Search

On Friday, 7 March 2009, a 200 m-long section of the tourist pier in Puerto Colombia collapsed under the impact of the waves generated by a cold front in the area. The aim of this study is to determine the contribution and importance of cold fronts and storms on extreme 5 waves in different areas of the Colombian Caribbean to determine the degree of the threat posed by the flood processes to which these coastal populations are exposed and the actions to which coastal engineering constructions should be subject. In the calculation of maritime constructions, the most important parameter is the wave's height; therefore, it is necessary to definitively know the design wave height to which a coastal engineering structure should be resistant. This wave height varies according to the return period considered. Using Gumbel's extreme value methodology, the significant height values for the study area were calculated. The methodology was evaluated using data from the re-analysis of the spectral NOAA Wavewatch III (WW3) model for points along the 1600km of the Colombia Caribbean coast (continental and insu15 lar) of the last 15 years. The results demonstrated that the extreme waves caused by tropical cyclones and cold fronts have different effects along the Colombian Caribbean coast. Storms and hurricanes are of greater importance in the Guajira Peninsula (Alta Guajira). In the central area formed by Baja Guajira, Santa Marta, Barranquilla, and Cartagena, the strong influence of cold fronts on extreme waves is evident. On the other hand, in the southern region of the Colombian Caribbean coast, from the Gulf of Morrosquillo to the Gulf of Urabá, even though extreme waves are lower than in the previous regions, extreme waves are dominated mainly by the passage of cold fronts. Extreme waves in the San Andrés and Providencia insular region present a different dynamic from that in the continental area due to its geographic location. The wave heights in the extreme regime are similar in magnitude to those found in Alta Guajira, but the extreme waves associated with the passage of cold fronts in this region have lower return periods than the extreme waves associated with hurricane season. These results are of great importance when evaluating the threat of extreme waves in the coastal and port infrastructure, for purposes of the design of new constructions, and in the coastal flood processes due to run-up because, according to the site of interest in the coast, the forces that shape extreme waves are not the same. [ABSTRACT FROM AUTHOR]

Purpose: To describe a case of Vogt-Koyanagi-Harada (VKH) disease after a Covid-19 mRNA vaccine (tozinameran) and to present the results of a pharmacovigilance disproportionality study., Methods: A retrospective chart review and a pharmacovigilance disproportionality study using the WHO global individual case safety reports database (VigiBase)., Results: A 57-year-old female with no medical history developed a VKH disease 3 weeks after Covid-19 mRNA vaccine. Symptoms at onset were headaches and blurred vision associated with aseptic meningitis and bilateral diffuse granulomatous panuveitis with serous retinal detachment. One month from diagnosis and glucocorticoids treatment, the patient recovered. Five similar cases have been reported in VigiBase. VKH disease is disproportionately reported with tozinameran and other vaccines., Conclusion: VKH disease is disproportionately reported with tozinameran, suggesting a possible safety signal. Cases after vaccination support the screening for any possible immune triggers such as vaccines when assessing patients with VKH disease.

Objectives: The emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. We aimed to evaluate seroconversion, cross-neutralisation and T-cell responses induced by BNT162b2 in immunocompromised patients with systemic inflammatory diseases., Methods: Prospective monocentric study including patients with systemic inflammatory diseases and healthcare immunocompetent workers as controls. Primary endpoints were anti-spike antibodies levels and cross-neutralisation of Alpha and Delta variants after BNT162b2 vaccine. Secondary endpoints were T-cell responses, breakthrough infections and safety., Results: Sixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analysed. Kinetics of anti-spike IgG after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralising response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralised Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralising activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after two doses of BNT162b2. Third dose of vaccine improved immunogenicity in patients with low responses., Conclusion: Rituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (ClinicalTrials.gov number, NCT04870411)., Competing Interests: Competing interests: TB, IS and OS are coinventors on provisional patent no. US 63/020,063 entitled ‘S-Flow: a FACS-based assay for serological analysis of SARS-CoV-2 infection’ submitted by Institut Pasteur., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Phosphatase and tensin homolog (PTEN) is a phosphatidylinositol-3,4,5-triphosphate (PIP 3 ) phospholipid phosphatase that is commonly mutated or silenced in cancer. PTEN's catalytic activity, cellular membrane localization and stability are orchestrated by a cluster of C-terminal phosphorylation (phospho-C-tail) events on Ser380, Thr382, Thr383 and Ser385, but the molecular details of this multi-faceted regulation have remained uncertain. Here we use a combination of protein semisynthesis, biochemical analysis, NMR, X-ray crystallography and computational simulations on human PTEN and its sea squirt homolog, VSP, to obtain a detailed picture of how the phospho-C-tail forms a belt around the C2 and phosphatase domains of PTEN. We also visualize a previously proposed dynamic N-terminal α-helix and show that it is key for PTEN catalysis but disordered upon phospho-C-tail interaction. This structural model provides a comprehensive framework for how C-tail phosphorylation can impact PTEN's cellular functions., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: French national guidelines recommend searching for anti-SS-A antibodies during the second-line assessment of stroke in adults < 55 years of age in the absence of an identified etiology. We aimed to assess the impact of finding anti-SS-A antibodies during the etiological investigations of stroke in young adults., Methods: Medical files from all patients ≤ 55 years of age admitted to a single stroke unit during a five-year period and for whom anti-SS-A antibodies were positive were retrospectively analyzed., Results: Twelve patients were included (9 women; median age 48.5 years), with a rate of anti-SS-A antibody positivity of 1.6% (95% confidence interval [0.71-2.55] %; 12/735 admissions). The etiologies of the 12 ischemic events based on the TOAST classification were large-artery atherosclerosis (n = 1), cardioembolism (n = 1), small-vessel disease (n = 1), other determined etiology (n = 3), multiple etiology (n = 1), and no determined etiology (n = 5). A connective tissue disease (CTD) was discovered in 8/12 patients (1 primary Sjögren's Syndrome, 1 mixed CTD, 1 systemic sclerosis, 2 antiphospholipid syndromes, 1 undetermined CTD, 2 lupus). Anti-SSA antibodies were not directly responsible for the stroke in any of the 12 cases. A link between the autoimmune disease and the neurological vascular episode could be hypothesized for four patients, but it never influenced the therapeutic decision., Conclusions: Finding anti-SS-A antibodies during the etiological assessment of a stroke of young adults is rare. However, it may be worthwhile to refer the patient to a rheumatologist/an internist because CTD may be discovered and may require specific follow-up., Competing Interests: Declaration of Competing Interest Dr. NOEL reports personal fees from MSD outside the submitted work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Despite improvement in the prognosis of ANCA-associated vasculitides (AAVs), increased mortality, mainly from a cardiovascular origin, persists. We aimed to determine the role of cardiovascular risk factors (CVRFs) on the occurrence of major cardiovascular events (MACEs) in AAVs. Patients with AAVs were successively included in a prospective cohort study, which assessed CVRFs (defined by age >50 years in men and >60 years in women, personal history of cardiovascular disease, smoking status, obesity, diabetes, dyslipidemia, hypertension, and sedentary lifestyle), the use of glucocorticoids and immunosuppressive agents at baseline and during follow-up, and the occurrence of MACEs. One hundred and three patients were included, with a median follow-up time of 3.5 years. In the glucocorticoids and cyclophosphamide adjusted multivariate analysis, the occurrence of MACEs was associated with older age ( p = 0.001, OR = 14.71, 95% CI (confidence interval) = 2.98-72.68), cardiovascular history ( p = 0.007, OR (odds ratio) = 6.54, 95% CI = 1.66-25.71), sedentary lifestyle ( p = 0.011, OR = 4.50, 95% CI = 1.42-14.29), hypertension ( p = 0.017, OR = 5.04, 95% CI = 1.33-19.12), and dyslipidemia ( p = 0.03, OR = 3.86, 95% CI = 1.14-13.09). The occurrence of MACEs was associated with the number of CVRFs ( p < 0.001), but not with the use of glucocorticoids or cyclophosphamide ( p = 0.733 and p = 0.339, respectively). The implementation of a screening and management program for modifiable CVRFs, particularly hypertension, sedentary lifestyle, and dyslipidemia, may be beneficial for AAV patients in order to reduce their cardiovascular risk.

Objective: Sarcopenia has been associated with poor outcomes in various medical and surgical conditions. However, its impact in systemic necrotizing vasculitides (SNV) had never been characterized. We aimed to assess the prevalence, associated factors and prognostic impact of sarcopenia in SNV., Methods: Patients with SNV were successively included in a prospective longitudinal study assessing comorbidities. At inclusion, we evaluated sarcopenia by assessing skeletal muscle mass index using DXA and muscle strength using handgrip strength. Vasculitis and treatments-related events were recorded and analysed using Cox models., Results: One hundred and twenty patients were included. At inclusion, low handgrip strength (<30 kg for men and 20 kg for women) was identified in 28 (23%) patients, while no patient exhibited low skeletal muscle mass index (<7.23 kg/m2 for men and 5.67 kg/m2 for women). Low handgrip strength was associated with age (P <0.0001), type of vasculitis (P =0.01), vasculitis damage index (P =0.01), history of falls (P =0.0002), osteoporosis (P =0.04), low serum albumin (P =0.003) and prealbumin (P =0.0007), high CRP (P =0.001), high FRAX® tool (P =0.002) and low bone mineral density at femoral neck (P =0.0002). After median follow-up of 42 months, low handgrip strength was associated with higher risk of bone fracture [HR 4.25 (1.37-13.2), P =0.01] and serious adverse events [HR 2.80 (1.35-5.81), P =0.006]., Conclusion: Handgrip strength is associated in SNV with nutritional status and comorbidities such as bone disease, and seems to predict, as in other medical conditions, the risk of fracture and serious adverse events during follow-up. In contrast, assessment of skeletal muscle mass index in this population remains uncertain., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The activity and localization of PTEN, a tumor suppressor lipid phosphatase that converts the phospholipid PIP3 to PIP2, is governed in part by phosphorylation on a cluster of four Ser and Thr residues near the C terminus. Prior enzymatic characterization of the four monophosphorylated (1p) PTENs by using classical expressed protein ligation (EPL) was complicated by the inclusion of a non-native Cys at the ligation junction (aa379), which may alter the properties of the semisynthetic protein. Here, we apply subtiligase-mediated EPL to create wt 1p-PTENs. These PTENs are more autoinhibited than previously appreciated, consistent with the role of Tyr379 in driving autoinhibition. Alkaline phosphatase sensitivity analysis revealed that these autoinhibited 1p conformations are kinetically labile. In contrast to the Cys mutant 1p-PTENs, which are poorly recognized by an anti-phospho-PTEN antibody, three of the four wt 1p-PTENs are recognized by a commonly used anti-phospho-PTEN antibody., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This work sought to confirm the human-like expression of exhaustion and senescence markers in a mouse model with a humanized immune system (HIS): the Balb/c Rag2 KO IL2rgc KO Sirpα NOD Flk2 KO HLA-A2 HHD (BRGSF-A2) mouse reconstituted with human CD34 + cord blood cells. With regard to senescence markers, the percentage of CD57 + T cells was higher in the bone marrow (BM) than in the spleen or blood. The same was true for KLRG1 + hCD8 + T cells. With regard to exhaustion markers, the percentage of programmed death 1 (PD-1 + ) T cells was higher in the BM than in the spleen or blood; the same was true for TIGIT + hCD4 + cells. These tissue-specific differences were related to both higher proportions of memory T cells in BM and intrinsic differences in expression within the memory fraction. In blood samples from HIS mice and healthy human donors (HDs), we found that the percentage of KLRG1 + cells among hCD8 + T cells was lower in HIS compared to HDs. The opposite was true for CD4 + T cells. Unexpectedly, a high frequency of KLRG1 + cells was observed among naive T cells in HIS mice. CD57 expression on T cells was similar in blood samples from HIS mice and HDs. Likewise, PD-1 expression was similar in the two systems, although a relatively low proportion of HIS hCD4 + T cells expressed TIGIT. The BRGSF-A2 HIS mouse's exhaustion and senescence profile was tissue specific and relatively human like; hence, this mouse might be a valuable tool for determining the preclinical efficacy of immunotherapies., (©2019 Society for Leukocyte Biology.)

Background: HIV infection has often been linked to faster immune ageing. We sought to determine whether or not treatment-naive spontaneous HIV-1 controllers (HICs) and ART-exposed patients differ with regard to the expression of cell senescence markers., Methods: Eighty-eight chronically infected HICs and ART-exposed patients (median time since infection: 15 years) with an undetectable plasma HIV RNA load (at least for the previous 2 years) were included. We used flow cytometry to measure immunosenescence markers (KLRG-1 and CD57) expression in fresh blood samples collected from patients and healthy donors., Results: For the CD8 T-cell population as a whole, the ART-exposed but not the HIC patients exhibited a much higher proportion of KLRG-1 and CD57 CD8 T cells than healthy blood donors. For the CD8 T-cell subsets, HICs had a lower proportion of CD57 effector CD8 T cells than ART patients or healthy blood donors, whereas the proportions of KLRG-1 effector were similar. A similar trend was observed for terminal effectors. No impact of age, sex or standard parameters of infection (CD4 percentage, protective HLA allele, viral blips) was observed. The difference in the proportion of CD57 cells between HICs and ART was observed more specifically in long-term infected patients (>20 years). However, whenever considering the CD57 effector memory and effector subsets, the cytotoxic granule content was greater in HICs than in ART., Conclusion: The proportion of CD57 effector CD8 T cells is lower in HICs than in ART-exposed patients. This profile may be beneficial by ensuring limited senescence associated with consistent cytotoxic potential.

An estradiol metabolite, 2-methoxyestradiol (2ME), has emerged as an important regulator of ovarian physiology. 2ME is recognized as a potent anti-angiogenic agent in clinical trials and laboratory studies. However, little is known about its molecular actions and its endogenous targets. 2ME is produced by human ovarian cells during the normal menstrual cycle, being higher during regression of the corpus luteum, and is postulated to be involved in the anti-angiogenic process that plays out during luteolysis. We utilized cell biology techniques to understand the molecular mechanism of 2ME anti-angiogenic effects on human granulosa luteal cells. The principal effect of 2ME was to alter Hypoxia Inducible Factor 1A (HIF1A) sub-cellular localization. Molecular modelling and multiple bioinformatics tools indicated that 2ME impairs Hypoxia Inducible Factor complex (HIF) nuclear translocation by binding to a buried pocket in the HIF1A Per Arnt Sim (PAS)-B domain. Binding of 2ME to HIF1A protein is predicted to perturb HIF1A-Hypoxia Inducible Factor B (HIFB) interaction, a key step in HIF nuclear translocation, preventing the transcriptional actions of HIF, including Vascular Endotelial Growth Factor (VEGF) gene activation. To our knowledge, 2ME is the first putative HIF endogenous ligand characterized with anti-angiogenic activity. This postulate has important implications for reproduction, because angiogenic processes are critical for ovarian follicular development, ovulation and corpus luteum regression. The present research could contribute to the development of novel pharmacological approaches for controlling HIF activity in human reproductive diseases., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: Cardiovascular (CV) events are highly prevalent in systemic necrotising vasculitides (SNV). Visceral/subcutaneous adipose tissue (VAT/SAT) ratio has been shown to be associated with CV events in various diseases. We aimed to assess the relevance of abdominal adipose tissue measurement to predict major CV events (MCVEs) in SNV., Methods: Patients with SNV were successively included in a longitudinal study assessing MCVEs and other sequelae. Dual x-ray absorptiometry was performed to evaluate abdominal adipose tissue. Patients were prospectively followed for MCVEs, defined as myocardial infarction, unstable angina, stroke, arterial revascularisation and/or hospitalisation for or death from CV causes., Results: One hundred and twenty consecutive SNV patients were included and analysed (54 males, mean age 53±18 years). High CV risk was found in 28 (23.3%) patients. In univariate analysis, age, male gender, VDI, VAT/SAT ratio and serum troponin level were significantly associated with high CV risk, whereas age and VAT/SAT ratio remained independently associated with high CV risk. Variables associated with high tertile of VAT/SAT ratio included age and metabolic risk factors. After median follow-up of 42 months, 19 (16%) patients experienced MCVEs. Hazard ratios for incident MCVEs compared with 1st tertile of VAT/SAT ratio were 7.22 (1.02-51.3; p=0.048) and 9.90 (3.15-31.2; p=0.0002) in the 2nd and 3rd tertile, respectively., Conclusions: Abdominal visceral adipose tissue is a reliable surrogate marker of CV risk and predicts incident MCVEs in SNV patients. Abdominal adipose tissue should be probably evaluated routinely in these patients to assess CV risk.

Glucocorticoids are involved in several responses triggered by a variety of environmental and physiological stimuli. These hormones have a wide-range of regulatory effects in organisms. Synthetic glucocorticoids are extensively used to suppress allergic, inflammatory, and immune disorders. Although glucocorticoids are highly effective for therapeutic purposes, some patients chronically treated with glucocorticoids can develop reduced glucocorticoid sensitivity or even resistance, increasing patient vulnerability to exaggerated inflammatory responses. Glucocorticoid resistance can occur in several chronic diseases, including asthma, major depression, and cardiovascular conditions. In this review, we discuss the complexity of the glucocorticoid receptor and the potential role of glucocorticoid resistance in the development of chronic diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The recent discovery of significant hydropersulfide (RSSH) levels in mammalian tissues, fluids and cells has led to numerous questions regarding their possible physiological function. Cysteine hydropersulfides have been found in free cysteine, small molecule peptides as well as in proteins. Based on their chemical properties and likely cellular conditions associated with their biosynthesis, it has been proposed that they can serve a protective function. That is, hydropersulfide formation on critical thiols may protect them from irreversible oxidative or electrophilic inactivation. As a prelude to understanding the possible roles and functions of hydropersulfides in biological systems, this study utilizes primarily chemical experiments to delineate the possible mechanistic chemistry associated with cellular protection. Thus, the ability of hydropersulfides to protect against irreversible electrophilic and oxidative modification was examined. The results herein indicate that hydropersulfides are very reactive towards oxidants and electrophiles and are modified readily. However, reduction of these oxidized/modified species is facile generating the corresponding thiol, consistent with the idea that hydropersulfides can serve a protective function for thiol proteins., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Recent reports indicate the ubiquitous prevalence of hydropersulfides (RSSH) in mammalian systems. The biological utility of these and related species is currently a matter of significant speculation. The function, lifetime and fate of hydropersulfides will be assuredly based on their chemical properties and reactivity. Thus, to serve as the basis for further mechanistic studies regarding hydropersulfide biology, some of the basic chemical properties/reactivity of hydropersulfides was studied. The nucleophilicity, electrophilicity and redox properties of hydropersulfides were examined under biological conditions. These studies indicate that hydropersulfides can be nucleophilic or electrophilic, depending on the pH (i.e. the protonation state) and can act as good one- and two-electron reductants. These diverse chemical properties in a single species make hydropersulfides chemically distinct from other, well-known sulfur containing biological species, giving them unique and potentially important biological function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: to asses Total Energy Expenditure (TEE) in healthy Chilean institutionalized or independently older people Methods: twenty seven young (27-30 years), 27 institutionalized (> 65 years old) and 27 free-living older (> 65 years old) participants were studied. Body composition was estimated by dual energy X-ray absorptiometry. Physical activity energy expenditure (AEE) and TEE were assessed using Actiheart accelerometers. The Mini Nutritional Assessment (MNA) was applied and Timed Up and Go (TUG) was measured., Results: AEE was 171, 320 and 497 kcal/day in institutionalized, free living older and young participants, respectively (p < 0.01 between young and older participants). Both absolute TEE and TEE/RMR was higher in young people. Multiple regression analysis accepted age, MNA and TUG as significant predictors of AEE (r2 = 0.24 p < 0.01)., Conclusion: AEE and PAL were lower among older people, with no differences by institutionalization., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Background: Simple and reliable methods to evaluate muscle mass in older people are lacking., Aim: To evaluate ultrasound as a measure of RF muscle mass and quality in healthy subjects of different ages and gender, assessing its concordance with dual energy X-ray densitometry (DEXA) and association with muscle strength and walking capacity., Methods: We selected 54 adults of both genders, aged 20-55 years and 51 adults older than 60 years. Ultrasound images of the RF were obtained at the mid-thigh to measure its thickness and ultrasonographic density using a GE Logiq e equipment. Body composition was assessed by DEXA. Quadriceps isometric strength and 12 minutes' walk were also measured and gender specific t scores for older adults were calculated using the values obtained in adults., Results: RF ultrasound measurements correlated significantly with lean body mass assessed by DEXA (Double energy X-ray absorptiometry). The concordance between both measures was also adequate. Older people had lower muscle mass and worse ultrasound parameters than adults. Older males with a t score for quadriceps strength of -2 or less, had a significantly higher RF grayscale density. Older males with a 12 minutes' walk t score of -2 or less and old males and females with a walking speed of 1m/s or less had a lower RF thickness., Discussion: There is a good concordance between RF ultrasound and DEXA., Conclusions: Assessment of RF using ultrasound appears to be a reliable and accurate method to evaluate muscle mass in older people., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Caveolin-1 (CAV1) has been implicated both in tumor suppression and progression, whereby the specific role appears to be context dependent. Endometrial cancer is one of the most common malignancies of the female genital tract; however, little is known about the role of CAV1 in this disease., Methods: Here, we first determined by immunohistochemistry CAV1 protein levels in normal proliferative human endometrium and endometrial tumor samples. Then using two endometrial cancer cell lines (ECC: Ishikawa and Hec-1A) we evaluated mRNA and protein levels of CAV1 by real time qPCR and Western blot analysis, respectively. The role of CAV1 expression in ECC malignancy was further studied by either inducing its expression in endometrial cancer cells with the tumor promotor 12-O-tetradecanoyl-phorbol-13-acetate (4β-TPA) or decreasing expression using short-hairpin RNA constructs, and then evaluating the effects of these changes on ECC proliferation, transmigration, matrigel invasion, and colony formation in soft agar., Results: Immunohistochemical analysis of endometrial epithelia revealed that substantially higher levels of CAV1 were present in endometrial tumors than the normal proliferative epithelium. Also, in Ishikawa and Hec-1A endometrial cancer cells CAV1 expression was readily detectable. Upon treatment with 4β-TPA CAV1 levels increased and coincided with augmented cell transmigration, matrigel invasion, as well as colony formation in soft agar. Reduction of CAV1 expression using short-hairpin RNA constructs ablated these effects in both cell types whether treated or not with 4β-TPA. Alternatively, CAV1 expression appeared not to modulate significantly proliferation of these cells., Conclusion: Our study shows that elevated CAV1, observed in patients with endometrial cancer, is linked to enhanced malignancy of endometrial cancer cells, as evidenced by increased migration, invasion and anchorage-independent growth.