Decylprodigiosin: a new member of the prodigiosin family isolated from a seaweed-associated Streptomyces.

Bioprospecting actinobacterial secondary metabolism from untapped marine sources may lead to the discovery of biotechnologically-relevant compounds. While studying the diversity and bioactive potential of Actinomycetota associated with Codium tomentosum, a green seaweed collected in the northern Portuguese cost, strain CT-F61, identified as Streptomyces violaceoruber, was isolated. Its extracts displayed a strong anticancer activity on breast carcinoma T-47D and colorectal carcinoma HCT116 cells, being effective as well against a panel of human and fish pathogenic bacteria. Following a bioactivity-guided isolation pipeline, a new analogue of the red-pigmented family of the antibiotics prodigiosins, decylprodigiosin (1), was identified and chemically characterized. Despite this family of natural products being well-known for a long time, we report a new analogue and the first evidence for prodigiosins being produced by a seaweed-associated actinomycete.

Anaesthetic management of caesarean section in a patient with myofibrillar myopathy.

Myofibrillar myopathies (MFMs) are a group of rare genetic disorders that affect the function of skeletal, cardiac and smooth muscle.MFM exhibits a considerable degree of clinical heterogeneity. In numerous instances of MFM, muscle weakness is the predominant manifestation. Certain MFM subtypes are distinguished by respiratory and cardiac impairment.There is little information available about anaesthetic management in MFM, and even less is known about obstetric anaesthesia.A successful case of a patient with MFM undergoing a caesarean section under combined neuraxial anaesthesia is reported. The patient experienced no complications, and functional recovery was swift.

Correction: Wilson's Disease: A Prevalence Study in a Portuguese Population.

[This corrects the article DOI: 10.7759/cureus.43718.].

Wilson's Disease: A Prevalence Study in a Portuguese Population.

Introduction Wilson's disease (WD) is a rare and underdiagnosed genetic disorder caused by anomalous tissue copper deposition, and for which epidemiological studies, specifically in Portugal, are scarce. Objectives This study aimed to evaluate the prevalence and incidence of WD and provide a description of its main clinical and laboratory features. Methods A retrospective study was carried out, with a search between 1995 and 2015, of all patients with a minimum follow-up of three months and birth confirmed in the northern region of Portugal, with an estimated population of 3,689,682 inhabitants. Database collection was based on the Portuguese National Health Service's clinical coding system, relying on clinical data from 13 northern Portuguese hospitals, liver biopsy histology results, and hospital prescription records. Clinical and biochemical correlations were statistically assessed using chi-square, Mann-Whitney U, Friedman, and Wilcoxon tests. Results Over the 20-year period, a prevalence of 1:37.000 and an incidence of one per million person-year was found. A total of 94 patients were analyzed, with a slight male predominance (53%), the majority with the onset of clinical manifestations in pediatric age (56%), with a median age at diagnosis of 16.6 years (interquartile range of 12.3-20,.8 years). Most patients presented with predominant liver disease (54.8%), with more than a third with cirrhosis; mixed hepatic and neurological manifestations in 17.9%; and mainly neurological symptoms in 10.7% of the patients. Neurological impairment was strongly associated with delayed development of the manifestations of the disease (p = 0.001) and also a higher detection of Kayser-Fleischer rings (p < 0.001), present in 27.0% of the patients. Regarding therapy, penicillamine has been the most widely used, with adverse reactions reported in 24.8%. At six and 12 months after initiation of therapy, a significant decrease in liver enzymes was found (ALT: p = 0.002; AST: p = 0.002, respectively), but no significant reduction was observed in urinary copper excretion. Conclusion This was one of the first studies regarding WD prevalence in a Portuguese population, contributing to a better understanding of the epidemiology, diagnosis, and management of WD in the northern region of Portugal. WD should be considered in any individual with unexplained hepatic or neurological manifestations, and initial symptoms may manifest at an early age, even in children less than five years old. A high percentage of patients were identified in the early stages of the disease by asymptomatic elevation of transaminases. Following copper chelation therapy, cytolysis markers appear to be more sensitive indicators of treatment response.

Splenic Infarction: A Rare Complication of Infectious Mononucleosis.

Infectious mononucleosis (IM) is caused by Epstein-Barr virus (EBV), and the condition is characterized by sore throat, fever, lymphadenopathy, and atypical lymphocytosis. These infections are common in early childhood, with a second peak occurring in late adolescence. EBV is spread by contact with oral secretions. Most cases of IM are self-limited. However, there are associated complications, some of which can be serious and fatal. We report the case of a 20-year-old man with splenic infarction and exuberant peritonsillar abscess secondary to an EBV infection. This case highlights the importance of accurate diagnoses and frequent monitoring in IM patients, given the risk of airway obstruction.

Incorporation and modification of fatty acids in cyanobacterial natural products biosynthesis.

Fatty acid-derived alkyl chains are often found in natural products, where they can exert a number of different functions, most notably biological membrane interactions. Such alkyl chains are difficult to modify regio- and stereoselectively, since most positions are distant from any directing functional group. Chemical and biochemical diversification of these moieties is therefore a challenge, and most organisms do not modify alkyl moieties to a great extent. Still, one particular group of microorgansims - cyanobacteria - display not only a large number of fatty acid-incorporating natural products, but also modify these to a great extent. Here, we provide an overview of the unique fatty acid metabolism of cyanobacteria in the context of natural products biosynthesis. We cover the diverse range of fatty acid incorporation mechanisms that these organisms use to recruit and commit fatty acids to natural products biosynthetic pathways. A variety of alkyl chain decorations and modifications that are found in cyanobacterial natural products are highlighted, illustrating the rich enzymatic arsenal that these organisms have evolved to diversify fatty acid-derived alkyl chains.

Diagnosis of Fibrotic Hypersensitivity Pneumonitis: Is There a Role for Biomarkers?

Hypersensitivity pneumonitis is a complex interstitial lung syndrome and is associated with significant morbimortality, particularly for fibrotic disease. This condition is characterized by sensitization to a specific antigen, whose early identification is associated with improved outcomes. Biomarkers measure objectively biologic processes and may support clinical decisions. These tools evolved to play a crucial role in the diagnosis and management of a wide range of human diseases. This is not the case, however, with hypersensitivity pneumonitis, where there is still great room for research in the path to find consensual diagnostic biomarkers. Gaps in the current evidence include lack of validation, validation against healthy controls alone, small sampling and heterogeneity in diagnostic and classification criteria. Furthermore, discriminatory accuracy is currently limited by overlapping mechanisms of inflammation, damage and fibrogenesis between ILDs. Still, biomarkers such as BAL lymphocyte counts and specific serum IgGs made their way into clinical guidelines, while others including KL-6, SP-D, YKL-40 and apolipoproteins have shown promising results in leading centers and have potential to translate into daily practice. As research proceeds, it is expected that the emergence of novel categories of biomarkers will offer new and thriving tools that could complement those currently available.

New Frontiers in Colorectal Cancer Treatment Combining Nanotechnology with Photo- and Radiotherapy.

Colorectal cancer is the third most common cancer worldwide. Despite recent advances in the treatment of this pathology, which include a personalized approach using radio- and chemotherapies in combination with advanced surgical techniques, it is imperative to enhance the performance of these treatments and decrease their detrimental side effects on patients' health. Nanomedicine is likely the pathway towards solving this challenge by enhancing both the therapeutic and diagnostic capabilities. In particular, plasmonic nanoparticles show remarkable potential due to their dual therapeutic functionalities as photothermal therapy agents and as radiosensitizers in radiotherapy. Their dual functionality, high biocompatibility, easy functionalization, and targeting capabilities make them potential agents for inducing efficient cancer cell death with minimal side effects. This review aims to identify the main challenges in the diagnosis and treatment of colorectal cancer. The heterogeneous nature of this cancer is also discussed from a single-cell point of view. The most relevant works in photo- and radiotherapy using nanotechnology-based therapies for colorectal cancer are addressed, ranging from in vitro studies (2D and 3D cell cultures) to in vivo studies and clinical trials. Although the results using nanoparticles as a photo- and radiosensitizers in photo- and radiotherapy are promising, preliminary studies showed that the possibility of combining both therapies must be explored to improve the treatment efficiency.

Structure and Biosynthesis of Desmamides A-C, Lipoglycopeptides from the Endophytic Cyanobacterium Desmonostoc muscorum LEGE 12446.

Certain cyanobacteria of the secondary metabolite-rich order Nostocales can establish permanent symbioses with a large number of cycads, by accumulating in their coralloid roots and shifting their metabolism to dinitrogen fixation. Here, we report the discovery of two new lipoglycopeptides, desmamides A (1) and B (2), together with their aglycone desmamide C (3), from the nostocalean cyanobacterium Desmonostoc muscorum LEGE 12446 isolated from a cycad (Cycas revoluta) coralloid root. The chemical structures of the compounds were elucidated using a combination of 1D and 2D NMR spectroscopy and mass spectrometry. The desmamides are decapeptides featuring O-glycosylation of tyrosine (in 1 and 2) and an unusual 3,5-dihydroxy-2-methyldecanoic acid residue. The biosynthesis of the desmamides was studied by substrate incubation experiments and bioinformatics. We describe herein the dsm biosynthetic gene cluster and propose it to be associated with desmamide production. The discovery of this class of very abundant (>1.5% d.w.) bacterial lipoglycopeptides paves the way for exploration of their potential role in root endosymbiosis.

SUMO E3 ligase SIZ1 connects sumoylation and reactive oxygen species homeostasis processes in Arabidopsis.

The ubiquitin-like modifying peptide SMALL UBIQUITIN-LIKE MODIFIER (SUMO) has become a known modulator of the plant response to multiple environmental stimuli. A common feature of many of these external stresses is the production of reactive oxygen species (ROS). Taking into account that SUMO conjugates rapidly accumulate in response to an external oxidative stimulus, it is likely that ROS and sumoylation converge at the molecular and regulatory levels. In this study, we explored the SUMO-ROS relationship, using as a model the Arabidopsis (Arabidopsis thaliana) null mutant of the major SUMO-conjugation enhancer, the E3 ligase SAP AND MIZ 1 (SIZ1). We showed that SIZ1 is involved in SUMO conjugate increase when primed with both exogenous and endogenous ROS. In siz1, seedlings were sensitive to oxidative stress imposition, and mutants accumulated different ROS throughout development. We demonstrated that the deregulation in hydrogen peroxide and superoxide homeostasis, but not of singlet O2 (1O2), was partially due to SA accumulation in siz1. Furthermore, transcriptomic analysis highlighted a transcriptional signature that implicated siz1 with 1O2 homeostasis. Subsequently, we observed that siz1 displayed chloroplast morphological defects and altered energy dissipation activity and established a link between the chlorophyll precursor protochlorophyllide and deregulation of PROTOCHLOROPHYLLIDE OXIDOREDUCTASE A (PORA), which is known to drive overproduction of 1O2. Ultimately, network analysis uncovered known and additional associations between transcriptional control of PORA and SIZ1-dependent sumoylation. Our study connects sumoylation, and specifically SIZ1, to the control of chloroplast functions and places sumoylation as a molecular mechanism involved in ROS homeostatic and signaling events.

Effect of the execution order from concurrent exercise session on blood pressure responses in hypertensive older men

Abstract Aim: To compare blood pressure (BP) responses among the different orders of execution of concurrent exercise (CE) sessions in controlled hypertensive older men. Methods: Fifteen older men (64 ± 5 years) participated in three randomized crossover sessions: control session (C), CE in aerobic-resistance order (AR), and resistance-aerobic order (RA). The CE was performed for 1 h, in which 30 min were for the resistance exercise with 5 exercises at 70% of 1RM and 30 min for the aerobic exercise on a treadmill with intensity corresponding to the first ventilatory threshold. Clinical systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP) were measured at rest and over 2 h and 24 h after the session. For analysis, the Generalized Estimating Equations (GEE) test was used with Bonferroni's complimentary test (α = 0.05). Results: The SBP decreased by 30 min after AR, while after RA we obtained reductions during 1 h after a session concerning rest. Between sessions, we found lower values in both CE compared to the C at 30 min, 45 min, and 90 min. In the RA there was a lower pressure in relation to the C at minute 60. The DBP reduced 30 min after the AR regarding the pre-session, however with no difference between sessions. The MBP was lower in relation to 30 min rest after AR. Among sessions, a pressure drop was observed in the AR compared to the C at 30 min and 45 min. Conclusion: We can conclude that the CE was effective in generating post-exercise hypotension regardless of the order in controlled hypertensive older men.

Light-Chain Multiple Myeloma: A Diagnostic Challenge.

Light-chain multiple myeloma (LCMM) is a less frequent type of multiple myeloma (MM), with a more aggressive course and poorer prognosis. It is characterized by the inability of the malignant plasma cells to produce heavy chains, resulting in the exclusive production of light chains. Therefore, no M-spike is visible in serum protein electrophoresis. We described the case of a 67-year-old female who presents to the emergency department with anemia, severe renal insufficiency, and multiple lytic bone lesions. After three days, the diagnosis of kappa light chain multiple myeloma was made in a patient with elevated serum and urinary kappa light chains and a bone marrow aspirate with 21.7% of atypical plasma cells. The rapid diagnosis allowed prompt referral to a specialized multiple myeloma center and early initiation of treatment.

Pervasive hybridization with local wild relatives in Western European grapevine varieties.

Grapevine (Vitis vinifera L.) diversity richness results from a complex domestication history over multiple historical periods. Here, we used whole-genome resequencing to elucidate different aspects of its recent evolutionary history. Our results support a model in which a central domestication event in grapevine was followed by postdomestication hybridization with local wild genotypes, leading to the presence of an introgression signature in modern wine varieties across Western Europe. The strongest signal was associated with a subset of Iberian grapevine varieties showing large introgression tracts. We targeted this study group for further analysis, demonstrating how regions under selection in wild populations from the Iberian Peninsula were preferentially passed on to the cultivated varieties by gene flow. Examination of underlying genes suggests that environmental adaptation played a fundamental role in both the evolution of wild genotypes and the outcome of hybridization with cultivated varieties, supporting a case of adaptive introgression in grapevine.

Eosinophilic Granulomatosis With Polyangiitis With Extensive Cutaneous Involvement.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis. This report describes the case of a 68-year-old female that showed up at the emergency department with extensive haemorrhagic bullous lesions, affecting elbows, the dorsal side of hands, feet and knees, with loss of tissue and necrotic areas. The evaluation led to the diagnosis of antineutrophil cytoplasmic antibody-positive EGPA with multisystem involvement: cutaneous, pulmonary, renal, intestinal and peripheral and central nervous system. She received corticosteroids and intravenous immunoglobulin. She developed multiple infectious complications with multidrug-resistant bacteria. Two months after the diagnosis, the patient had no respiratory or gastrointestinal signs or symptoms, and the proteinuria was mild. Yet, she maintained extensive ulcers and was suffering from disabling dysesthesias. After the resolution of all infections, we decided to start rituximab. She was also submitted to excisional debridement and heterologous graft repair and later to autologous graft repair of elbows and feet. She had a good clinical response with complete healing of the wounds. This case intends to illustrate a serious form of EGPA, with severe multisystem involvement that resulted in great morbidity. It was a clinical challenge to balance the need for immunosuppressive therapy with the high infectious risk of the patient. Nonetheless, we considered that disease control was fundamental to skin recovery, better physical rehabilitation and better quality of life.

Heart failure: the importance of getting the right cause

Amyloidosis is a systemic disease, with an incidence of 5-12 people per million per year. Autopsy studies suggest a higher incidence1. Is characterized by deposition of amyloid fibrils in extracellular tissue of various organs and systems, and therefore with multiple possible presentations. The causative amyloid fibril deposits are of monoclonal light chain (AL) or transthyretin (TTR) in most cases. TTR amyloidosis may be acquired, associated with wild type TTR or hereditary (associated with variants in TTR gene2 (table 1).The AL amyloidosis condition can occur alone or associated with multiple myeloma or other B-cell dyscrasias3. The main affected organs in AL amyloidosis are the heart, kidney, liver, gastrointestinal tract and the peripheral and autonomic nervous systems. Patients often present with non-specific symptoms, such as asthenia, weight loss, palpitations and syncopal attacks4. Thus, diagnosis is usually delayed, and renal and cardiac failure can be forms of pres-entation. We report a case of a 68-year-old woman, who presented with new onset heart failure as the main presentation form of multiple myeloma with associ-ated cardiac amyloidosis. This case highlights the need of a high level of suspicion in order establish an early diagnosis and initiate specific therapy, and therefore delay the development of this condition

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Behçet's Disease and Tuberculosis: A Complex Relationship.

Behçet's disease (BD) is a systemic vasculitis characterized by recurrent orogenital ulceration and several systemic manifestations (such as gastrointestinal involvement, vascular disease or arthritis). The pathogenesis is still unknown but the trigger role of certain pathogens such as Mycobacterium tuberculosis is well documented. Furthermore, patients with BD are more susceptible to tuberculosis due to immunity defects. Here, we describe the case of a 70-year-old woman with a history of recurrent oral aphthae and inflammatory arthritis presenting with extensive thrombosis of left upper limb major veins, a positive HLA B51 genotype and colon ulceration; hence, BD diagnosis was made after excluding other causes. Simultaneously, the patient had cutaneous abscesses not associated with immunosuppressive therapy with continuous development, and after recurrent negative tuberculosis work-up, M. tuberculosis was isolated in an abscess culture. LEARNING POINTS: Patients with Behçet's disease (BD), in the absence of anti-TNF-alpha therapy, have increased susceptibility to tuberculosis due to a defect in cell-mediated immunity.It is very important to distinguish between BD and pseudo-Behçet's at the onset of tuberculosis, since Behçet-like manifestations achieve complete remission with anti-bacillar therapy.Cutaneous tuberculosis is a rare condition, with a wide clinical spectrum; hence, high clinical suspicion, and sometimes, multiple bacteriological examinations, are required in order to diagnose.

Why do some patients with systemic lupus erythematosus fail to respond to B-cell depletion using rituximab?

OBJECTIVES: The Centre for Rheumatology has treated 165 lupus patients with rituximab (RTX) since 2000. Our aim was to identify patients who failed to respond, identify any obvious distinguishing features, and to optimise individual patient treatment. METHODS: We reviewed all 165 lupus patients treated with RTX and reviewed the data up to 6 months after treatment. We excluded those who developed allergic reactions, had discoid lupus only or were lost to follow-up. We assessed patients with active disease after 6 months, using the British Isles Lupus Assessment Group (BILAG) disease activity scores. Those patients whose A and B scores did not decrease, were deemed to have failed to respond. RESULTS: 144 patients were included in the final analysis. The median disease duration was 6.68 (IQR 2.32-11.90) years. 13.9% of the patients failed to decrease their BILAG scores. Two of the 144 patients died during the 6 months after treatment. The median BILAG at baseline was lower in the failure group (8.50, SD 6.00-12.75) at the time of treatment as opposed to those patients who improved (17, SD12.0-23.0) (p<0.001).We found that patients with renal involvement failed less often than those without it (p=0.021). No other significant differences were observed. CONCLUSIONS: Patients with a lower BILAG score are less likely to benefit from RTX treatment. Patients with renal involvement were less likely to fail to respond to RTX. We could not identify other features predictive of failure.

Comparison of Three Classification Criteria Sets for Systemic Lupus Erythematosus: A Study Looking at Links to Outcome and Mortality.

OBJECTIVE: To compare the ability of the American College of Rheumatology (ACR), Systemic Lupus International Collaborating Clinics (SLICC), and European League Against Rheumatism (EULAR)/ACR systemic lupus erythematosus (SLE) classification criteria sets to provide information regarding organ damage and mortality, over a 10-year follow-up period. METHODS: Using data from 100 patients, we completed each classification set at the time of diagnosis and recorded the SLICC/ACR Damage Index (SDI) score, renal damage, major cardiovascular events, and death, 10 years later. We reviewed the presence of other autoantibodies, linked to SLE but not included in the classification criteria sets, and assessed whether they impacted the predictive capacity of the classification sets. RESULTS: We found a statistically significant association between the EULAR/ACR set and renal damage and SDI score, the latter after adjustment for age and sex. In the patients negative for other autoantibodies, higher EULAR/ACR scores were associated with higher rates of organ damage. CONCLUSION: These data suggest that the EULAR/ACR set may offer useful prognostic information, because higher scores were associated with higher rates of organ damage. These findings were clearer in patients negative for nondiagnostic SLE autoantibodies, who may benefit more from the predictive capacity of the EULAR/ACR set.