The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.

De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.

Procalcitonin and C-reactive protein as early markers of anastomotic leakage in intestinal resections for advanced ovarian cancer (EDMOCS).

INTRODUCTION: Serum levels of procalcitonin and C-reactive protein (CRP) have been used to predict anastomotic leakage after colorectal surgery, but information is scarce in advanced ovarian cancer (AOC) surgery with bowel resection. This study aimed to assess the predictive value of procalcitonin and CRP in detecting anastomotic leakage after AOC surgery with bowel resection. The study also aimed to determine the optimal postoperative reference values and the best day for evaluating these markers. MATERIAL AND METHODS: This prospective, observational and multicentric trial included 92 patients with AOC undergoing debulking surgery with bowel resection between 2017 and 2020 in 10 reference hospitals in Spain. Procalcitonin and CRP levels were measured at baseline and on postoperative days 1-6. Receiver operating characteristic analysis was performed to evaluate the predictive value of procalcitonin and CRP at each postoperative day. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: Anastomotic leakage was detected in six patients (6.5%). Procalcitonin and CRP values were consistently higher in patients with anastomotic leakage at all postoperative days. The maximum area under the curve (AUC) for procalcitonin was observed at postoperative day 1 (AUC = 0.823) with a cutoff value of 3.8 ng/mL (83.3% sensitivity, 81.3% specificity). For CRP, the maximum AUC was found at postoperative day 3 (AUC = 0.833) with a cutoff level of 30.5 mg/dL (100% sensitivity, 80.4% specificity). CONCLUSIONS: Procalcitonin and C-reactive protein are potential biomarkers for early detection of anastomotic leakage after ovarian cancer surgery with bowel resection. Further prospective studies with a larger sample size are needed to confirm these findings.

Low sensitivity of conventional fungal agars in fungemia by Rhodotorula mucilaginosa: description of two cases.

BACKGROUND: Although most bloodstream yeast infections are caused by Candida spp., infections by rare or less common species have increased in recent years. Diagnosis of infections caused by these species is difficult due to the lack of specific symptoms and adequate diagnostic tools. CASES PRESENTATION: We describe two cases of fungemia by Rhodotorula mucilaginosa within a few months of each other, in a secondary Spanish hospital. In both cases, diagnosis was challenging. Blood subcultures in conventional fungal media were persistently negatives and the use of non-conventional fungal media was essential for isolating the yeasts and achieving a correct diagnosis. 1-3 beta-D-glucan detection and a panfungal PCR assay were helpful techniques to confirm the diagnosis CONCLUSION: It is highly important to establish an early diagnosis for fungemia. The process is challenging because often non-specific symptoms are presents. When yeasts grow in blood cultures other genera than Candida spp. could be the cause of infection. Patient risk factors should be assessed to incorporate alternative culture media and the available rapid diagnostic test, in order to provide an early recognition of the pathogen.

May Measurement Month 2019: blood pressure screening results from Chile.

Hypertension is a major preventable cause of death worldwide. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high blood pressure (BP) and identifying individuals with increased BP. A cross-sectional survey of volunteers aged ≥18 years old was carried out in May 2019 in Chile. Participating sites were distributed across the country, most of them from the Public Health System outpatient clinics. In addition, clinical research sites, universities, and private clinics participated. Blood pressure measurement protocol, hypertension categories, and statistical analysis followed the MMM protocol. Hypertension was diagnosed as mean systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg or receiving antihypertensive medication. Overall, 6876 individuals were screened. After multiple imputations, hypertension prevalence was 35.4%, of which 65.9% were aware of their condition. While 60.1% were on antihypertensive medication and 34.4% of the total number of hypertensives had their BP controlled. Of participants not receiving antihypertensive treatment, 17.9% were identified as hypertensive. The MMM 2019 survey demonstrated a high proportion of participants with hypertension, with only one-third of these individuals having controlled BP (systolic BP <140 mmHg and diastolic BP <90 mmHg). The high percentage of participants with hypertension who were either untreated (39.9%) or were treated but uncontrolled (57.2%) suggesting that such opportunistic screening programmes may be a useful tool to improve hypertension control in Chile.

May Measurement Month 2018: an analysis of blood pressure screening results from Chile.

Hypertension is highly prevalent in Chile. The National Health Survey 2016-17 reported a 27.6% prevalence, 68.7% awareness, and 33.3% of hypertensives had controlled blood pressure (BP). May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programmes worldwide. A cross-sectional survey of volunteers aged ≥18 years old was carried out in May 2018. Blood pressure measurement, the definition of hypertension, and statistical analysis followed the MMM protocol. Ninety-four sites participated, most of them from the Public Health System outpatient clinics distributed along the country. In addition, universities, clinical research sites, and private clinics participated. Hypertension was diagnosed as mean systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg or receiving antihypertensive medication. Overall 9344 individuals were screened. After multiple imputation, hypertension prevalence was 29.2%, of which 64.0% were aware of their condition. Of those aware of their hypertension diagnosis, 87.7% were receiving antihypertensive medication and 56.1% of the total number of hypertensives were on antihypertensive medication. Moreover, 15.3% of the participants who were not receiving treatment were considered potential hypertensives identified in the MMM18. MMM18 was one of the largest BP screening campaigns performed in Chile. It demonstrated a high prevalence of hypertension with one-third of these individuals having controlled BP. The high percentage of persons untreated or with uncontrolled hypertension while on pharmacologic treatment suggests that systematic screening programmes may be a useful tool to improve hypertension control in Chile.

Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid.

MT1-MMP (MMP14) is a collagenolytic enzyme located at the cell surface and implicated in extracellular matrix (ECM) remodeling. Mmp14(-/-) mice present dwarfism, bone abnormalities, and premature death. We demonstrate herein that the loss of MT1-MMP also causes cardiac defects and severe metabolic changes, and alters the cytoskeleton and the nuclear lamina structure. Moreover, the absence of MT1-MMP induces a senescent phenotype characterized by up-regulation of p16(INK4a) and p21(CIP1/WAF) (1), increased activity of senescence-associated ß-galactosidase, generation of a senescence-associated secretory phenotype, and somatotroph axis alterations. Consistent with the role of retinoic acid signaling in nuclear lamina stabilization, treatment of Mmp14(-/-) mice with all-trans retinoic acid reversed the nuclear lamina alterations, partially rescued the cell senescence phenotypes, ameliorated the pathological defects in bone, skin, and heart, and extended their life span. These results demonstrate that nuclear architecture and cell senescence can be modulated by a membrane protease, in a process involving the ECM as a key regulator of nuclear stiffness under cell stress conditions.

May Measurement Month 2017 in Chile-Americas.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programmes worldwide. National Health Surveys, PURE and CESCAS Chilean cohorts have shown a high prevalence of hypertension, with a significant proportion of people unaware of being hypertensive or under treatment but with uncontrolled BP. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017. BP measurement, the definition of hypertension and statistical analysis followed the MMM protocol. Sixty-seven sites participated. Most screening sites were National Heath Public System outpatient clinics, mainly in the 9th region of the country. In addition, clinical research sites and private clinics participated. Overall, 4754 individuals were screened during MMM17. After multiple imputations, 1153 (24.2%) had hypertension. Of individuals not receiving anti-hypertensive medication, 653 (15.3%) were hypertensive. Of the 500 individuals receiving anti-hypertensive medication, 162 (32.5%) had uncontrolled BP. MMM17 was one of the largest BP screening campaigns performed in Chile. It demonstrated a high proportion of hypertension among screenees with a low proportion the individuals with controlled hypertension in the community. The high percentage of persons untreated or with uncontrolled hypertension whilst on pharmacologic treatment suggests that systematic screening programmes may be a useful tool to improve hypertension control in Chile.

Androgen receptor dysfunction as a prevalent manifestation in young male carriers of a FLNA gene mutation.

Androgenic actions require the proper signal transmission by the androgen receptor (AR), a nuclear transcription factor. This is initially located in the cell cytoplasm and should translocates to the nucleus to interact with DNA. AR functional impairment causes diverse blockage degrees of androgenic steroid action, known as androgen insensitivity syndromes. Filamin A, a protein coded by the FLNA gene, is a co-activator of various cytoplasmic factors, including AR. The mutational inactivation of the FLNA gene induces insufficiency of translocation and activation of AR. Consequently, it causes a developmental disorder of the male gonad and hypogonadism, similar to those observed in partial androgen insensitivity. We report two brothers carrying a loss-of-function mutation of FNLA with gonadal differentiation disorder and hypospadias. Specific staining for AR shows almost an absolute absence of these receptors in the testicular tissue. This association recommends investigating a possible mutational inactivation of the FLNA gene in patients with cryptorchidism and epididymo-testicular dissociation. The study is especially indicated when the family history, more often that of the mother, is suggestive. Likewise, growth and gonadal development of all male patients carrying this genetic trait should be monitored since childhood.

Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice.

Mitochondria are dynamic subcellular organelles that convert nutrient intermediates into readily available energy equivalents. Optimal mitochondrial function is ensured by a highly evolved quality control system, coordinated by protein machinery that regulates a process of continual fusion and fission. In this work, we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1). We also show that OMA1 deficiency causes a profound perturbation of the mitochondrial fusion-fission equilibrium that has important implications for metabolic homeostasis. Thus, ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters. Additionally, Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis. These alterations are especially significant under metabolic stress conditions, indicating that an intact OMA1-OPA1 system is essential for developing the appropriate adaptive response to different metabolic stressors such as a high-fat diet or cold-shock. This study provides the first description of an unexpected role in energy metabolism for the metalloprotease OMA1 and reinforces the importance of mitochondrial quality control for normal metabolic function.

Decision-Making Time Analysis for Assessing Processing Speed in Athletes during Motor Reaction Tasks.

Reaction time (RT) is a widely used measure for testing physical performance in motor tasks. This study focused on assessing the processing speed in athletes. Twenty-five healthy volunteers were assigned to the control (n = 16) or athletes groups (n = 9). They were evaluated during motor reaction tasks based on visual stimuli and three difficulty conditions. Physiological measures were obtained from motion capture and electromyography recordings of several muscles. Two RT phases, decision-making (DMK) and electromechanical delay (EMD), were used to analyze the processing speed. The results show significant RT differences between groups. The athletes were ~30% faster compared to the control group. Despite the fact that all participants were right-handed, RT did not show any differences between hands performances in any group. However, DMK time revealed significant differences between the hands. Controls showed a longer DMK time for the right-hand election, ~20% more than the left, while athletes showed no such disparity. These findings reveal that quantifying the decision-making component of reaction time is crucial to assessing processing speed in sport. This approach could facilitate the monitoring of adaptations in both motor-cognitive and neuromuscular processes. The theoretical implications presented in this study offer perspectives on handedness research.

Inflammation and matrix remodeling during repair of ventilator-induced lung injury.

High-pressure ventilation triggers different inflammatory and matrix remodeling responses within the lung. Although some of them may cause injury, the involvement of these mediators in repair is largely unknown. To identify mechanisms of repair after ventilator-induced lung injury (VILI), mice were randomly assigned to baseline conditions (no ventilation), injury [90 min of high-pressure ventilation without positive end-expiratory pressure (PEEP)], repair (injury followed by 4 h of low-pressure ventilation with PEEP), and ventilated controls (low-pressure ventilation with PEEP for 90 and 330 min). Histological injury and lung permeability increased during injury, but were partially reverted in the repair group. This was accompanied by a proinflammatory response, together with increases in TNF-α and IFN-γ, which returned to baseline during repair, and a decrease in IL-10. However, macrophage inflammatory protein-2 (MIP-2) and matrix metalloproteinases (MMP)-2 and -9 increased after injury and persisted in being elevated during repair. Mortality in the repair phase was 50%. Survivors showed increased cell proliferation, lower levels of collagen, and higher levels of MIP-2 and MMP-2. Pan-MMP or specific MMP-2 inhibition (but not MIP-2, TNF-α, or IL-4 inhibition) delayed epithelial repair in an in vitro wound model using murine or human alveolar cells cultured in the presence of bronchoalveolar lavage fluid from mice during the repair phase or from patients with acute respiratory distress syndrome, respectively. Similarly, MMP inhibition with doxycycline impaired lung repair after VILI in vivo. In conclusion, VILI can be reverted by normalizing ventilation pressures. An adequate inflammatory response and extracellular matrix remodeling are essential for recovery. MMP-2 could play a key role in epithelial repair after VILI and acute respiratory distress syndrome.

Inexpensive ion-selective electrodes for the simultaneous monitoring of potassium and nitrate concentrations in nutrient solutions.

A fast, simple and inexpensive potentiometric method has been developed for the determination of the major ions potassium and nitrate in nutrient solutions, by means of ion-selective electrodes (ISEs) based on plasticized polyvinyl membranes containing an ion-exchanger. Tridodecylmethylammonium chloride (TDMACl) and potassium tetrakis(4-chlorophenyl)borate (KTClPB) were used as ion-exchangers for the nitrate and potassium electrodes, respectively. Electrode membranes built with different plasticizers, bis-[2-ethylhexyl]-sebacate (DOS), tricresyl phosphate (TCP) and 2-nitrophenyloctyl ether (NPOE), were tested, and NPOE was selected. The electrodes were calibrated over both wide and narrow concentration ranges and residual analysis was made. Based on the results of these calibrations, the method of standard addition was developed and found to be suitable for the simultaneous determination of potassium and nitrate in nutrient solutions. A large group of samples taken from different stages of hydroponic crops was analysed. Several approaches recommended for statistical comparisons of the results obtained by potentiometric and by reference methods were tested, obtaining satisfactory results. The potentiometric methodology developed is promising for monitoring the concentration of these essential nutrients in nutrient solutions.

Integration of health care in the Basque Country during COVID-19: the importance of an integrated care management approach in times of emergency.

The main objective of this study is to analyse the process of integration of health care implemented in the public health system (Osakidetza) of the Autonomous Community of the Basque Country (CAPV), and assess whether the steps taken to date have helped or hindered the work of health personnel in times of COVID-19. Based on a case study, an assessment is made of the way in which certain tools of the integration process have been applied, if they have worked well and if they have led to better management of the pandemic.For the purpose of this study, a qualitative methodology is chosen consisting of a case study and in-depth interviews with health personnel at the front line of the integration process and the fight against COVID-19.This study makes two fundamental contributions. First, it analyses the health integration process in recent years in the public health system of the Basque Country. Second, it gathers the perceptions of different agents related to the Basque Health System of the way in which the tools of the integration process implemented in recent years have worked during the pandemic, detailing the positive and negative perceptions in this regard.Our conclusions offer a series of strategic recommendations linked to comprehensive patient care and the use of tools related to teleconsulting: the unified medical record, electronic prescription, and non-face-to-face care channels.

Aphthous Stomatitis and Laryngitis, Another Form of Presentation of an IgG4-Related Disease? / Aftosis oral y laringitis, ¿otra forma de presentación de la enfermedad relacionada con IgG4?

IgG4-related disease is characterized by a lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis. It can present as parotid gland enlargement, tubulointerstitial nephritis, retroperitoneal fibrosis or pancreatitis, although nearly any organ can be affected. We report the case of a 37-year-old woman who presented with severe dysphonia and recurrent painful aphthous ulcers, with histopathological findings at the level of the larynx that revealed a lymphoplasmacytic infiltrate and IgG4 positivity. In addition, extensive studies were performed to rule out other diseases. Thus the diagnosis was IgG4-related laryngitis, an exceptional finding in the literature.

Malignant triton tumor of the infratemporal fossa.

Malignant triton tumor is a very aggressive type of sarcoma that comprises rhabdomyoblasts and malignant Schwann cells. It is a different entity from malignant schwannoma, characterized by their aggressiveness and poor prognosis. Head and neck location is frequent, and early diagnosis and complete resection followed by radiation therapy is important for long-term survival. However, the therapeutic plan should be individualized, taking into account the location and size of the primary tumor. The use of adjuvant chemotherapy and molecular therapies should be considered in the treatment of these tumors. We report an unusual presentation of a malignant triton tumor located in the infratemporal fossa, describing its clinical and pathologic features, and we try to update the knowledge in the management of these tumors, including the use of molecular therapies.

[Luetic hepatitis. An emerging entity]. / Hepatitis luética. Una entidad emergente.

Liver involvement is unusual in the course of syphilitic infection. We present four cases of luetic hepatitis diagnosed at our hospital in the last 5 years. One patient was coinfected with hepatitis B virus and another patient was coinfected with hepatitis C virus and HIV. The presence of maculopapular skin lesions in palmoplantar distribution, as well as serological confirmation, were decisive for the diagnosis of syphilitic hepatitis, allowing early antibiotic therapy to be established, with clinical and analytical improvement in all patients. Luetic hepatitis should be considered in patients with risky sexual behavior, skin lesions and altered liver function tests with a predominance of cholestasis, despite the finding of other, more frequent, liver diseases, given that these entities may be concurrent. Early diagnosis of syphilis leads to effective treatment of the patient and to epidemiological control of the infection.

Bone metastases as initial presentation of hepatocellular carcinoma.

Extra-hepatic spread is present in 5% to 15% of patients with hepatocellular carcinoma (HCC) at the time of diagnosis. The most frequent sites are lung and regional lymph nodes. Here, we report 3 cases of unsuspected HCC with symptoms due to bone lesions as initial presentation. Morphological characteristics and immunohistochemistry from the examined bone were the key data for diagnosis. None of the patients had an already known chronic liver disease. Differential diagnoses with HCC upon ectopic liver disease or hepatoid adenocarcinoma were shown. Therapy with the orally active multikinase inhibitor sorafenib plus symptomatic treatment was indicated.

A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes.

The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.

Sarcoidosis-lymphoma syndrome. / Síndrome sarcoidosis-linfoma.

A 65 year-old female with a history of sarcoidosis with pulmonary and joint involvement, who after 5 years of diagnosis begins with central nervous system involvement manifesting as diplopia. She presents normal analysis results. In imaging results, a mass is identified in the right intraconal space; it depends of right optic nerve, and shows multiple lymph node involvement. Biopsy was performed diagnosed with large B-cell lymphoma, an atypical form of tumor associated with sarcoidosis.

A behavior model for blood donors and marketing strategies to retain and attract them.

OBJECTIVE: analyze and propose a theoretical model that describes blood donor decisions to help staff working in blood banks (nurses and others) in their efforts to capture and retain donors. METHODS: analysis of several studies on the motivations to give blood in Spain over the last six years, as well as past literature on the topic, the authors' experiences in the last 25 years in over 15 Non Governmental Organizations with different levels of responsibilities, their experiences as blood donors and the informal interviews developed during those 25 years. RESULTS: a model is proposed with different internal and external factors that influence blood donation, as well as the different stages of the decision-making process. CONCLUSION: the knowledge of the donation process permits the development of marketing strategies that help to increase donors and donations.