Antimycobacterial and anti-inflammatory activities of fractions and substances from Erythrina verna Vell focusing on dual severe TB treatment approach.

Tuberculosis remains a major health problem worldwide. Drug-resistant and hypervirulent Mycobacterium tuberculosis (Mtb) strains can lead to a hyperinflammatory response and necrotic pathology in hyper-reactive individuals that require adjunctive treatment. Plant-derived substances have been investigated for TB treatment, among which flavonoids stand out. We evaluate the anti-Mtb, anti-inflammatory and cytotoxicity activities of fractions and substances 1, 2 and 3 isolated from Erythrina verna through a bioassay guided fractionation. Seven fractions (1, 3-5 and 7-9) obtained from dichloromethane E. verna extract inhibited NO production (IC50 ≤ 15 µg/mL) with none or poor cytotoxic effect, while the fractions 4 and 5 notably reduced TNF-a production. Fractions 4, 6 and 9 suppressed Mycobacterium growth with MIC50 ≤ 20 µg/mL. Fraction 4 was the most potent due to dual biological activities. Erythratidinone and alpinumisoflavone inhibited the growth of Mtb H37Rv and hypervirulent strain in bacterial cultures (MIC50 ≤ 20 µg/mL), with erythratidinone standing out in reducing intracellular growth of Mtb H37Rv (5.8 ± 1.1 µg/mL). Alpinumisoflavone and erythratidinone were capable of inhibiting NO and TNF-α production besides showing significant inhibitory effects against Mycobacterium tuberculosis strains with low toxicity in macrophages. Both substances are promising for further studies focusing on an anti-TB dual treatment approach.

Dupilumab for atopic dermatitis: a real-world Portuguese multicenter retrospective study.

INTRODUCTION: Atopic dermatitis (AD) is a difficult-to-treat inflammatory skin disease with a high impact on patients' quality of life. Dupilumab, an IL-4 and IL-13 inhibitor, was the first monoclonal antibody approved for the treatment of moderate-to-severe AD and is currently approved in patients aged 6 or older. METHODS: This is a nationwide, multicenter, retrospective, 48-week study designed by the Portuguese Group of AD to assess real-world efficacy and safety of dupilumab for the treatment of AD. RESULTS: A total of 169 patients were enrolled, with a mean disease duration of 22.75 (±11.98) years. The percentage of patients achieving an improvement of at least 75% in Eczema Area and Severity Index (EASI) compared to baseline (EASI75 response) at weeks 12 and 48 was 67.6% and 74.1%, respectively. In the same timepoints, 25.0% and 44.1% achieved an EASI90 response. Patient-reported outcome measures also improved throughout the study period. Regarding safety, 32.0% of the patients developed adverse events, with conjunctivitis (26.6%), persistent facial erythema (4.7%), and arthritis/arthralgia (3.6%) as the more frequently reported. CONCLUSION: Data from real-world populations are crucial to guide clinicians in their daily decisions. This study provides data demonstrating that dupilumab is an effective and safe therapeutic option for AD.

Management of hepatocellular carcinoma after progression on first-line systemic treatment: defining the optimal sequencing strategy in second line and beyond.

Hepatocellular carcinoma (hcc) is one of the most common cancers in the world. It has a high mortality rate, especially when localized treatments fail. For about a decade, the only systemic treatment shown to improve survival was sorafenib. Recently, lenvatinib was found to be noninferior to sorafenib for overall survival, and combination atezolizumab-bevacizumab improved survival compared with sorafenib. Similarly, in the post-sorafenib setting, a number of recent positive clinical trials have been reported, and they indicate that regorafenib, cabozantinib, and ramucirumab are effective and safe in the second-line setting. With so many new options available, including immunotherapy, it is challenging to define the best sequence of systemic treatment for patients with hcc. In the present review, we introduce the current data for second-line systemic treatment and beyond in hcc. A treatment algorithm is also suggested, based on the best available evidence and expert opinion.

Management of congenital ichthyoses: European guidelines of care, part two.

These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert-based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.

Management of congenital ichthyoses: European guidelines of care, part one.

These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016 and a consensus on the discussions. They summarize evidence and expert-based recommendations and are intended to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part one, covering topical therapies, systemic therapies, psychosocial management, communicating the diagnosis and genetic counselling.

Comprehensive identification of Vibrio vulnificus genes required for growth in human serum.

Vibrio vulnificus can be a highly invasive pathogen capable of spreading from an infection site to the bloodstream, causing sepsis and death. To survive and proliferate in blood, the pathogen requires mechanisms to overcome the innate immune defenses and metabolic limitations of this host niche. We created a high-density transposon mutant library in YJ016, a strain representative of the most virulent V. vulnificus lineage (or phylogroup) and used transposon insertion sequencing (TIS) screens to identify loci that enable the pathogen to survive and proliferate in human serum. Initially, genes underrepresented for insertions were used to estimate the V. vulnificus essential gene set; comparisons of these genes with similar TIS-based classification of underrepresented genes in other vibrios enabled the compilation of a common Vibrio essential gene set. Analysis of the relative abundance of insertion mutants in the library after exposure to serum suggested that genes involved in capsule biogenesis are critical for YJ016 complement resistance. Notably, homologues of two genes required for YJ016 serum-resistance and capsule biogenesis were not previously linked to capsule biogenesis and are largely absent from other V. vulnificus strains. The relative abundance of mutants after exposure to heat inactivated serum was compared with the findings from the serum screen. These comparisons suggest that in both conditions the pathogen relies on its Na+ transporting NADH-ubiquinone reductase (NQR) complex and type II secretion system to survive/proliferate within the metabolic constraints of serum. Collectively, our findings reveal the potency of comparative TIS screens to provide knowledge of how a pathogen overcomes the diverse limitations to growth imposed by serum.

Acute Hemorrhagic Edema of Infancy.

Acute Hemorrhagic Edema of Infancy is a small vessel leucocytoclastic vasculitis affecting young infants. It is characterized by large, target-like, macular to purpuric plaques predominantly affecting the face, ear lobes and extremities. Non-pitting edema of the distal extremities and low-grade fever may also be present. Extra-cutaneous involvement is very rare. Although the lesions have a dramatic onset in a twenty-four to forty-eight hour period, usually the child has a non-toxic appearance. In most cases there are no changes in laboratory parameters. The cutaneous biopsy reveals an inflammatory perivascular infiltrate. It is a benign and auto-limited disease, with complete resolution within two to three weeks leaving no sequelae in the majority of cases. No recurrences are described. We report a case of a 42-day old girl admitted at our hospital with Acute Hemorrhagic Edema of Infancy.

Cobblestone mouth: an exuberant oral presentation of pemphigus vegetans / Una boca en empedrado: una presentación oral exuberante de pénfigo vegetante

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Lyme disease: sudden hearing loss as the sole presentation.

BACKGROUND: Lyme disease is an uncommon tick-borne multisystemic infection caused by Borrelia burgdorferi. The most common clinical manifestation is erythema migrans. In this report, a very unusual presentation of this condition is described, in which sudden onset sensorineural hearing loss was the sole presenting symptom. METHODS: Case report and review of English-language literature. RESULTS: A patient presented with sensorineural hearing loss, with no other symptoms or signs. Acute Lyme infection was detected by laboratory tests. Magnetic resonance imaging showed signs of labyrinthitis of the same inner ear. After hyperbaric oxygen and systemic antibiotic treatment, the patient showed total hearing recovery, and magnetic resonance imaging showed complete resolution of the labyrinthitis. CONCLUSION: To our knowledge, this is the first reported case of Lyme disease presenting only with sensorineural hearing loss. Borreliosis should be considered as an aetiological factor in sensorineural hearing loss. Adequate treatment may provide total recovery and prevent more severe forms of Lyme disease.

Methodology for porphyrin isolation by high-performance countercurrent chromatography.

Countercurrent chromatography is a versatile technique for the isolation of a wide variety of plant substances. However, little attention has been devoted to the application of this technique for the isolation of porphyrins. This class of compounds are of great importance in the medical area and in photocatalysis due to their heterocyclic structure, composed of four modified pyrrol subunits interconnected on their a carbon atoms by methinic bridges. The methanol extract of Gallesia integrifolia was partitioned using different solvents; the dichloromethane fraction was then submitted to countercurrent chromatography. The solvent system composed of n-hexane, ethyl acetate, methanol, and water (1:2.5:2.5:1) was chosen to perform the chromatographic analysis due to the enhanced solubility and the best distribution coefficients of the target compounds. Two porphyrins were isolated by this method and identified as 13(2)-hydroxypheophorbide a methyl ester and pheophorbide a, methyl ester. The solvent system proposed provided good distribution coefficients for both substances (1.27 and 1.87, respectively), and a high resolution factor.

Characterization of PAMP/PRR interactions in European eel (Anguilla anguilla) macrophage-like primary cell cultures.

The eel (Anguilla anguilla) has been identified as a vulnerable species with stocks dramatically declining over the past decade. In an effort to support the species from overfishing of wild stocks increased interest in eel aquaculture has been notable. In order to expand the scarce knowledge concerning the biology of this species significant research efforts are required in several fields of biology. The development of cell culture systems to study the immune response is a key step towards an increased understanding of the immune response and to develop resources to support further study in this threatened species. Macrophages are one of the most important effector cells of the innate immune system. The capacity to engulf pathogens and orchestrate the immune response relies on the existence of different surface receptors, such as scavenger receptors and toll-like receptors. We have developed and described an eel macrophage-like in vitro model and studied its functional and transcriptomic responses. Macrophage-like cells from both head kidney and purified peripheral blood leukocytes were obtained and phagocytic activity measured for different whole bacteria and yeast. Moreover, based on PAMP-PRR association the innate immune response of both head kidney and PBL derived macrophage-like cells was evaluated against different pathogen-associated molecular patterns (PAMPs). Results highlight that peptidoglycan stimulation strongly induces inflammatory mRNA expression reflected in the up-regulation of pro-inflammatory genes IL1ß and IL18 in PBL derived cells whereas IL8 is upregulated in head kidney derived cells. Furthermore TLR2 mRNA abundance is regulated by all stimuli supporting a multifunctional role for this pathogen recognition receptor (PRR) in eel macrophage-like cells.

Integrated solutions for urban runoff pollution control in Brazilian metropolitan regions.

One of the most important causes for poor water quality in urban rivers in Brazil is the low collection efficiency of the sewer system due to unforeseen interconnections with the stormwater drainage system. Since the beginning of the 20th century, Brazilian cities have adopted separate systems for sanitary sewers and stormwater runoff. Gradually these two systems became interconnected. A major challenge faced today by water managers in Brazil is to find efficient and low cost solutions to deal with this mixed system. The current situation poses an important threat to the improvement of the water quality in urban rivers and lakes. This article presents an evaluation of the water quality parameters and the diffuse pollution loads during rain events in the Pinheiros River, a tributary of the Tietê River in São Paulo. It also presents different types of integrated solutions for reducing the pollution impact of combined systems, based on the European experience in urban water management. An evaluation of their performance and a comparison with the separate system used in most Brazilian cities is also presented. The study is based on an extensive water quality monitoring program that was developed for a special investigation in the Pinheiros River and lasted 2.5 years. Samples were collected on a daily basis and water quality variables were analyzed on a daily, weekly or monthly basis. Two hundred water quality variables were monitored at 53 sampling points. During rain events, additional monitoring was carried out using an automated sampler. Pinheiros River is one of the most important rivers in the São Paulo Metropolitan Region and it is also a heavily polluted one.

Serum antibodies to Vibrio vulnificus biotype 3 lipopolysaccharide and susceptibility to disease caused by the homologous V. vulnificus biotype.

In 1996 an outbreak of severe soft tissue infections caused by Vibrio vulnificus unexpectedly erupted in fish consumers in Israel with relatively little morbidity in fish farmers. To test the hypothesis that recurrent exposure of fishermen to the virulent strain may have provided protection against severe or symptomatic disease, we investigated the association between the immune response to V. vulnificus biotype 3 lipopolysaccharide (BT3 LPS) and disease susceptibility in fish farmers and fish consumers. Serum samples were tested for IgA and IgG of anti-BT3 LPS in fishermen and fish consumers who suffered from V. vulnificus BT3 infections and their matched controls. Pre-existing levels of IgG (IgG0) of anti-BT3 LPS were significantly lower in diseased fishermen who developed disease associated with the homologous biotype, compared to controls. In multivariate analysis, levels of IgG0 anti-BT3 LPS remained the only variable significantly associated with disease occurrence in fishermen. Higher levels of pre-existing IgG anti-BT 3 LPS antibodies may be associated with protection against severe or symptomatic disease with the homologous biotype in fishermen but not in subjects from the general public.

A comparative epizootiologic study of the two fish-pathogenic serovars of Vibrio vulnificus biotype 2.

Vibrio vulnificus biotype 2 is subdivided into two main serovars, serovar E, able to infect fish and humans, and serovar A, only virulent for fish. Serovar E emerged in 1976 as the causative agent of a haemorrhagic septicaemia (warm-water vibriosis) affecting eels cultured in brackish water. Serovar A emerged in 2000 in freshwater-cultured eels vaccinated against serovar E, causing warm-water vibriosis with fish showing a haemorrhagic intestine as the main differential sign. The aim of the present work was to compare the disease caused by both serovars in terms of transmission routes, portals of entry and host range. Results of bath, patch-contact and oral-anal challenges demonstrated that both serovars spread through water and infect healthy eels, serovar A entering mainly by the anus and serovar E by the gills. The course of the disease under laboratory conditions was similar for both serovars in terms of transmission and dependence of degree of virulence on water parameters (temperature and salinity). However, the decrease in degree of virulence in fresh water was significantly greater in serovar E than in serovar A. Finally, both serovars proved pathogenic for tilapia, sea bass and rainbow trout, but not for sea bream, with significant differences in degree of virulence only in rainbow trout. In conclusion, serovar A seems to represent a new antigenic form of V. vulnificus biotype 2 with an unusual portal of entry and is better adapted to fresh water than serovar E.

Multiple trichoepitheliomas--a novel mutation in the CYLD gene.

BACKGROUND: Trichoepitheliomas are benign neoplasms with follicular differentiation. They may present as a solitary lesion or as multiple lesions. Multiple trichoepitheliomas are inherited in an autosomal dominant pattern within families, with both variable penetrance and expressivity. Recent investigations support that mutations in CYLD, the gene affected in familial cylindromatosis as well as in Brooke-Spiegler syndrome, are also responsible for multiple trichoepitheliomas. OBJECTIVE: The authors report the case of a 9-year-old African girl with multiple facial trichoepitheliomas in whom a mutation in the CYLD gene was hypothesised. MATERIALS AND METHODS: After genomic DNA extraction from the peripheral blood, a molecular analysis of the CYLD gene was performed by PCR, DHPLC and automated sequencing. RESULTS: A novel heterozygous mutation in exon 18 of the CYLD gene (c.2449delT) was identified, with a deletion of one nucleotide resulting in a premature translational termination codon at amino acid position 831 on the affected allele (p.Cys817Valfs X15). CONCLUSIONS: The predominating tumours define the classification of these three entities. Nevertheless, studies suggest that they can simply represent phenotypic variations of the same disease spectrum, sharing common genetic mutations.

Spontaneous quinolone resistance in the zoonotic serovar of Vibrio vulnificus.

This work demonstrates that Vibrio vulnificus biotype 2, serovar E, an eel pathogen able to infect humans, can become resistant to quinolone by specific mutations in gyrA (substitution of isoleucine for serine at position 83) and to some fluoroquinolones by additional mutations in parC (substitution of lysine for serine at position 85). Thus, to avoid the selection of resistant strains that are potentially pathogenic for humans, antibiotics other than quinolones must be used to treat vibriosis on farms.

Microbial and histopathological study of the vibriosis caused by Vibrio vulnificus serovar E in eels: the metalloprotease Vvp is not an essential lesional factor.

Vibrio vulnificus biotype 2 serovar E (Bt2-serE) is a zoonotic pathogen that causes a haemorrhagic septicaemia in eels, called warm water vibriosis. The main objective of the present work was to study the onset of the eel vibriosis from the microbiological and histopathological viewpoint, as well as to ascertain the role of the protease Vvp as a lesional factor by comparing the histopathological lesions caused by the wild strain and its vvp deficient derivative. The wild-type strain was observed to attach to the gills, where it multiplied following saturation dynamics, subsequently invading the blood stream and reaching the internal organs. Here it reached population sizes that are notably lower than those associated with other fish septicaemia. Parallel to bacterial growth, there was a notable decrease in haematocrit values and haemoglobin concentration in blood as well as extensive haemorrhages in all the analysed organs. The main histopathological lesions were detected in the head kidney in the form of extensive necrosis affecting the haematopoietic tissue. Very few bacteria were visualized in the different organs, most of which were close to blood cells and capillary vessels, which is compatible with the results obtained in the microbiological study. The same lesions were produced when extracellular products (ECPs) were injected instead of bacteria or when the vvp-defective mutant or its ECPs were injected. The overall results suggest that the pathology caused by V. vulnificus in the eel is not caused by massive bacterial growth in the blood and internal organs but, rather, by the effect of potent toxic factors other than the metalloprotease, which have yet to be determined.