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Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.
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Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Receptor Muscarínico M1/agonistas , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Inhibidores de la Colinesterasa/farmacología , Cricetulus , Cristalización , Modelos Animales de Enfermedad , Perros , Donepezilo/farmacología , Electroencefalografía , Femenino , Células HEK293 , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , Modelos Moleculares , Simulación de Dinámica Molecular , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Primates , Ratas , Receptor Muscarínico M1/química , Transducción de Señal , Homología Estructural de ProteínaRESUMEN
Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1AL263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an Scn1aL263V knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization. The L263V mutation caused gain of NaV1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1aL263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1AL263V can cause life-threatening apneic events, which in a mouse model were caused by profound brainstem depolarization. In addition to being potentially relevant to sudden infant death syndrome pathophysiology, these data indicate that sodium channel blockers may be considered therapeutic for apneic events in patients with these and other gain-of-function SCN1A mutations.
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Apnea , Mutación con Ganancia de Función , Bloqueadores de los Canales de Sodio , Animales , Humanos , Ratones , Apnea/tratamiento farmacológico , Apnea/genética , Tronco Encefálico , Células HEK293 , Migraña con Aura/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Bloqueadores de los Canales de Sodio/uso terapéutico , Lactante , FemeninoRESUMEN
Many bacterial pathogens and symbionts utilize type III secretion systems to deliver bacterial effector proteins into host cells. These effector proteins have the capacity to modulate a large variety of cellular functions in a highly regulated manner. Here, we report that the phosphoinositide phosphatase SopB, a Salmonella Typhimurium type III secreted effector protein, diversifies its function by localizing to different cellular compartments in a ubiquitin-dependent manner. We show that SopB utilizes the same enzymatic activity to modulate actin-mediated bacterial internalization and Akt activation at the plasma membrane and vesicular trafficking and intracellular bacterial replication at the phagosome. Thus, by exploiting the host cellular machinery, Salmonella Typhimurium has evolved the capacity to broaden the functional repertoire of a virulence factor to maximize its ability to modulate cellular functions.
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Proteínas Bacterianas/metabolismo , Ubiquitina/metabolismo , Actinas/metabolismo , Interacciones Huésped-Patógeno , Humanos , Pinocitosis , Proteínas Proto-Oncogénicas c-akt/metabolismo , Infecciones por Salmonella/microbiología , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidadRESUMEN
BACKGROUND: Hypoxemia is the main modifiable factor preventing lungs from being transplanted from organ donors after brain death. One major contributor to impaired oxygenation in patients with brain injury is atelectasis. Apnea testing, an integral component of brain death declaration, promotes atelectasis and can worsen hypoxemia. In this study, we tested whether performing a recruitment maneuver (RM) after apnea testing could mitigate hypoxemia and atelectasis. METHODS: During the study period, an RM (positive end-expiratory pressure of 15 cm H2O for 15 s then 30 cm H2O for 30 s) was performed immediately after apnea testing. We measured partial pressure of oxygen, arterial (PaO2) before and after RM. The primary outcomes were oxygenation (PaO2 to fraction of inspired oxygen [FiO2] ratio) and the severity of radiographic atelectasis (proportion of lung without aeration on computed tomography scans after brain death, quantified using an image analysis algorithm) in those who became organ donors. Outcomes in RM patients were compared with control patients undergoing apnea testing without RM in the previous 2 years. RESULTS: Recruitment maneuver was performed in 54 patients after apnea testing, with a median immediate increase in PaO2 of 63 mm Hg (interquartile range 0-109, p = 0.07). Eighteen RM cases resulted in hypotension, but none were life-threatening. Of this cohort, 37 patients became organ donors, compared with 37 donors who had apnea testing without RM. The PaO2:FiO2 ratio was higher in the RM group (355 ± 129 vs. 288 ± 127, p = 0.03), and fewer had hypoxemia (PaO2:FiO2 ratio < 300 mm Hg, 22% vs. 57%; p = 0.04) at the start of donor management. The RM group showed less radiographic atelectasis (median 6% vs. 13%, p = 0.045). Although there was no difference in lungs transplanted (35% vs. 24%, p = 0.44), both better oxygenation and less atelectasis were associated with a higher likelihood of lungs being transplanted. CONCLUSIONS: Recruitment maneuver after apnea testing reduces hypoxemia and atelectasis in organ donors after brain death. This effect may translate into more lungs being transplanted.
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PURPOSE: Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a pediatric epilepsy with typically good seizure control. Although BECTS may increase patients' risk of developing neurological comorbidities, their clinical care and short-term outcomes are poorly quantified. METHODS: We retrospectively assessed adherence to National Institute for Health and Care Excellence (NICE) guidelines relating to specialist referral, electroencephalogram (EEG) conduct and annual review in the care of patients with BECTS, and measured their seizure, neurodevelopmental and learning outcomes at three years post-diagnosis. RESULTS: Across ten centers in England, we identified 124 patients (74 male) diagnosed with BECTS between 2015 and 2017. Patients had a mean age at diagnosis of 8.0 (95% CI = 7.6-8.4) years. 24/95 (25%) patients were seen by a specialist within two weeks of presentation; 59/100 (59%) received an EEG within two weeks of request; and 59/114 (52%) were reviewed annually. At three years post-diagnosis, 32/114 (28%) experienced ongoing seizures; 26/114 (23%) had reported poor school progress; 15/114 (13%) were diagnosed with a neurodevelopmental disorder (six autism spectrum disorder, six attention-deficit/hyperactivity disorder); and 10/114 (8.8%) were diagnosed with a learning difficulty (three processing deficit, three dyslexia). Center-level random effects models estimated neurodevelopmental diagnoses in 9% (95% CI: 2-16%) of patients and learning difficulty diagnoses in 7% (95% CI: 2-12%). CONCLUSIONS: In this multicenter work, we found variable adherence to NICE guidelines in the care of patients with BECTS and identified a notable level of neurological comorbidity. Patients with BECTS may benefit from enhanced cognitive and behavioral assessment and monitoring.
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Trastorno del Espectro Autista , Epilepsia Rolándica , Humanos , Niño , Masculino , Epilepsia Rolándica/diagnóstico , Epilepsia Rolándica/epidemiología , Epilepsia Rolándica/psicología , Estudios Retrospectivos , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/epidemiología , Convulsiones , ElectroencefalografíaRESUMEN
Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders.
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Modelos Moleculares , Receptor del Glutamato Metabotropico 5/química , Secuencias de Aminoácidos , Sitios de Unión , Cristalografía por Rayos X , Células HEK293 , Humanos , Estructura Terciaria de Proteína , Rodopsina/químicaRESUMEN
OBJECTIVE: The aim of the study is to investigate serum stem cell factor (SCF) concentrations as potential biomarker for oocyte retrieval efficiency in IVF patients with poor prognosis. METHODS: A pilot case-control study was performed on 30 poor and 30 normal responders that were stimulated with antagonist protocol. SCF concentrations were evaluated in samples of serum and follicular fluid obtained by all patients on the day of oocyte retrieval. At the time of oocyte retrieval, follicular fluid from at least two follicles ≥ 14 mm and two follicles < 14 mm was collected for SCF determination. RESULTS: We did not find any statistical difference when comparing serum and follicular fluid levels of SCF in both poor- and normal-responder patients, the same results were achieved when poor-responder patients were stratified according to the number of MII oocytes retrieved. Moreover, levels of SCF (OR 1.000, 0.994-1.006) or in follicular fluid from ovarian follicles ≥ 14 mm (OR 0.995, CI 0.989-1.001) or from ovarian follicles < 14 mm (OR 1.003, CI 0.999-1.0069), were not significantly associated with the chances of ongoing pregnancies in poor-responder patients. CONCLUSION: SCF was unable to predict oocyte retrieval efficiency or the chances of reaching embryo transfer.
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Biomarcadores/química , Fertilización In Vitro/métodos , Líquido Folicular/metabolismo , Recuperación del Oocito/métodos , Inducción de la Ovulación/métodos , Factor de Células Madre/metabolismo , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Proyectos PilotoRESUMEN
Recently, growing interest in vitamin D has emerged from findings that demonstrate a low vitamin D status in populations. Similarly, much interest has been shown in the role that anti-Müllerian hormone (AMH) plays in reproductive physiology. Considerable confusion as to whether vitamin D status is related to ovarian function can be found in the literature. Our retrospective study was performed from June 2014 to April 2015. Oocyte donors were recruited and stimulated under the antagonist protocol with gonadotrophin-releasing hormone (GnRH) agonist to trigger ovulation. In 851 stimulation cycles, we determined the association among serum total and bioavailable vitamin D levels, ovarian reserve and response to ovarian stimulation and the reproductive outcome in their recipients. We showed that vitamin D levels were unrelated to ovarian reserve or ovarian response after ovarian stimulation; in oocyte recipients, gestational outcome did not differ according to a donor's vitamin D serum status. No correlation was observed between serum AMH and vitamin D. Bioavailable vitamin D was not related to recipients' ongoing pregnancy rate. Highly prevalent vitamin D insufficiency neither impaired ovarian reserve nor response or oocyte quality in egg donors. No evidence was found for recommending the analysis of vitamin D status in oocyte donors.
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Donación de Oocito , Reserva Ovárica , Inducción de la Ovulación/métodos , Vitamina D/sangre , Adolescente , Adulto , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Persona de Mediana Edad , Embarazo , Resultado del Embarazo , Índice de Embarazo , Estudios Retrospectivos , Adulto JovenRESUMEN
AIM: The aim of this study was to evaluate the effect of Kava-241, an optimized Piper methysticum Kava compound, on periodontal destruction in a collagen antibody primed oral gavage model of periodontitis. METHODS: Experimental periodontitis was induced by oral gavage of Porphyromonas gingivalis (P. gingivalis) + type II collagen antibody (AB) in mice during 15 days. Mice were treated with Kava-241 concomitantly or prior to P. gingivalis gavage and compared to untreated mice. Comprehensive histomorphometric analyses were performed. RESULTS: Oral gavage with P. gingivalis induced mild epithelial down-growth and alveolar bone loss, while oral gavage with additional AB priming had greater tissular destruction in comparison with gavage alone (p < .05). Kava-241 treatment significantly (p < .05) reduced epithelial down-growth (72%) and alveolar bone loss (36%) in P. gingivalis+AB group. This Kava-241 effect was associated to a reduction in inflammatory cell counts within soft tissues and an increase in fibroblasts (p < .05). CONCLUSION: Priming with type II collagen antibody with oral gavage is a fast and reproducible model of periodontal destruction adequate for the evaluation of novel therapeutics. The effect of Kava-241 shows promise in the prevention and treatment of inflammation and alveolar bone loss associated with periodontitis. Further experiments are required to determine molecular pathways targeted by this therapeutic agent.
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Kava/química , Periodontitis/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Porphyromonas gingivalis/metabolismo , Animales , Anticuerpos/inmunología , Colágeno/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Masculino , Ratones , Ratones Endogámicos DBA , Periodontitis/microbiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Casting is the first step toward the production of majority of metal products whether the final processing step is casting or other thermomechanical processes such as extrusion or forging. The high shear melt conditioning provides an easily adopted pathway to producing castings with a more uniform fine-grained microstructure along with a more uniform distribution of the chemical composition leading to fewer defects as a result of reduced shrinkage porosities and the presence of large oxide films through the microstructure. The effectiveness of high shear melt conditioning in improving the microstructure of processes used in industry illustrates the versatility of the high shear melt conditioning technology. The application of high shear process to direct chill and twin roll casting process is demonstrated with examples from magnesium melts.
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AIM: To determine the role of ethnicity on IVF/ICSI outcomes between Indian and white Caucasian women. SETTINGS AND DESIGN: Retrospective cohort study. MATERIALS AND METHODS: White Caucasian and Indian women undergoing IVF/ICSI treatment cycles. Total 5549 self, non-donor, fresh IVF cycles conducted from January 2014 to March 2015, out of which, 4227 were white Caucasian and 1322 were Indian. Data were collected on baseline characteristics, IVF cycle parameters and outcomes. Ongoing pregnancy rate (OPR) was measured as main outcome. RESULTS: Indian women differed significantly from white Caucasian women in baseline characteristics like age (30.6 ± 0.2 versus 37.6 ± 0.1 years; p < 0.001), BMI (22.3 ± 0.2 versus 26.6 ± 1.0 kg/m2; p < 0.05), duration of infertility (6.9 ± 3.0 versus 2.5 ± 0.1 years; p < 0.001) and antral follicle count (AFC) (8.9 ± 0.4 versus 7.5 ± 0.2; p < 0.001). Indian women had lower implantation rate (30.1% versus 39.6%: p < 0.001) and OPR (35.1% versus 41.7%: p < 0.001) compared with white Caucasian women. Regression analysis proved independent effect of ethnicity on OPR (OR 0.944; 95% CI 0.928-0.961: p < 0.001) Conclusions: OPR was significantly lower among Indian ethnic group following IVF/ICSI suggest that ethnicity, like age, is a major and an independent predictor of IVF outcome.
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Fertilización In Vitro/estadística & datos numéricos , Infertilidad Femenina/etnología , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Adulto , Femenino , Humanos , India/etnología , Embarazo , Estudios Retrospectivos , España/etnología , Inyecciones de Esperma Intracitoplasmáticas/estadística & datos numéricos , Población Blanca/etnologíaRESUMEN
The present work deals with two different CdS nanostructures produced via hydrothermal and solvothermal decompositions of aminocaproic acid (ACA)-mixed Cd-thiourea complex precursor at 175 °C. Both nanostructures were extensively characterized for their structural, morphological and optical properties. The powder X-ray diffraction characterization showed that the two CdS nanostructures present a wurtzite morphology. Scanning electron microscopy and energy-dispersive X-ray characterizations revealed that the hydrothermal decomposition produced well-shaped CdS flowers composed of six dendritic petals, and the solvothermal decomposition produced CdS microspheres with close stoichiometric chemical composition. The UV-vis absorption and photoluminescence spectra of CdS dendritic flowers and microsphere nanostructures showed that both nanostructures present a broad absorption between 200 and 700 nm and exhibit strong green emissions at 576 and 520 nm upon excitations at 290 nm and 260 nm, respectively. The transmission electron microscopy (TEM) and Brunauer-Emmett-Teller (BET) characterizations confirmed that CdS microspheres were mesoporous and were composed of small nanocrystals. A possible growth mechanism in the formation of the CdS nanostructures was proposed based on morphology evolution as a function of the reaction time. Furthermore, the as-synthesized CdS nanostructures were found to exhibit highly efficient photocatalytic activities for the degradation of methyl orange (MeO) and rhodamine B (RhB) dyes.
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Ácido Aminocaproico/química , Compuestos de Cadmio/química , Nanoestructuras/química , Sulfuros/química , Tiourea/química , Calor , FotólisisRESUMEN
INTRODUCTION: This study compared the clinical effectiveness of switching from tumor necrosis factor inhibitor (TNFi) to upadacitinib (TNFi-UPA), another TNFi (TNFi-TNFi), or an advanced therapy with another mechanism of action (TNFi-other MOA) in patients with rheumatoid arthritis (RA). METHODS: Data were drawn from the Adelphi RA Disease Specific Programme™, a cross-sectional survey administered to rheumatologists and their consulting patients in Germany, France, Italy, Spain, the UK, Japan, Canada, and the USA from May 2021 to January 2022. Patients who switched treatment from an initial TNFi were stratified by subsequent therapy of interest: TNFi-UPA, TNFi-TNFi, or TNFi-other MOA. Physician-reported clinical outcomes including disease activity (with formal DAS28 scoring available for 29% of patients) categorized as remission, low/moderate/high disease activity, as well as pain were recorded at initiation of current treatment and ≥ 6 months from treatment switch. Fatigue and treatment adherence were measured ≥ 6 months from treatment switch. Inverse-probability-weighted regression adjustment compared outcomes by subsequent class of therapy: TNFi-UPA versus TNFi-TNFi, or TNFi-UPA versus TNFi-other MOA. RESULTS: Of 503 patients who switched from their first TNFi, 261 were in TNFi-UPA, 128 in TNFi-TNFi, and 114 in TNFi-other MOA groups. At the time of switch, most patients had moderate/high disease activity (TNFi-UPA: 73%; TNFi-TNFi: 52%; TNFi-other MOA: 60%). After adjustment for differences in characteristics at point of switch, patients in TNFi-UPA group (n = 261) were significantly more likely to achieve physician-reported remission (67.7% vs. 40.3%; p = 0.0015), no pain (55.7% vs. 25.4%; p = 0.0007), and complete adherence (60.0% vs. 34.2%; p = 0.0049) compared with patients in TNFi-TNFi group (n = 121). Similar findings were observed for TNFi-UPA versus TNFi-other MOA groups (n = 111). CONCLUSION: Patients who switched from TNFi to UPA had significantly better clinical outcomes of remission, no pain, and complete adherence than those who cycled TNFi or switched to another MOA.
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CONTEXT: Peripheral neuropathy (PN) is a multifaceted complication characterized by nerve damage due to oxidative stress, inflammatory mediators, and dysregulated metabolic processes. Early PN manifests as sensory changes that develop progressively in a "stocking and glove" pattern. METHODS AND MECHANISMS: A thorough review of literature has been done to find the molecular pathology, clinical trials that have been conducted to screen the effects of different drugs, current treatments and novel approaches used in PN therapy. Diabetic neuropathy occurs due to altered protein kinase C activity, elevated polyol pathway activity in neurons, and Schwann cells-induced hyperglycemia. Other causes involve chemotherapy exposure, autoimmune ailments, and chronic ethanol intake. CONCLUSION: Symptomatic treatments for neuropathic pain include use of tricyclic antidepressants, anticonvulsants, and acetyl-L-carnitine. Patients will have new hope if clinicians focus on novel therapies including gene therapy, neuromodulation techniques, and cannabidiol as an alternative to traditional medications, as management is still not ideal.
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[This corrects the article DOI: 10.1371/journal.pone.0278550.].
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Banana harvesting generates a large amount of banana pseudostem waste, which is generally burnt or thrown away, despite containing many nutrients. Bio-enriched organic fertilizer (BOF) was prepared from banana pseudostem sap (BPS), and it has been patented (Patent No. WO 2013/001478 Al). Several reports revealed that its application increases plant growth promotion of various horticulture crops. Apart from macro- and micronutrients, it also contained phytohormones. Hence, the present study aims to detect and quantify phytohormone in it. A novel method was developed to extract four phytohormones, viz., indole-3-acetic acid (IAA), indole-3-butyric acid (IBA), gibberellic acid (GA3), and salicylic acid (SA) using single solvent from BPS and BOF. Extracted hormones were analyzed by ultrahigh-performance liquid chromatography coupled with heated electrospray ionization tandem mass spectrometry (UHPLC-HESI-MS/MS). BOF showed a higher concentration of IAA, IBA, GA3, and SA than BPS. Thus, this is the first time a method has been reported to extract and detect phytohormones from banana pseudostem sap.
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Musa , Reguladores del Crecimiento de las Plantas , Reguladores del Crecimiento de las Plantas/análisis , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Musa/química , Fertilizantes/análisis , Ácido Salicílico/análisisRESUMEN
ZYIL1 is a nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome inhibitor, which prevents NLRP3-induced apoptosis-associated speck-like protein containing a caspase activation and recruitment domain oligomerization, thus inhibiting NLRP3 inflammasome pathway. We investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ZYIL1 after single and multiple doses in healthy subjects. The subjects aged 18-55 years were enrolled in 2 different studies: single and multiple ascending dose. Blood/urine samples were collected at designated time points for pharmacokinetic and pharmacodynamic analysis. In the single-ascending-dose study, 30 subjects were enrolled (6 subjects each in 5 dose groups). One adverse event was reported during the study. ZYIL1 was well absorbed with median time to maximum plasma concentration at 1-1.5 hours. The exposures were dose proportional across the dose ranges. ZYIL1 is excreted as an unchanged form via the renal route. The mean elimination half-life was 6-7 hours. In the multiple-ascending-dose study, 18 subjects were enrolled (6 subjects each in 3 dose groups). Eleven adverse events were reported by 6 subjects during the study. The accumulation index at steady state for area under the plasma concentration-time curve indicated that ZYIL1 has a marginal accumulation upon repeated dosing. Dose-proportional exposure was observed across the dose ranges. All subjects showed >90% interleukin (IL)-1ß inhibition in all dose groups for both studies. Inhibition in IL-1ß and IL-18 was observed throughout the 14 days of treatment in the multiple-dose study. The safety profile, rapid absorption, marginal accumulation, and significant inhibition of IL-1ß and IL-18 level support its development for the management of inflammatory disorders.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-18/metabolismo , Área Bajo la CurvaRESUMEN
BACKGROUND: Filter clotting is a major issue in continuous kidney replacement therapy (CKRT) that interrupts treatment, reduces delivered effluent dose, and increases cost of care. While a number of variables are involved in filter life, treatment modality is an understudied factor. We hypothesized that filters in pre-filter continuous venovenous hemofiltration (CVVH) would have shorter lifespans than in continuous venovenous hemodialysis (CVVHD). METHODS: This was a single center, pragmatic, unblinded, quasi-randomized cluster trial conducted in critically ill adult patients with severe acute kidney injury (AKI) at the University of Iowa Hospitals and Clinics (UIHC) between March 2020 and December 2020. Patients were quasi-randomized by time block to receive pre-filter CVVH (convection) or CVVHD (diffusion). The primary outcome was filter life, and secondary outcomes were number of filters used, number of filters reaching 72 hours, and in-hospital mortality. RESULTS: In the intention-to-treat analysis, filter life in pre-filter CVVH was 79% of that observed in CVVHD (mean ratio 0.79, 95% CI 0.65-0.97, p = 0.02). Median filter life (with interquartile range) in pre-filter CVVH was 21.8 (11.4-45.3) and was 26.6 (13.0-63.5) for CVVHD. In addition, 11.8% of filters in pre-filter CVVH were active for >72 hours, versus 21.2% in the CVVHD group. Finally, filter clotting accounted for the loss of 26.7% of filters in the CVVH group compared to 17.5% in the CVVHD group. There were no differences in overall numbers of filters used or mortality between groups. CONCLUSIONS: Among critically patients with severe AKI requiring CKRT, use of pre-filter CVVH resulted in significantly shorter filter life compared to CVVHD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04762524. Registered 02/21/21-Retroactively registered, https://clinicaltrials.gov/ct2/show/NCT04762524?cond=The+Impact+of+CRRT+Modality+on+Filter+Life&draw=2&rank=1.
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Lesión Renal Aguda , Terapia de Reemplazo Renal Continuo , Hemodiafiltración , Hemofiltración , Adulto , Humanos , Hemofiltración/métodos , Hemodiafiltración/métodos , Diálisis Renal , Lesión Renal Aguda/terapiaRESUMEN
Spinal cord arterio-venous malformations (AVMs) are rare and the diagnosis is often delayed or missed. We describe two cases presenting in different ways, as subarachnoid haemorrhage (SAH) or myelopathy. A catheter angiogram confirmed the diagnosis following which they were treated with coil occlusion or embolisation, or a combination of both, without any complications.
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Malformaciones Vasculares del Sistema Nervioso Central/diagnóstico , Médula Espinal/irrigación sanguínea , Adolescente , Malformaciones Vasculares del Sistema Nervioso Central/terapia , Niño , Embolización Terapéutica/métodos , Femenino , Hemorragia/etiología , Humanos , Imagen por Resonancia Magnética , Masculino , Paraparesia/etiología , Enfermedades de la Médula Espinal/etiología , Hemorragia Subaracnoidea/etiologíaRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin's lymphoma (NHL). This subtype can be present in various extranodal sites, including the brain, bones, intestines, kidneys, adrenal glands, and other soft tissues. As demonstrated in this case, one rare site of DLBCL is the nasal septum, which presents as a rapidly enlarging mass resistant to antibiotics and steroids. The definitive diagnosis for this case involved biopsy, but further workup, such as computed tomography (CT) and fluorescence in situ hybridization (FISH), helped support the diagnosis of DLBCL. While determining the stage of the lymphoma, treatment with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) was initiated immediately. This case demonstrates a rare presentation of DLBCL in the nasal septum and describes the significance of urgent examination as well as treatment.