Differential impairment of catecholaminergic cell maturation and survival by genetic mitochondrial complex II dysfunction

The SDHD gene (subunit D of succinate dehydrogenase) has been shown to be involved in the generation of paragangliomas and pheochromocytomas. Loss of heterozygosity of the normal allele is necessary for tumor transformation of the affected cells. As complete SdhD deletion is lethal, we have generated mouse models carrying a “floxed” SdhD allele and either an inducible (SDHD-ESR strain) or a catecholaminergic tissue-specific (TH-SDHD strain) CRE recombinase. Ablation of both SdhD alleles in adult SDHD-ESR mice did not result in generation of paragangliomas or pheochromocytomas. In contrast, carotid bodies from these animals showed smaller volume than controls. In accord with these observations, the TH-SDHD mice had decreased cell numbers in the adrenal medulla, carotid body, and superior cervical ganglion. They also manifested inhibited postnatal maturation of mesencephalic dopaminergic neurons and progressive cell loss during the first year of life. These alterations were particularly intense in the substantia nigra, the most affected neuronal population in Parkinson’s disease. Unexpectedly, TH_ neurons in the locus coeruleus and group A13, also lacking the SdhD gene, were unaltered. These data indicate that complete loss of SdhD is not sufficient to induce tumorigenesis in mice. They suggest that substantia nigra neurons are more susceptible to mitochondrial damage than other catecholaminergic cells, particularly during a critical postnatal maturation period

EphrinA4 plays a critical role in α4 and αL mediated survival ofhuman CLL cells during extravasation

A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assays. In addition, the CLL cells of patients having lymphadenopathy (LApos) show a survival advantage during TEM that can be linked to increased expression of α4 and αL integrin chains. Within this context, ephrinA4 expressed on the surface of CLL cells sequestrates integrins and inactivates them resulting in reduced adhesion and inhibition of apoptotic/survival signals through them. In agreement, ephrinA4 silencing resulted in increased survival of CLL cells of LApos patients but not LA neg patients. Similarly was observed when a soluble ephrinA4 isoform was added to TEM assays strongly suggesting that accumulation of this isoform in the serum of LApos patients could contribute to CLL cells dissemination and survival in vivo. In supporting, CLL lymphadenopathies showed a preferential accumulation of apoptotic CLL cells around high endothelial venules lacking ephrinA4. Moreover, soluble ephrinA4 isolated from sera of patients increased the number and viability of CLL cells recovered from the lymph nodes of adoptively transferred mice. Finally, we present evidence suggesting that soluble ephrinA4 mediated survival during TEM could enhance a transcellular TEM route of the CLL cells. Together these findings point to an important role of ephrinA4 in the nodal dissemination of CLL cells governing extravasation and survival

Alteración de la síntesis y metabolismo de los neurotransmisores monoaminérgicos en el hipocampo de rata tras exposición pre y posnatal a clordimeformo por disrupción de las hormonas sexuales

Introduction: Chlordimeform, just as other formamidine pesticides, induces permanent region- and sex-dependent on monoaminergic neurotransmitter systems’ development, effects that may be related to monoamine oxidase (MAO) inhibition. Nevertheless, chlordimeform is a very weak MAO inhibitor, which suggests other mechanisms’ implication. In this regard, as chlordimeform alters testosterone and estradiol levels in frontal cortex and stratium, which may dysregulate the enzymes’ expression that mediates the synthesis and metabolism of monoaminergic neurotransmitters systems. Thus, an alteration of these hormones and enzymes in other altered brain regions could also mediate the observed effects. Objectives and methods: For the purpose of confirming that formamidines produce permanent alterations of monoamine neurotransmitters’ systems through the disruption of sex hormones in the hipoccampus, by alteration of the expression of the enzymes that synthesize and or metabolize these neurotransmitters, hippocampus’ testosterone and estradiol levels at 11 days of age, as well as the expression of MAO, COMT, BDH, TH, TRH and AD enzymes at 60 days of age after maternal exposure to chlordimeform (5mg/kg body weight) were evaluated. Results: Our results show an important decrease in testosterone levels, in addition to a significant decrease in estradiol levels in hippocampus of rats at 11 days of age. We also observed sex interaction with treatment in the content of T and E2, and we determined a bigger increase in the expression of COMT in females than in males. Chlordimeform treatment did not alter the expression of MAO and BDH enzymes, yet decreased the expression of the TH enzyme and increased the COMT, BDH, TH and TRH enzymes in both sexes. Conclusions: The present findings indicate that after maternal exposure to formamidines, in general, and chlordimeform, in particular, the previously mentioned compound induces a permanent alteration of monoaminergic neurotransmitters, by the alteration of the enzymes that synthetize these neurotransmitters, which is successively mediated by sex hormones disruption, in hippocampusIntroducción: El clordimeformo, al igual que otros plaguicidas formamidínicos, induce alteraciones permanentes de los sistemas de neurotransmisores monoaminérgicos región- y sexo-dependientes. Es posible que la inhibición de la enzima monoamino oxidasa (MAO) pueda mediar estos efectos, pero la inhibición tan leve sufrida por la MAO en presencia de este compuesto sugiere la existencia de otros mecanismos implicados. En este sentido, se ha descrito una alteración en los niveles de testosterona y estradiol en el cuerpo estriado y en la corteza frontal en presencia de clordimeformo, que puede dar lugar a una alteración de la expresión de las enzimas que sintetizan y metabolizan dichos neurotransmisores. Así, una alteración en estas hormonas y enzimas en las otras regiones afectadas también podría mediar los efectos observados en las mismas. Objetivos y métodos: Con el objetivo de confirmar que las formamidinas causan alteraciones permanentes de los neurotransmisores monoaminérgicos mediante la disrupción de las hormonas sexuales en el hipocampo debido a la alteración de la expresión de las enzimas responsables de sintetizarlos y/o metabolizarlos, se evaluaron los efectos en el hipocampo de ratas macho y hembra sobre los niveles de testosterona y estradiol a los 11 días de edad. Aparte, también se evaluó la expresión de las enzimas MAO, COMT, BDH, TH, TRH, y AD a los 60 días de edad tras la exposición maternal al clordimeformo (5 mg/kg de peso corporal). Resultados: Nuestros resultados demuestran que el clordimeformo indujo, en el hipocampo de las ratas observadas a los 11 días de edad, una disminución significativa de los niveles de testosterona, así como un incremento reseñable de los niveles de estradiol. Por otro lado, se observó una interacción por sexo con el tratamiento en el contenido de T y E2 y se advirtió también una mayor expresión de las enzimas COMT &#091;58,83% (P<0,001)&#093;, AD &#091;46,74% (P<0,001)&#093;, TH &#091;43,65% (P<0,001)&#093; y TRH &#091;37,85% (P<0,001)&#093; en las hembras que en los machos. El tratamiento con clordimeformo no causó alteración ninguna sobre la expresión de las enzimas MAO y BDH, pero indujo una disminución en la expresión de la enzima TH y un aumento en la expresión de las enzimas COMT, BDH, y TRH tanto en machos como en hembras. Conclusiones: Los presentes resultados indican que las formamidinas, en general, y particularmente el clordimeformo, inducen una alteración permanente de los sistemas de neurotransmisores monoaminérgicos en el cuerpo estriado tras la exposición maternal, mediante la alteración de las enzimas que metabolizan y sintetizan estos neurotransmisores, que es causada a su vez por la alteración de las hormonas sexuales

Multicentric study of cervical cancer screening with human papillomavirus testing and assessment of triage methods in Latin America : the ESTAMPA screening study protocol

Q1Q1Introduction Human papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC. Methods and analysis Women aged 30–64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre. Ethics and dissemination The study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings. Trial registration number NCT01881659Revista Internacional - Indexad

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake