ABSTRACT
D-Glyceraldehyde, a reactive aldehyde metabolite of fructose and glucose, is neurotoxic in vitro by forming advanced glycation end products (AGEs) with neuronal proteins. In Alzheimer's disease brains, glyceraldehyde-containing AGEs have been detected intracellularly and in extracellular plaques. However, little information exists on how the brain handles D-glyceraldehyde metabolically or if glyceraldehyde crosses the blood-brain barrier from the circulation into the brain. We injected [U-13C]-D-glyceraldehyde intravenously into awake mice and analyzed extracts of serum and brain by 13C nuclear magnetic resonance spectroscopy. 13C-Labeling of brain lactate and glutamate indicated passage of D-glyceraldehyde from blood to brain and glycolytic and oxidative D-glyceraldehyde metabolism in brain cells. 13C-Labeling of serum glucose and lactate through hepatic metabolism of [U-13C]-D-glyceraldehyde could not explain the formation of 13C-labeled lactate and glutamate in the brain. Cerebral glyceraldehyde dehydrogenase and reductase activities, leading to the formation of D-glycerate and glycerol, respectively, were 0.27-0.28 nmol/mg/min; triokinase, which phosphorylates D-glyceraldehyde to D-glyceraldehyde-3-phosphate, has been demonstrated previously at low levels. Thus, D-glyceraldehyde metabolism toward glycolysis could proceed both through D-glycerate, glycerol, and D-glyceraldehyde-3-phosphate. The aldehyde group of D-glyceraldehyde was overwhelmingly hydrated into a diol in aqueous solution, but the diol dehydration rate greatly exceeded glyceraldehyde metabolism and did not restrict it. We conclude that (1) D-glyceraldehyde crosses the blood-brain barrier, and so blood-borne glyceraldehyde could contribute to AGE formation in the brain, (2) glyceraldehyde is taken up and metabolized by brain cells. Metabolism thus constitutes a detoxification mechanism for this reactive aldehyde, a mechanism that may be compromised in disease states.
ABSTRACT
BACKGROUND AND AIMS: HIV-positive patients on tenofovir hydroxyl fumarate (TDF)/emtricitabine have a lower risk of COVID-19 and hospitalization than those given other treatments. Our aim was to analyze the severity of COVID-19 in patients with chronic hepatitis B (CHB) on TDF or entecavir (ETV). METHODS: Spanish hospital databases (n = 28) including information regarding adult CHB patients on TDF or ETV for the period February 1st to November 30th 2020 were searched for COVID-19, defined as a positive SARS-CoV-2 polymerase chain reaction, and for severe COVID-19. RESULTS: Of 4736 patients, 117 had COVID-19 (2.5%), 67 on TDF and 50 on ETV. Compared to patients on TDF, those on ETV showed (p < 0.05) greater rates of obesity, diabetes, ischemic cardiopathy, and hypertension. COVID-19 incidence was similar in both groups (2.3 vs. 2.6%). Compared to TDF, patients on ETV more often (p < 0.01) had severe COVID-19 (36 vs. 6%), required intensive care unit (ICU) (10% vs. 0) or ventilatory support (20 vs. 3%), were hospitalized for longer (10.8 ± 19 vs. 3.1 ± 7 days) or died (10 vs. 1.5%, p = 0.08). In an IPTW propensity score analysis adjusted for age, sex, obesity, comorbidities, and fibrosis stage, TDF was associated with a sixfold reduction in severe COVID-19 risk (adjusted-IPTW-OR 0.17, 95%CI 0.04-0.67, p = 0.01). CONCLUSION: Compared to ETV, TDF seems to play a protective role in CHB patients with SARS-CoV-2 whereby the risk of severe COVID-19 is lowered.
Subject(s)
COVID-19 , Hepatitis B, Chronic , Adult , Humans , Tenofovir/therapeutic use , Antiviral Agents/therapeutic use , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/drug therapy , Treatment Outcome , COVID-19/complications , SARS-CoV-2 , Retrospective StudiesABSTRACT
Cerebellar mutism syndrome (CMS) is a common surgical sequela in children following posterior fossa tumor (PFT) resection. Here, we analyze the neuropsychological features associated with PFT in children, focusing particularly on the differential profiles associated with the presence or absence of CMS after surgery. We further examine the effect of post-resection treatments, tumor type, and presence/absence of hydrocephalus on surgical outcome. Thirty-six patients diagnosed with PFT (19 with and 17 without CMS) and 34 age- and gender-matched healthy controls (HCs) were recruited. A comprehensive neuropsychological evaluation was conducted in all patients postoperatively and in HCs, including an assessment of general cognitive ability, motor skills, perception, language, memory, attention, executive functions, and academic competence. CMS was found to be a clinical marker of lower neuropsychological profile scores across all cognitive domains except auditory-verbal processing and visual memory tasks. PFT patients not presenting CMS exhibited milder impairment in intellectual functioning, motor tasks, reasoning, language, verbal learning and recall, attention, cognitive executive functions, and academic competence. High-grade tumors were associated with slower processing speed and verbal delayed recall as well as alterations in selective and sustained attention. Hydrocephalus was detrimental to motor functioning and nonverbal reasoning. Patients who had undergone surgery, chemotherapy, and radiotherapy presented impaired processing speed, verbal learning, and reading. In addition to the deleterious effects of PFT, post-resection PFT treatments have a negative cognitive impact. These undesired consequences and the associated tumor-related damage can be assessed using standardized, long-term neuropsychological evaluation when planning rehabilitation.
Subject(s)
Cerebellar Neoplasms/psychology , Infratentorial Neoplasms/psychology , Mutism/psychology , Neuropsychological Tests , Postoperative Complications/psychology , Adolescent , Cerebellar Neoplasms/diagnosis , Cerebellar Neoplasms/surgery , Child , Child, Preschool , Female , Humans , Infratentorial Neoplasms/diagnosis , Infratentorial Neoplasms/surgery , Male , Mutism/diagnosis , Mutism/etiology , Postoperative Complications/diagnosis , Postoperative Complications/etiologyABSTRACT
BACKGROUND & AIMS: The interferon-free regimen paritaprevir/ritonavir, ombitasvir + dasabuvir (PTV/r/OBV/DSV) has shown high efficacy in patients with hepatitis C virus (HCV) genotype 1b infection when administered for 8 or 12 weeks, but data regarding the 8-week treatment are scarce. The aim of our study was to assess the efficacy and safety of the 8-week administration of PTV/r/OBV/DSV in a real-world cohort. METHODS: We performed a multicentre observational study from Spanish Hepa-C database including patients receiving 8 weeks of PTV/r/OBV/DSV (October 2016-November 2017). Those with advanced fibrosis, with non-genotype 1b or who were treatment-experienced were excluded. RESULTS: A total of 211 patients were registered from 23 Spanish centres; eleven were excluded. At baseline, 42.5% (n = 85) were male, median (range) age was 57 (23-86), ALT was 45 (11-494) IU/mL, viral load was 6.1 (3.3-8.2) log10 IU/mL, and 74.5% had mild liver fibrosis (F0-F1) and 25.5% moderate fibrosis (F2). At the end of treatment (EOT), HCV viral load was undetectable in 100% (200/200). Seven patients relapsed after treatment discontinuation. Sustained virological response (SVR12) rates by intention-to-treat analysis were 96% (192/200). Regarding treatment safety, 2 patients developed ALT elevation >5x ULN, but there were no treatment discontinuations. One patient died 7 weeks after EOT. CONCLUSION: Treatment with PTV/r/OBV/DSV in genotype 1b-infected treatment-naive patients with mild-moderate fibrosis shows excellent efficacy and safety in real life, similarly to clinical trials. Clinicaltrials.gov, number: NCT03122132.
Subject(s)
Anilides/therapeutic use , Antiviral Agents/therapeutic use , Carbamates/therapeutic use , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/virology , Macrocyclic Compounds/therapeutic use , Sulfonamides/therapeutic use , Uracil/analogs & derivatives , 2-Naphthylamine , Adult , Aged , Aged, 80 and over , Cyclopropanes , Drug Therapy, Combination , Female , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/pathology , Humans , Lactams, Macrocyclic , Male , Middle Aged , Proline/analogs & derivatives , Prospective Studies , Spain , Sustained Virologic Response , Uracil/therapeutic use , Valine , Viral Load , Young AdultABSTRACT
BACKGROUND & AIMS: Patients with advanced liver fibrosis remain at risk of cirrhosis-related outcomes and those with severe comorbidities may not benefit from hepatitis C (HCV) eradication. We aimed to collect data on all-cause mortality and relevant clinical events within the first two years of direct-acting antiviral therapy, whilst determining the prognostic capability of a comorbidity-based model. METHODS: This was a prospective non-interventional study, from the beginning of direct-acting antiviral therapy to the event of interest (mortality) or up to two years of follow-up, including 14 Spanish University Hospitals. Patients with HCV infection, irrespective of liver fibrosis stage, who received direct-acting antiviral therapy were used to build an estimation and a validation cohort. Comorbidity was assessed according to Charlson comorbidity and CirCom indexes. RESULTS: A total of 3.4% (65/1,891) of individuals died within the first year, while 5.4% (102/1,891) died during the study. After adjusting for cirrhosis, platelet count, alanine aminotransferase and sex, the following factors were independently associated with one-year mortality: Charlson index (hazard ratio [HR] 1.55; 95% CI 1.29-1.86; pâ¯=â¯0.0001), bilirubin (HR 1.39; 95% CI 1.11-1.75; pâ¯=â¯0.004), age (HR 1.06 95% CI 1.02-1.11; pâ¯=â¯0.005), international normalized ratio (HR 3.49; 95% CI 1.36-8.97; pâ¯=â¯0.010), and albumin (HR 0.18; 95% CI 0.09-0.37; pâ¯=â¯0.0001). HepCom score showed a good calibration and discrimination (C-statistics 0.90), and was superior to the other prognostic scores (model for end-stage liver disease 0.81, Child-Pugh 0.72, CirCom 0.68) regarding one- and two-year mortality. HepCom score identified low- (≤5.7 points: 2%-3%) and high-risk (≥25 points: 56%-59%) mortality groups, both in the estimation and validation cohorts. The distribution of clinical events was similar between groups. CONCLUSIONS: The HepCom score, a combination of Charlson comorbidity index, age, and liver function (international normalized ratio, albumin, and bilirubin) enables detection of a group at high risk of one- and two-year mortality, and relevant clinical events, after starting direct-acting antiviral therapy. LAY SUMMARY: The prognosis of patients with severe comorbidities may not benefit from HCV viral clearance. An algorithm to decide who will benefit from the treatment is needed to manage the chronic HCV infection better.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Aged , Algorithms , Cohort Studies , Comorbidity , Female , Hepatitis C/mortality , Humans , Male , Middle Aged , Models, Biological , Multivariate Analysis , Outcome Assessment, Health Care/statistics & numerical data , Prognosis , Proportional Hazards Models , Prospective Studies , Spain/epidemiology , Sustained Virologic ResponseABSTRACT
Background: Tigecycline is indicated for the treatment of complicated skin infections, soft tissue and intraabdominal infections. Its use could be extended to community-acquired pneumonia (CAP) and hospital pneumonia (HN). The objective was to evaluate the efficacy and safety of tigecycline in the treatment of respiratory infections. Methods: systematic review (2012). Databases used were MEDLINE, EMBASE, Cochrane Library, CRD and WOK. We identified clinical trials of adults with respiratory infection, treated with tigecycline. The quality of the studies was assessed using CASPe checklist. Results: We selected four clinical trials of high-moderate quality. Three studies with patients with CAP and a trial with HN patients. In patients with CAP, efficacy of tigecycline (88.6 to 90.6%) was higher than levofloxacin (85.3 to 87.2%). The non inferiority testing was statistically significant (p < 0.001). In the study of patients with HN tigecycline showed an efficiency of 67.9% versus 78.2% for imipenem/cilastatin. Main adverse effects were gastrointestinal. Conclusions: The efficacy of tigecycline is non inferior than levofloxacin in patients with CAP, but less than imipenem in patients with HN. Tigecycline demonstrates noninferiority versus others tested antibiotics, and it shows a good safety profile.
Introducción: Tigeciclina está indicada en el tratamiento de infecciones complicadas de piel, tejidos blandos e intra-abdominales. Su utilización podría extenderse para neumonías adquiridas en la comunidad (NAC) y neumonías hospitalarias (NH). El objetivo ha sido evaluar la eficacia y seguridad de tigeciclina en el tratamiento de infecciones respiratorias. Material y Métodos: Revisión sistemática (2012). Se realizaron búsquedas en MedLine, Embase, Cochrane Library, CRD y WOK. Se localizaron ensayos clínicos de adultos con infección respiratoria, tratados mediante tigeciclina. La calidad de los estudios se valoró mediante los criterios CASPe. Resultados: Se seleccionaron cuatro ensayos clínicos de calidad alta-moderada. Tres estudios incluyeron pacientes con NAC y un estudio a pacientes con NH. En pacientes con NAC la eficacia de tigeciclina (88,6-90,6%) fue no inferior a la de levofloxacina (85,3-87,2%). El "test de no inferioridad" fue estadísticamente significativo (p < 0,001). En el estudio de pacientes con NH, tigeciclina presentó una eficacia de 67,9% frente a 78,2% de imipenem/cilastatina. Los principales efectos adversos fueron gastrointestinales. Conclusiones: la eficacia de tigeciclina es no inferior a la de levofloxacina en pacientes con NAC, pero inferior a imipenem en pacientes con NH. Tigeciclina ha demostrado no inferioridad frente a los otros antimicrobianos testados. Tigeciclina demuestra tener un buen perfil de seguridad.
Subject(s)
Adult , Humans , Anti-Bacterial Agents/therapeutic use , Cross Infection/drug therapy , Minocycline/analogs & derivatives , Pneumonia/drug therapy , Anti-Bacterial Agents/adverse effects , Clinical Trials as Topic , Community-Acquired Infections/drug therapy , Minocycline/adverse effects , Minocycline/therapeutic use , Respiratory Tract Infections/drug therapyABSTRACT
BACKGROUND: Tigecycline is indicated for the treatment of complicated skin infections, soft tissue and intraabdominal infections. Its use could be extended to community-acquired pneumonia (CAP) and hospital pneumonia (HN). The objective was to evaluate the efficacy and safety of tigecycline in the treatment of respiratory infections. METHODS: systematic review (2012). Databases used were MEDLINE, EMBASE, Cochrane Library, CRD and WOK. We identified clinical trials of adults with respiratory infection, treated with tigecycline. The quality of the studies was assessed using CASPe checklist. RESULTS: We selected four clinical trials of high-moderate quality. Three studies with patients with CAP and a trial with HN patients. In patients with CAP, efficacy of tigecycline (88.6 to 90.6%) was higher than levofloxacin (85.3 to 87.2%). The non inferiority testing was statistically significant (p < 0.001). In the study of patients with HN tigecycline showed an efficiency of 67.9% versus 78.2% for imipenem/cilastatin. Main adverse effects were gastrointestinal. CONCLUSIONS: The efficacy of tigecycline is non inferior than levofloxacin in patients with CAP, but less than imipenem in patients with HN. Tigecycline demonstrates noninferiority versus others tested antibiotics, and it shows a good safety profile.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Cross Infection/drug therapy , Minocycline/analogs & derivatives , Pneumonia/drug therapy , Adult , Anti-Bacterial Agents/adverse effects , Clinical Trials as Topic , Community-Acquired Infections/drug therapy , Humans , Minocycline/adverse effects , Minocycline/therapeutic use , Respiratory Tract Infections/drug therapy , TigecyclineABSTRACT
La incidencia y la prevalencia de las cardiopatías congénitas (CC) en nuestro medio y en otros países en vías de desarrollo son desconocidas. A pesar de que contamos con una extensa cobertura en salud, vemos con frecuencia adultos no tratados con este tipo de padecimientos. Debido al crecimiento demográfico y a la disminución de la mortalidad infantil el médico actual se enfrenta a más enfermos con CC, a los cuales debe diagnosticar, referir para tratamiento y aconsejar. Con el objeto de conocer más de la realidad nacional específica en este campo y a la edad en el momento del diagnóstico estudiamos todos los pacientes egresados de los Hospitales Generales del área metropolitana con CC, ya que a éstos son referidos desde todo el territorio nacional. Se escogió el año 1998, para que la investigación fuera reciente y para observar al menos 2 años de seguimiento después del tratamiento. Hubo un total de 45 pacientes, 75 por ciento mujeres, 25 hombres, con un rango de edad de 15 a 64 años. La mayoría habían nacido en San José. Las CC encontradas en orden de frecuencia fueron: CIA (66.6 por ciento), CIV (11.5 por ciento), Tetralogía de Fallot (4.4 por ciento), y un caso de cada una de las siguientes: coartación de la aorta, estenosis aórtica, anomalía de Ebstein, tronco arterioso común, Bloqueo A-V congénito y aneurisma roto del seno de Valsalva. En 61.53 por ciento de los enfermos el diagnóstico se hizo a edades mayores a los 10 años, y el 81 por ciento estaban entre 20 y 40 años. El examen definitivo más utilizado fue la ecocardiografía. De las 34 mujeres, 12 tuvieron hijos, hubo 48 partos vaginales, y 8 cesáreas sin complicaciones. Una paciente con CIA tuvo un hijo con CIA. Treinta y dos individuos fueron intervenidos durante el año en estudio y todos sobrevivieron. La clase funcional (NYHA) postoperatoria es I en 30 de ellos. Otras razones de internamiento a los hospitales fueron obstétricas o para tratamiento médico. Veinticuatro pacientes trabajan...