paraplegia in the debilitated immunocompromised patients.

Pathogenesis of a newly isolated rat virus in newborn and juvenile rats.

The pathogenesis of the UT-1 strain, a newly isolated rat virus (RV), in juvenile and newborn rats was examined. Intracerebrally (ic) inoculated newborns developed severe pantropic infections resulting in emaciation, stunted growth, diarrhea, dehydration and icterus, and died 13 to 15 days after the inoculation. Newborns inoculated intraperitoneally (ip) developed similar, but milder diseases. The virus replicated in all the organs tested, which was followed by severe viremia. Histopathologically, diffuse vacuolation and necrosis of the hepatocytes were observed in the liver. Juvenile rats inoculated with the virus showed neither clinical signs nor histopathologic lesions, although viral recovery and antibody production were observed. Thus, we conclude that the UT-1 strain of RV caused asymptomatic infections in juvenile rats, and fatal infections with hepatic lesions in newborn rats.