Observations of diapycnal upwelling within a sloping submarine canyon.

Small-scale turbulent mixing drives the upwelling of deep water masses in the abyssal ocean as part of the global overturning circulation1. However, the processes leading to mixing and the pathways through which this upwelling occurs remain insufficiently understood. Recent observational and theoretical work2-5 has suggested that deep-water upwelling may occur along the ocean's sloping seafloor; however, evidence has, so far, been indirect. Here we show vigorous near-bottom upwelling across isopycnals at a rate of the order of 100 metres per day, coupled with adiabatic exchange of near-boundary and interior fluid. These observations were made using a dye released close to the seafloor within a sloping submarine canyon, and they provide direct evidence of strong, bottom-focused diapycnal upwelling in the deep ocean. This supports previous suggestions that mixing at topographic features, such as canyons, leads to globally significant upwelling3,6-8. The upwelling rates observed were approximately 10,000 times higher than the global average value required for approximately 30 × 106 m3 s-1 of net upwelling globally9.

On the role of seamounts in upwelling deep-ocean waters through turbulent mixing.

Turbulent mixing in the ocean exerts an important control on the rate and structure of the overturning circulation. However, the balance of processes underpinning this mixing is subject to significant uncertainties, limiting our understanding of the overturning's deep upwelling limb. Here, we investigate the hitherto primarily neglected role of tens of thousands of seamounts in sustaining deep-ocean upwelling. Dynamical theory indicates that seamounts may stir and mix deep waters by generating lee waves and topographic wake vortices. At low latitudes, stirring and mixing are predicted to be enhanced by a layered vortex regime in the wakes. Using three realistic regional simulations spanning equatorial to middle latitudes, we show that layered wake vortices and elevated mixing are widespread around seamounts. We identify scalings that relate mixing rate within seamount wakes to topographic and hydrographic parameters. We then apply such scalings to a global seamount dataset and an ocean climatology to show that seamount-generated mixing makes an important contribution to the upwelling of deep waters. Our work thus brings seamounts to the fore of the deep-ocean mixing problem and urges observational, theoretical, and modeling efforts toward incorporating the seamounts' mixing effects in conceptual and numerical ocean circulation models.

Development of a Multiplex Immunofluorescence Assay for Tumor Microenvironment Studies of Human and Murine Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Checkpoint inhibitor immunotherapy plays an essential role in management of advanced MCC; however, predictors of immunotherapy response remain poorly defined. Syngeneic mouse models suitable for testing novel immunotherapy and combination therapy approaches are likely to soon become available and will require assays for evaluating the tumor microenvironment (TME). Multiplex immunofluorescence (mIF) is a powerful approach to characterize the TME for understanding immunotherapy responses and immune surveillance. In this method article, we provide detailed instructions on assay development for mIF, using as examples 2 new mIF panels for TME investigations of human and murine MCC tumors. Specifically, we demonstrate panels that allow simultaneous visualization of the Merkel cell master transcription factor SOX2 for tumor cell identification, alongside T-cell markers (CD3, CD8, and FOXP3), macrophage markers (F4/80 for mouse and CD163 for human tumors), together with the checkpoint marker PD-L1 for human tumors, and the myeloid-derived suppressor cell marker Arg1 for mouse tumors. We provide detailed protocols for investigators to incorporate these mIF panels into their investigations of human and murine MCC. We also provide fundamental guidance for mIF assay development that will be broadly useful for investigators who consider modifying the panels presented in this study or developing their own mIF panels.

Haematopoietic cell transplantation for 106 infants and preschoolers with acquired and inherited bone marrow failures.

Aplastic anaemia in infants and young children presents unique challenges due to high prevalence of inherited bone marrow failure syndromes (IBMFS) in this age group. The objective of this study is assessing clinical characteristics and outcomes of haematopoietic cell transplantation in children ≤5 years with bone marrow failure syndromes. We analysied 106 patients (66% males), median age 4.6 years, including 40 with Fanconi anaemia (FA), 32 with Acquired Severe Aplastic anaemia (aSAA), 15 with Diamond-Blackfan Anaemia, 11 with Amegakaryocytic Purpura and 8 with other IBMFS. Molecular testing was limited (39%), with 25.4% confirmed genetically. Retrospective longitudinal study across three paediatric transplantation centres (1982-2020). Overall survival (OS) was 76.4% over a median 10-year follow-up. OS rates were similar between aSAA and IBMFS (FA 77.5%, other IBMFS 76.5%). Transplant-related mortality (TRM) was lower in aSAA (9.4%) compared with IBMFS (16.2%). Recent years showed improved outcomes, with TRM declining post-2010. Choice of stem cell source impacted OS, favouring bone marrow over umbilical cord, but showing encouraging results with haploidentical. Late complications were common, including endocrine-metabolic issues and delayed neuropsychomotor development. Diagnosing and managing bone marrow failures in young children pose significant challenges. Despite advancements in transplant practices, ongoing vigilance and comprehensive care are necessary to improve long-term survival rates.

The urinary and prostatic microbiome in non-neurogenic male LUTS/BPH: A systematic review.

INTRODUCTION: Despite advancements in the treatment of benign prostatic hyperplasia (BPH), the mechanisms underlying BPH development and progression remain elusive and lacks a one-size-fits-all therapeutic solution. Prostatic inflammation contributes to BPH and lower urinary tract symptoms (LUTS), but the initial trigger remains unknown. Current research suggests dysbiosis of the urinary microbiome as a potential culprit. This systematic review explores the emerging field of the male urinary and prostatic microbiome and its relationship with BPH/LUTS. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. A systematic search in the Pubmed and Scopus databases was performed using specific terms. Inclusion criteria considered male non-neurogenic patients with LUTS due to BPH with analyses of urinary microbiome, concerning evaluation of English-language publications with relevance. RESULTS: Among seven articles involving 542 patients, there was an association between male LUTS/BPH and the urinary microbiome. Findings indicate a correlation between urinary microbiome dysbiosis and LUTS severity, with specific bacterial genera such as Streptococcus and Haemophilus linked to higher International Prostate Symptom Score (IPSS) scores and PSA levels. The fecal microbiome may be associated with LUTS, although contradictory findings are reported. The review also highlights methodological inconsistencies, small sample sizes, few negative controls and a lack of comprehensive clinical data as major limitations. CONCLUSIONS: While there is an undeniable correlation between the microbiome and LUTS/BPH, future research should aim to standardize sampling techniques and expand the score to include functional microbiome characterization, potentially leading to novel, microbiome-targeted therapeutic strategies for BPH.

Grapevine woody tissues accumulate stilbenoids following bud burst.

MAIN CONCLUSION: After bud burst, a transcriptional reprogramming of the shikimate and phenylpropanoid pathways occurs in grapevine canes resulting in the accumulation of stilbenoids like resveratrol and viniferin. Stilbenoids are phenylpropanoid compounds with important biological properties and biotechnological applications that are synthesized in grapevine in response to different stresses. Although they are found in woody tissues, such as canes and buds, their biosynthesis and accumulation have been essentially described in berries. We have previously shown that transcripts encoding secondary metabolism enzymes accumulate in grapevine canes following the transition from dormancy (E-L 1) to bud burst (E-L 4) suggesting that secondary metabolites may accumulate in grapevine canes during this transition. In the present study, using UPLC-MS we demonstrate the accumulation of important metabolites such as ferulic acid and the stilbenoids E-resveratrol, E-piceatannol and E-ε-viniferin. Stilbenoids accumulation correlated with the increased expression of several stilbene synthase genes and of VviMYB14, encoding a transcription factor that regulates stilbene biosynthesis. In addition, a general stimulation of the plastidial shikimate pathway was observed. Taken together, results show that important secondary metabolites accumulate in the woody canes during bud burst. These findings may aid biotechnological approaches aimed at extracting biologically active phenolic compounds, including stilbenoids, from grapevine woody tissues.

Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.

BACKGROUND: Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes. OBJECTIVE: To describe the outcome of TBD patients transplanted for marrow failure. STUDY DESIGN: This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019. RESULTS: The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD. CONCLUSIONS: Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.

Vigorous lateral export of the meltwater outflow from beneath an Antarctic ice shelf.

The instability and accelerated melting of the Antarctic Ice Sheet are among the foremost elements of contemporary global climate change. The increased freshwater output from Antarctica is important in determining sea level rise, the fate of Antarctic sea ice and its effect on the Earth's albedo, ongoing changes in global deep-ocean ventilation, and the evolution of Southern Ocean ecosystems and carbon cycling. A key uncertainty in assessing and predicting the impacts of Antarctic Ice Sheet melting concerns the vertical distribution of the exported meltwater. This is usually represented by climate-scale models as a near-surface freshwater input to the ocean, yet measurements around Antarctica reveal the meltwater to be concentrated at deeper levels. Here we use observations of the turbulent properties of the meltwater outflows from beneath a rapidly melting Antarctic ice shelf to identify the mechanism responsible for the depth of the meltwater. We show that the initial ascent of the meltwater outflow from the ice shelf cavity triggers a centrifugal overturning instability that grows by extracting kinetic energy from the lateral shear of the background oceanic flow. The instability promotes vigorous lateral export, rapid dilution by turbulent mixing, and finally settling of meltwater at depth. We use an idealized ocean circulation model to show that this mechanism is relevant to a broad spectrum of Antarctic ice shelves. Our findings demonstrate that the mechanism producing meltwater at depth is a dynamically robust feature of Antarctic melting that should be incorporated into climate-scale models.

Red biocolorant from endophytic Talaromyces minnesotensis: production, properties, and potential applications.

Fungal colorants are gradually entering the global color market, given their advantages of being less harmful to human health, as well as having greater stability and biotechnological potential, compared to other natural sources. The present work concerns the isolation and identification of an endophytic filamentous fungus, together with the chemical characterization and assessment of the fluorescence, toxicity, stability, and application potential of its synthesized red colorant. The endophytic fungus was isolated from Hymenaea courbaril, a tree from the Brazilian savannah, and was identified as Talaromyces minnesotensis by phenotypic and genotypic characterization. Submerged cultivation of the fungus resulted in the production of approximately 12 AU500 of a red biocolorant which according to LC-DAD-MS analysis is characterized by being a complex mixture of molecules of the azaphilone class. Regarding cytotoxicity assays, activity against human hepatoblastoma (HepG2) cells was only observed at concentrations above 5.0 g L-1, while antimicrobial effects against pathogenic bacteria and yeast occurred at concentrations above 50.0 g L-1. The biocolorant showed high stability at neutral pH values and low temperatures (10 to 20 °C) and high half-life values (t1/2), which indicates potential versatility for application in different matrices, as observed in tests using detergent, gelatin, enamel, paint, and fabrics. The results demonstrated that the biocolorant synthesized by Talaromyces minnesotensis has potential for future biotechnological applications. KEY POINTS: • An endophytic fungus, which was isolated and identified, synthesize a red colorant. • The colorant showed fluorescence property, low toxicity, and application potential. • The red biocolorant was highly stable at pH 8.0 and temperatures below 20°C.

Movement and vertical habitat use of yellowfin tuna Thunnus albacares in a vertically compressed habitat: the Galápagos Marine Reserve.

Tropical pelagic predators are exploited by fisheries and their movements are influenced by factors including prey availability, temperature, and dissolved oxygen levels. As the biophysical parameters vary greatly within the range of circumtropical species, local studies are needed to define those species' habitat preference and model possible behavioral responses under different climate change scenarios. Here, we tagged yellowfin tuna Thunnus albacares in the Galápagos Marine Reserve and tracked the horizontal and vertical movements of eight individuals for 4-97 days. The tuna traveled a mean of 13.6 km day-1 horizontally and dispersed throughout the archipelago and in offshore waters inside the Galápagos Marine Reserve and in the surrounding Ecuadorian exclusive economic zone. Vertically, they traveled a mean of 2 km day-1 , although high-resolution data from a recovered tag suggested that transmitted data underestimated their vertical movement by a factor of 5.5. The tracked yellowfin tuna spent most of their time near the surface, with an overall mean swimming depth of 24.3 ± 46.6 m, and stayed shallower at night (11.1 ± 16.3 m) than during the day ( 37.7 ± 60.9 m), but on occasion dived to cold, oxygen-poor waters below 200 m. Deep dives were commonly made during the day with a mean recovery period of 51 min between exposures to modeled oxygen-limiting conditions <1.5 mL L-1 , presumably to re-oxygenate. The depth and frequency of dives were likely limited by dissolved oxygen levels, as oxygen-depleted conditions reach shallow depths in this region. The main habitat of tracked yellowfin tunas was in the shallow mixed layer, which may leave them vulnerable to fishing. Vertical expansion of low-oxygen waters under future climate change scenarios may further compress their habitat, increasing their vulnerability to surface fishing gear.

Neuronal membrane glycoprotein (nmgp-1) gene deficiency affects chemosensation-related behaviors, dauer exit and egg-laying in Caenorhabditis elegans.

The nervous system monitors the environment to maintain homeostasis, which can be affected by stressful conditions. Using mammalian models of chronic stress, we previously observed altered brain levels of GPM6A, a protein involved in neuronal morphology. However, GPM6A's role in systemic stress responses remains unresolved. The nematode Caenorhabditis elegans expresses a GPM6A ortholog, the neuronal membrane glycoprotein 1 (NMGP-1). Because of the shared features between nematode and mammalian nervous systems and the vast genetic tools available in C. elegans, we used the worm to elucidate the role of GPM6A in the stress response. We first identified nmgp-1 expression in different amphid and phasmid neurons. To understand the nmgp-1 role, we characterized the behavior of nmgp-1(RNAi) animals and two nmgp-1 mutant alleles. Compared to control animals, mutant and RNAi-treated worms exhibited increased recovery time from the stress-resistant dauer stage, altered SDS chemosensation and reduced egg-laying rate resulting in egg retention (bag-of-worms phenotype). Silencing of nmgp-1 expression induced morphological abnormalities in the ASJ sensory neurons, partly responsible for dauer exit. These results indicate that nmgp-1 is required for neuronal morphology and for behaviors associated with chemosensation. Finally, we propose nmgp-1 mutants as a tool to screen drugs for human nervous system pathologies.

Comparison of Sample Preparation Techniques for the (-)ESI-FT-ICR-MS Analysis of Humic and Fulvic Acids.

Soil organic matter (SOM) plays a key role in the global carbon and nitrogen cycles. Soil biogeochemistry is regularly studied by extracting the base-soluble fractions of SOM: acid-insoluble humic acid (HA) and acid-soluble fulvic acid (FA). Electrospray ionization-Fourier transform-ion cyclotron resonance-mass spectrometry (ESI-FT-ICR-MS) is commonly utilized for molecularly characterizing these fractions. Different sample preparation techniques exist for the analysis of HA and FA though questions remain regarding data comparability following different preparations. Comparisons of different sample preparation techniques here revealed that the negative-mode ESI-FT-ICR-MS analytical window can be skewed to detect different groups of molecules, with primary differences in oxygenation, aromaticity, and molecular weight. It was also observed that HA and FA from soils versus an aquatic matrix behaved very differently. Thus, we conclude that sample preparation techniques determined to be "most optimal" in our study are in no way universal. We recommend that future studies of HA and FA involve similar comparative studies for determining the most suitable sample preparation technique for their particular type of HA or FA matrices. This will enhance data comparability among different studies and environmental systems and ultimately allow us to better understand the complex composition of environmental matrices.

Rapid mixing and exchange of deep-ocean waters in an abyssal boundary current.

The overturning circulation of the global ocean is critically shaped by deep-ocean mixing, which transforms cold waters sinking at high latitudes into warmer, shallower waters. The effectiveness of mixing in driving this transformation is jointly set by two factors: the intensity of turbulence near topography and the rate at which well-mixed boundary waters are exchanged with the stratified ocean interior. Here, we use innovative observations of a major branch of the overturning circulation-an abyssal boundary current in the Southern Ocean-to identify a previously undocumented mixing mechanism, by which deep-ocean waters are efficiently laundered through intensified near-boundary turbulence and boundary-interior exchange. The linchpin of the mechanism is the generation of submesoscale dynamical instabilities by the flow of deep-ocean waters along a steep topographic boundary. As the conditions conducive to this mode of mixing are common to many abyssal boundary currents, our findings highlight an imperative for its representation in models of oceanic overturning.

COVID-19 and Acute Kidney Injury - Direct and Indirect Pathophysiological Mechanisms Underlying Lesion Development.

COVID-19 is a pandemic disease caused by the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) responsible for millions of deaths worldwide. Although the respiratory system is the main target of COVID-19, the disease can affect other organs, including the kidneys. Acute Kidney Injury (AKI), commonly seen in patients infected with COVID-19, has a multifactorial cause. Several studies associate this injury with the direct involvement of the virus in renal cells and the indirect damage stimulated by the infection. The direct cytopathic effects of SARS-CoV-2 are due to the entry and replication of the virus in renal cells, changing several regulatory pathways, especially the renin-angiotensin-aldosterone system (RAAS), with repercussions on the kallikrein-kinin system (KKS). Furthermore, the virus can deregulate the immune system, leading to an exaggerated response of inflammatory cells, characterizing the state of hypercytokinemia. The such exaggerated inflammatory response is commonly associated with hemodynamic changes, reduced renal perfusion, tissue hypoxia, generation of reactive oxygen species (ROS), endothelial damage, and coagulopathies, which can result in severe damage to the renal parenchyma. Thereby, understanding the molecular mechanisms and pathophysiology of kidney injuries induced by SARS-COV-2 is of fundamental importance to obtaining new therapeutic insights for the prevention and management of AKI.

Prognostic impact of lung adenocarcinoma second predominant pattern from a large European database.

BACKGROUND AND OBJECTIVES: Adenocarcinoma patterns could be grouped based on clinical behaviors: low- (lepidic), intermediate- (papillary or acinar), and high-grade (micropapillary and solid). We analyzed the impact of the second predominant pattern (SPP) on disease-free survival (DFS). METHODS: We retrospectively collected data of surgically resected stage I and II adenocarcinoma. SELECTION CRITERIA: anatomical resection with lymphadenectomy and pathological N0. Pure adenocarcinomas and mucinous subtypes were excluded. Recurrence rate and factors affecting DFS were analyzed according to the SPP focusing on intermediate-grade predominant pattern adenocarcinomas. RESULTS: Among 270 patients, 55% were male. The mean age was 68.3 years. SPP pattern appeared as follows: lepidic 43.0%, papillary 23.0%, solid 14.4%, acinar 11.9%, and micropapillary 7.8%. The recurrence rate was 21.5% and 5-year DFS was 71.1%. No difference in DFS was found according to SPP (p = .522). In patients with high-grade SPP, the percentage of SPP, age, and tumor size significantly influenced DFS (p = .016). In patients with lepidic SPP, size, male gender, and lymph-node sampling (p = .005; p = .014; p = .038, respectively) significantly influenced DFS. CONCLUSIONS: The impact of SPP on DFS is not homogeneous in a subset of patients with the intermediate-grade predominant patterns. The influence of high-grade SPP on DFS is related to its proportion in the tumor.

Synergy of Aspergillus niger and Components in Biofertilizer Composites Increases the Availability of Nutrients to Plants.

Intensive fertilization has been required to provide nutrients for plant growth under the current agricultural practices being applied to meet the global food demands. Micronutrients such as zinc, manganese, and copper are required in small quantities when compared to macronutrients (such as nitrogen, phosphorus and potassium), but they are essential for the plant growth cycle and consequently for increasing productivity. Mineral oxides such as ZnO, MnO, and CuO are used in agriculture as micronutrient sources, but their low solubility limits practical applications in plant nutrition. Similarly, elemental sulfur (S0) can provide a high-concentration source of sulfate, but its availability is limited by the ability of the soil to promote S0 oxidation. We propose here the integration of these nutrients in a composite based on a biodegradable starch matrix containing mineral oxides and S0 in a dispersion that allowed encapsulation of the acidifying agent Aspergillus niger, a native soil fungus. This strategy effectively improved the final nutrient solubility, with the composite starch/S0/oxidemixture multi-nutrient fertilizer showing remarkable results for solubilization of the oxides, hence confirming a synergic effect of S0 oxidation and microbial solubilization. This composite exhibited an extended shelf life and soil-plant experiments with Italian ryegrass (Lolium multiflorum Lam.) confirmed high efficiencies for dry matter production, nutrient uptake, and recovery. These findings can contribute to the development of environmentally friendly fertilizers towards a more sustainable agriculture and could open up new applications for formulations containing poorly soluble oxide sources.

In vivo anti-inflammatory and antinociceptive effects, and in vitro antioxidant, antiglycant and anti-neuroinflammatory actions of Syzygium malaccense.

Syzygium malaccense is popularly used to treat inflammation and pain-related ailments. The species was assessed regarding its antioxidant, antiglycant, anti-inflammatory, including anti-neuroinflammatory, and antinociceptive activities. Different models were employed to measure S. malaccense extract (ESM) antioxidant activity. The antiglycant activity was determined using the glucose-induced protein glycation model. LPS-induced neuroinflammation on murine BV-2 microglial cell line was used for anti-neuroinflammatory activity evaluation. The croton oil-induced ear edema test was accomplished to evaluate the in vivo anti-inflammatory activity. Acetic acid-induced writhing together with formalin-induced paw licking assays were performed to evaluate the antinociceptive potential. Finally, the chemical characterization was accomplished by a UHPLC-MS analysis. ESM presented relevant antioxidant and antiglycant activity. NO production by BV-2 cells was reduced, indicating the relevant neuroprotective activity. ESM significantly decreased the mice ear edema induced by croton oil and the nociceptive stimulus induced by acetic acid and formalin by central and peripheral mechanisms. The flavonoids myricitrin, myricetin and quercetin were identified and, as far as we know, the alkaloid reserpine was reported in the species for the first time. The antioxidant and antiglycant potential of ESM, may be related to the in vivo anti-inflammatory and antinociceptive effects, and to the in vitro neuroinflammation inhibition.

Primary Hodgkin lymphoma of the lung arising with hemoptysis and pulmonary consolidation: a case report.

Classic Hodgkin lymphomas are neoplasms originating from lymphoid tissue. Primary extra-nodal classic Hodgkin lymphoma (PE-cHL) of the lung is rare. A 37-years-old Caucasian male was referred to our hospital for recurrent episodes of hemoptysis, cough and bronchitis. A computed tomography (CT) scan showed a massive left upper lung consolidation, which was positive at the positron emission tomography (PET) scan. After several inconclusive tests and no benefit from medical therapies, the patient underwent a left upper lobectomy; pathology report showed a classical type Hodgkin lymphoma with no lymph-nodes involvement. Four cycles of adjuvant chemotherapy were administered with no toxicity. At the last follow up 14 months after surgery, the patient is alive and free from disease. Primary extra-nodal classical Hodgkin lymphoma of the lung is a rare entity, but it should be considered as a differential diagnosis in young patients with pulmonary consolidation even without systemic symptoms.

Cutaneous ulcers revealing diphtheria: A re-emerging disease imported from Indian Ocean countries?

INTRODUCTION: Diphtheria due to Corynebacteriumdiphtheriae (C. diphtheriae) has become rare in developed countries. In France only 10 cases of toxigenic diphtheria have been reported since 1989, in all cases causing pharyngitis and all emanating from endemic countries with exception of one contact case. We report herein 13 cases with cutaneous diphtheria, in 5 of which diphtheria toxin was produced, and all imported into France between 2015 and 2018. OBSERVATIONS: Thirteen patients aged 4 to 77 years presented painful and rapidly progressive round ulcerations of the legs, that were superficial and in some cases purulent, with an erythematous-purple border covered with greyish membrane. Bacteriological sampling of ulcers revealed the presence of C. diphtheriae. Only 6 patients had been properly immunized over the preceding 5 years. DISCUSSION: These cases underline the resurgence of cutaneous diphtheria and the circulation of toxigenic strains in France following importation from Indian Ocean countries. This may constitute an important reservoir for ongoing transmission of the disease. Re-emergence of this pathogen stems from the current migratory flow and decreased adult booster coverage. CONCLUSION: Cutaneous diphtheria should be considered in cases of rapidly developing painful skin ulcers with greyish membrane, especially among patients returning from endemic areas, regardless of their vaccination status. The clinician should order specific screening for C. diphtheriae from the bacteriologist, since with routine swabbing Corynebacteriaceae may be reported simply as normal skin flora. Vaccination protects against toxigenic manifestations but not against actual bacterial infection. Early recognition and treatment of cutaneous diphtheria and up-to-date vaccination are mandatory to avoid further transmission and spread of both cutaneous and pharyngeal diphtheria.

Randomized, placebo-controlled, double-blind, pilot trial to investigate safety and efficacy of Cerebrolysin in patients with aneurysmal subarachnoid hemorrhage.

ASBTRACT: BACKGROUND: There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI). RESULTS: No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 1.49; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79-15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28-2.59). CONCLUSIONS: Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients. CLINICAL TRIAL REGISTRATION: Name of Registry: ClinicalTrials.gov Trial Registration Number: NCT01787123 . Date of Registration: 8th February 2013.