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To form functional circuits, neurons must settle in their appropriate cellular locations and then project and elaborate neurites to contact their target synaptic neuropils. Laminar organization within the vertebrate retinal inner plexiform layer (IPL) facilitates pre- and postsynaptic neurite targeting, yet the precise mechanisms underlying establishment of functional IPL subdomains are not well understood. Here we explore mechanisms defining the compartmentalization of OFF and ON neurites generally, and OFF and ON direction-selective neurites specifically, within the developing IPL. We show that semaphorin 6A (Sema6A), a repulsive axon guidance cue, is required for delineation of OFF versus ON circuits within the IPL: in the Sema6a null IPL, the boundary between OFF and ON domains is blurred. Furthermore, Sema6A expressed by retinal ganglion cells (RGCs) directs laminar segregation of OFF and ON starburst amacrine cell (SAC) dendritic scaffolds, which themselves serve as a substrate upon which other retinal neurites elaborate. These results demonstrate that RGCs, the first neuron-type born within the retina, play an active role in functional specialization of the IPL.
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The retina is a tremendously complex image processor, containing numerous cell types that form microcircuits encoding different aspects of the visual scene. Each microcircuit exhibits a distinct pattern of synaptic connectivity. The developmental mechanisms responsible for this patterning are just beginning to be revealed. Furthermore, signals processed by different retinal circuits are relayed to specific, often distinct, brain regions. Thus, much work has focused on understanding the mechanisms that wire retinal axonal projections to their appropriate central targets. Here, we highlight recently discovered cellular and molecular mechanisms that together shape stereotypic wiring patterns along the visual pathway, from within the retina to the brain. Although some mechanisms are common across circuits, others play unconventional and circuit-specific roles. Indeed, the highly organized connectivity of the visual system has greatly facilitated the discovery of novel mechanisms that establish precise synaptic connections within the nervous system.
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Encéfalo/fisiología , Neuronas/fisiología , Retina/fisiología , Vías Visuales/fisiología , Animales , Encéfalo/metabolismo , Humanos , Neuronas/metabolismo , Estimulación Luminosa , Retina/metabolismo , Vías Visuales/metabolismoRESUMEN
Reading for Wellbeing (RfW) is a pilot initiative, aimed at improving mental health and well-being through supporting access and increasing opportunities to read for pleasure. RfW was implemented across six North-East local authorities in England and employed Community Reading Workers to support access to books and reading for targeted populations. The current study used realist methodology to understand context, potential mechanisms of action, acceptability and reported outcomes. Data generation and analysis were conducted iteratively, using focus groups, interviews and observations.The analysis of the collated data highlighted that a positive attitude towards reading and a desire for social connections were significant motivators for engagement with RfW. This paper postulates eight programme theories relating to that context, which describe key mechanisms within RfW linked to engagement with reading, well-being, connections and practice. The paper concludes that previous notions of positivity associated with reading for pleasure enable participants to experience RfW as a positive social encounter. This positive social encounter enhances participants' multiple resistance resources such as increased sense of self-efficacy and connectedness that could impact on their sense of well-being.
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Grupos Focales , Placer , Lectura , Humanos , Inglaterra , Femenino , Masculino , Salud Mental , Motivación , Adulto , Libros , Proyectos Piloto , Persona de Mediana Edad , Autoeficacia , ActitudRESUMEN
Large grazers (megaherbivores) have a profound impact on ecosystem functioning. However, how ecosystem multifunctionality is affected by changes in megaherbivore populations remains poorly understood. Understanding the total impact on ecosystem multifunctionality requires an integrative ecosystem approach, which is especially challenging to obtain in marine systems. We assessed the effects of experimentally simulated grazing intensity scenarios on ecosystem functions and multifunctionality in a tropical Caribbean seagrass ecosystem. As a model, we selected a key marine megaherbivore, the green turtle, whose ecological role is rapidly unfolding in numerous foraging areas where populations are recovering through conservation after centuries of decline, with an increase in recorded overgrazing episodes. To quantify the effects, we employed a novel integrated index of seagrass ecosystem multifunctionality based upon multiple, well-recognized measures of seagrass ecosystem functions that reflect ecosystem services. Experiments revealed that intermediate turtle grazing resulted in the highest rates of nutrient cycling and carbon storage, while sediment stabilization, decomposition rates, epifauna richness, and fish biomass are highest in the absence of turtle grazing. In contrast, intense grazing resulted in disproportionally large effects on ecosystem functions and a collapse of multifunctionality. These results imply that (i) the return of a megaherbivore can exert strong effects on coastal ecosystem functions and multifunctionality, (ii) conservation efforts that are skewed toward megaherbivores, but ignore their key drivers like predators or habitat, will likely result in overgrazing-induced loss of multifunctionality, and (iii) the multifunctionality index shows great potential as a quantitative tool to assess ecosystem performance. Considerable and rapid alterations in megaherbivore abundance (both through extinction and conservation) cause an imbalance in ecosystem functioning and substantially alter or even compromise ecosystem services that help to negate global change effects. An integrative ecosystem approach in environmental management is urgently required to protect and enhance ecosystem multifunctionality.
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Ecosistema , Tortugas , Animales , Biomasa , Peces , CarbonoRESUMEN
BACKGROUND: Rural youth often begin developing polysubstance use and other risk behaviors during middle school. However, little polysubstance use research focuses on rural middle school youth. Our research uses Latent Class Analysis to understand existing patterns of rural middle school polysubstance use and risk and protective factors associated with polysubstance use. METHODS: We used survey data from a rural middle school pregnancy prevention program (N = 2,708). The survey included measures of demographics, lifetime substance use, trauma (adverse childhood experiences and bullying victimization) and aspects of youth development (parent communication on drugs and alcohol, parent connectedness and school connectedness). We used latent class analysis to produce participant polysubstance use profiles and multinomial regression to examine associations between polysubstance use, demographics, trauma and aspects of youth development. RESULTS: We categorized our participants into four latent classes. Our analysis classified 2.2% of participants as Regular Polysubstance users, 6.9% as Polysubstance experimenters, 19% as Vape + Alcohol experimenters and 71.9% as Non-Users. More adverse childhood experiences were associated with greater risk of polysubstance use and experimentation. Bullying was positively associated with greater risk of vape and alcohol experimentation. Higher reported parental and school connectedness were associated with lower risk of high frequency polysubstance use. Higher reported school connection was also associated with lower risk of polysubstance experimentation. CONCLUSION: Rural substance use prevention programs should begin during middle school, as polysubstance use development is common among rural middle schoolers. These programs should be trauma informed and focus on connectedness as a modifiable factor to reduce risk of polysubstance use development. TRIAL REGISTRATION: This article does not report results of a health care intervention on human participants.
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Asunción de Riesgos , Trastornos Relacionados con Sustancias , Adolescente , Humanos , Análisis de Clases Latentes , Trastornos Relacionados con Sustancias/epidemiología , Población Rural , EstudiantesRESUMEN
Members of the differential screening-selected gene aberrative in neuroblastoma (DAN) protein family are developmentally conserved extracellular binding proteins that antagonize bone morphogenetic protein (BMP) signaling. This protein family includes the Gremlin proteins, GREM1 and GREM2, which have key functions during embryogenesis and adult physiology. While BMPs play essential roles in ovarian follicle development, the role of the DAN family in female reproductive physiology is less understood. We generated mice null for Grem2 to determine its role in female reproduction in addition to screening patients with primary ovarian insufficiency (POI) for variants in GREM2. Grem2-/- mice are viable, but female Grem2-/- mice have diminished fecundity and irregular estrous cycles. This is accompanied by significantly reduced production of ovarian anti-Müllerian hormone (AMH) from small growing follicles, leading to a significant decrease in serum AMH. Surprisingly, as AMH is a well-established marker of the ovarian reserve, morphometric analysis of ovarian follicles showed maintenance of primordial follicles in Grem2-/- mice like wild-type (WT) littermates. While Grem2 mRNA transcripts were not detected in the pituitary, Grem2 is expressed in hypothalami of WT female mice, suggesting the potential for dysfunction in multiple tissues composing the hypothalamic-pituitary-ovarian axis that contribute to the subfertility phenotype. Additionally, screening 106 women with POI identified one individual with a heterozygous variant in GREM2 that lies within the predicted BMP-GREM2 interface. In total, these data suggest that Grem2 is necessary for female fecundity by playing a novel role in regulating the HPO axis and contributing to female reproductive disease.
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Citocinas/genética , Ciclo Estral/genética , Fertilidad/genética , Insuficiencia Ovárica Primaria/genética , Transducción de Señal , Animales , Citocinas/metabolismo , Femenino , Humanos , Ratones , PeriodicidadRESUMEN
BACKGROUND AND AIMS: It is important to have an in-depth mechanistic understanding of tidal marsh establishment and dynamics to ensure the long-term persistence of these valuable ecosystems. As wave forcing may be expected to impact seedling establishment, we studied the effect of water-imposed drag forces on seedling survival, morphology and biomechanical properties of three marsh pioneer species that are dominant along the salinity gradient in many areas around the world: Spartina anglica (salt to brackish), Scirpus maritimus (brackish) and Phragmites australis (brackish to fresh). METHODS: Using a newly developed plant-shaking mesocosm (PSM) that mimicked water-imposed wave drag forces, the effect of wave stress on seedling survival was examined, together with impacts on morphology and biomechanical properties. KEY RESULTS: After 7 weeks of exposure to wave stress, lowered seedling survival and growth for all species was revealed. Wave treatments increased the root/shoot biomass ratio to enhance anchorage and made seedlings more flexible (i.e. reduced flexural rigidity), which might be regarded as a mixed outcome between a stress avoidance and stress tolerance strategy. CONCLUSIONS: The different biomechanical responses between the three dominant marsh pioneer species, overall, make them less resistant to external stress. Therefore, our results indicate that the likelihood of marshes becoming established is reduced if wave energy increases. Despite the different biomechanical response of these three pioneer species to waves, the seedlings of all species were found to have low resistance to external stresses.
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Plantones , Humedales , Ecosistema , Poaceae , SalinidadRESUMEN
OBJECTIVE: To describe a structured approach for managing a child with a new finding of neutropenia. METHOD: Literature review and consensus practice of clinicians in our regional centre. CONCLUSION: Neutropenia may arise in a variety of situations from a well child with a physiological neutropenia to a sick infant with life-threatening infection. In most cases a thoughtful history and directed examination will help to identify the severity in order to determine an appropriate care pathway. SCENARIO: A 6-year-old boy presented earlier in the day to the acute assessment unit with lethargy and a sore throat. At handover time his blood results are phoned through and show that he is neutropenic.
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Neutropenia/etiología , Niño , Técnicas de Laboratorio Clínico , Humanos , Anamnesis , Examen Físico , Derivación y ConsultaRESUMEN
The lysosomal storage disorders are a collection of progressive, multisystem disorders that frequently present in childhood. Their timely diagnosis is paramount as they are becoming increasingly treatable. Musculoskeletal manifestations often occur early in the disease course, hence are useful as diagnostics clues. Non-inflammatory joint stiffness or pain, carpal tunnel syndrome, trigger fingers, unexplained pain crises and short stature should all prompt consideration of a lysosomal storage disorder. Recurrent ENT infections, hepatosplenomegaly, recurrent hernias and visual/hearing impairment - especially when clustered together - are important extra-skeletal features. As diagnostic and therapeutic options continue to evolve, children with lysosomal storage disorders and their families are facing more sophisticated options for screening and treatment. The aim of this article is to highlight the paediatric presentations of lysosomal storage disorders, with an emphasis on the musculoskeletal features.
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Enfermedades por Almacenamiento Lisosomal/diagnóstico , Enfermedades por Almacenamiento Lisosomal/epidemiología , Enfermedades Musculoesqueléticas/epidemiología , Tamizaje Neonatal/organización & administración , Calidad de Vida , Adolescente , Distribución por Edad , Niño , Preescolar , Comorbilidad , Diagnóstico Precoz , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Enfermedades por Almacenamiento Lisosomal/terapia , Masculino , Enfermedades Musculoesqueléticas/diagnóstico , Enfermedades Musculoesqueléticas/terapia , Pronóstico , Medición de Riesgo , Índice de Severidad de la Enfermedad , Distribución por Sexo , Análisis de SupervivenciaRESUMEN
INTRODUCTION AND HYPOTHESIS: Recurrence rates of stress urinary incontinence after surgery are reported to be between 8 to 15%. Both surgical technique and non-surgical risk factors have been shown to affect post-operative outcomes. Tobacco use is a possible risk factor that may increase the surgical failure rate, however, there are currently conflicting reports in the literature regarding the affect of tobacco use on surgical outcomes. Our objective is to evaluate the effect of tobacco use on the risk of repeat surgery for stress urinary incontinence (SUI). METHODS: We performed a retrospective cohort analysis using a de-identified clinical database from a large multi-institution electronic health records data web application EPM:ExploreTM (Explorys Inc, Cleveland, Ohio) to identify women with and without a history of tobacco use who underwent reoperation for stress urinary incontinence within 2 years of the first surgery. We then evaluated previously described risk factors for reoperation: diabetes mellitus (DM), pelvic organ prolapse (POP), anti-muscarinic (AM) use at initial surgery, obesity, and advanced age on rate of reoperation and the impact of tobacco use on these risk factors. RESULTS: Tobacco use was associated with an increased rate of a second surgery for SUI (OR=1.43, p <0.001), as was anti-muscarinic use (OR = 1.68, p<0.001), DM (OR = 1.21, p = 0.005), age >50 years (OR= 1.16, p = 0.040), and BMI > 30 kg/m2 (OR = 2.97 p<0.001). The odds of a second surgery for SUI in patients who used tobacco and anti-muscarinic medications or had pelvic organ prolapse were lower when compared to non-users. The odds of a second surgery for SUI were higher in patients who used tobacco and had asthma when compared to non-users who had asthma. CONCLUSIONS: Tobacco increases the overall risk of second surgery for SUI, however, in patients with specific risk factors, tobacco use is associated with a decrease risk of reoperation.
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Procedimientos Quirúrgicos Ginecológicos/estadística & datos numéricos , Uso de Tabaco/efectos adversos , Incontinencia Urinaria de Esfuerzo/cirugía , Registros Electrónicos de Salud , Femenino , Humanos , Persona de Mediana Edad , Reoperación , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The BMP pathway is essential for scaling of the presynaptic motoneuron arbor to the postsynaptic muscle cell at the Drosophila neuromuscular junction (NMJ). Genetic analyses indicate that the muscle is the BMP-sending cell and the motoneuron is the BMP-receiving cell. Nevertheless, it is unclear how this directionality is established as Glass bottom boat (Gbb), the known BMP ligand, is active in motoneurons. We demonstrate that crimpy (cmpy) limits neuronal Gbb activity to permit appropriate regulation of NMJ growth. cmpy was identified in a screen for motoneuron-expressed genes and encodes a single-pass transmembrane protein with sequence homology to vertebrate Cysteine-rich transmembrane BMP regulator 1 (Crim1). We generated a targeted deletion of the cmpy locus and find that loss-of-function mutants exhibit excessive NMJ growth. In accordance with its expression profile, tissue-specific rescue experiments indicate that cmpy functions neuronally. The overgrowth in cmpy mutants depends on the activity of the BMP type II receptor Wishful thinking, arguing that Cmpy acts in the BMP pathway upstream of receptor activation and raising the possibility that it inhibits Gbb activity in motoneurons. Indeed, the cmpy mutant phenotype is strongly suppressed by RNAi-mediated knockdown of Gbb in motoneurons. Furthermore, Cmpy physically interacts with the Gbb precursor protein, arguing that Cmpy binds Gbb prior to the secretion of mature ligand. These studies demonstrate that Cmpy restrains Gbb activity in motoneurons. We present a model whereby this inhibition permits the muscle-derived Gbb pool to predominate at the NMJ, thus establishing the retrograde directionality of the pro-growth BMP pathway.
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Proteínas Morfogenéticas Óseas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/anatomía & histología , Drosophila melanogaster/crecimiento & desarrollo , Neuronas Motoras/fisiología , Unión Neuromuscular/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Alelos , Animales , Proteínas Morfogenéticas Óseas/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Masculino , Neuronas Motoras/citología , Fenotipo , Interferencia de ARN , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/genética , Técnicas del Sistema de Dos HíbridosRESUMEN
Soy attracts attention for its health benefits, such as lowering cholesterol or preventing breast and colon cancer. Soybeans contain isoflavones, which act as phytoestrogens. Even though isoflavones have beneficial health effects, a role for isoflavones in the initiation and progression of diseases including cancer is becoming increasingly recognized. While data from rodent studies suggest that neonatal exposure to genistein (the predominant isoflavone in soy) disrupts normal reproductive function, its role in ovarian cancers, particularly granulosa cell tumors (GCT), is largely unknown. Our study aimed to define the contribution of a soy diet in GCT development using a genetically modified mouse model for juvenile GCTs (JGCT; Smad1 Smad5 conditional double knockout mice) as well as a human JGCT cell line (COV434). While dietary soy cannot initiate JGCT development in mice, we show that it has dramatic effects on GCT growth and tumor progression compared to a soy-free diet. Loss of Smad1 and Smad5 alters estrogen receptor alpha (Esr1) expression in granulosa cells, perhaps sensitizing the cells to the effects of genistein. In addition, we found that genistein modulates estrogen receptor expression in the human JGCT cell line and positively promotes cell growth in part by suppressing caspase-dependent apoptosis. Combined, our work suggests that dietary soy consumption has deleterious effects on GCT development.
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Tumor de Células de la Granulosa/inducido químicamente , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Alimentación Animal , Animales , Línea Celular Tumoral , Dieta/veterinaria , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Genisteína/toxicidad , Tumor de Células de la Granulosa/metabolismo , Humanos , Ratones , Ratones Noqueados , Proteína Smad1/genética , Proteína Smad5/genética , Glycine maxRESUMEN
A literature review of the most current publications studying lower urinary tract symptoms (LUTS) and findings in diabetic women was conducted including articles from January 2013 to April 2014. Current reports consistently note that aging and obesity are significantly associated with worsened LUTS in diabetic women. Glucosuria has variable effects on urodynamic parameters and LUTS, but has a significant association with urinary tract infection (UTI) and incontinence at clinically relevant numbers, such as HbA1C values. The presence of severe nocturia in diabetic patients warrants careful surveillance for cardiovascular risks given the significant association with mortality. Diabetics appear to be at higher risk for colonization with the virulent, extended-spectrum, ß-lactamase-producing Escherichia coli and Klebsiella species in UTI. Novel therapies in glycemic control and for diabetic bladder dysfunction are undergoing animal model trials with encouraging results. The most promising of these includes stem cell therapy, although a need exists for human studies.
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Diabetes Mellitus/epidemiología , Síntomas del Sistema Urinario Inferior/epidemiología , Infecciones Urinarias/epidemiología , Glucemia , Diabetes Mellitus/metabolismo , Femenino , Hemoglobina Glucada/metabolismo , Glucosuria , HumanosRESUMEN
BACKGROUND AND PURPOSE: In 2020, a clinical practice guideline (CPG) highly recommended high-intensity gait training (HIGT) to improve walking outcomes in adults with chronic stroke, incomplete spinal cord injury (SCI), and brain injury. The success of implementing a CPG into a student-run pro bono clinic (SRPBC) utilizing knowledge translation (KT) to assess student learning is not well described. The purpose of this case report is to describe student learning by assessing the fidelity of HIGT implementation (time spent in HIGT and level of cardiovascular intensity) in a SRPBC. CASE DESCRIPTION: MoveMore is a HIGT program delivered by Doctor of Physical Therapy students and Bachelor of Science in Nursing in a SRPBC. OUTCOMES: During Spring/Summer 2023, 24 physical therapy students, 10 nursing students, and 13 community partners (12 diagnosed with stroke, 1 with incomplete SCI) participated in MoveMore. The average time students engaged the community partners in HIGT was 46 minutes (range 32-54), while only 6 community partners spent a minimum of 13% of the time in the target heart rate zone. DISCUSSION AND CONCLUSION: Students delivering HIGT are able to engage community partners for time parameters aligning with the locomotor CPG; however, they are not successful in having a person with stroke/incomplete SCI consistently reach a moderate to high level of cardiovascular intensity. Using KT to implement a CPG and tracking patient outcomes allows physical therapy educators to assess student learning.
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Bacillus anthracis, classified as a Tier 1 Select Agent by the Centers for Disease Control and Prevention (CDC), is the causative agent of anthrax in both humans and livestock. Herein, we report the full genome sequences of 13 bacteriophages that infect B. anthracis Sterne. These phages are grouped into four clusters and are similar to previously described Bacillus phages.
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PURPOSE: Early sexual onset contributes to poor health outcomes through the life course. We use the social behavioral model to examine the behaviors and attitudes associated with early sexual onset and the intention to delay sex in middle school youth. METHODS: Youth in rural communities with high rates of hepatitis C and HIV filled out a survey prior to implementation of an evidence-based sex education program. Participants were asked if they had ever had sex and whether they planned to abstain from sex until the end of high school. We collected demographics, attitudes about abstinence, agency for sexual refusal, parent communication, sexual health knowledge, and history of system involvement. Logistic regression was utilized to examine factors associated with each outcome. FINDINGS: Our sample included 6,799 students, 12.7 years old ± 0.9 and 50.3% female. 5.1% had ever had sex and 73.9% planned to abstain until the end of high school. Early sexual onset was associated with older age, negative attitudes toward abstinence, lower agency for sexual refusal, more frequent parent communication about sex, history of child welfare, and history of juvenile involvement. Planning to abstain until the end of high school was associated with being younger, female, positive attitudes toward abstinence, higher agency for sexual refusal, less communication with parents about sex, more communication with parents about relationships, not having a history of foster involvement, and not having a history of juvenile involvement. CONCLUSIONS: Age, agency, and parent communication were all associated with both outcomes. Our findings highlight the importance of early comprehensive, trauma-informed sex education.
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Objective: To develop a set of quality indicators (QIs) tailored to improve the care provided to children with juvenile idiopathic arthritis (JIA) in countries across the Asia-Pacific region. Methods: An adaptation of the Research and Development Corporation (RAND)/University of California, Los Angeles (UCLA) Appropriateness Method (RAM) was used. An initial set of 32 QIs was developed after a systematic search of the literature. These were presented to members of a Delphi panel composed of pediatric rheumatologists and other relevant stakeholders from the Asia Pacific League of Associations for Rheumatology Pediatric Special Interest Group (APLAR-Pediatric SIG). After each round, the mean scores for validity and reliability, level of disagreement, and median absolute deviation from the mean were calculated. Results: The panelists were presented with 32 QIs in two rounds of voting, resulting in the formulation of a final set of 22 QIs for JIA. These QIs are categorized within six domains of care, including access to care, clinical assessment, medications and medication monitoring, screening for comorbidities, counseling, and self-efficacy and satisfaction with care. Conclusion: These QIs have been developed to evaluate and improve the quality of care provided to children with JIA, aiming to enhance health outcomes and ensure that healthcare services are tailored to the unique needs of this patient population.
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BACKGROUND: The objective of the PERSONAL-CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID-19 Pandemic) trial was to assess the efficacy and safety of smartphone-enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID-19 pandemic. METHODS AND RESULTS: This was an open-label, remote, dose titration trial using daily home self-monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5-7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10-12)/7 (95% CI, 6-7) mm Hg, P<0.001). The majority of participants achieved BP control on novel doses (84%); of those participants, 35% were controlled by 1 mg daily. The majority (88%) controlled on novel doses had no peripheral edema. Adherence to BP recording and reported adherence to medication was 84% and 94%, respectively. Patient retention was 96% (196/205). Treatment was well tolerated with no withdrawals from adverse events. CONCLUSIONS: Personalized dose titration with amlodipine was safe, well tolerated, and efficacious in treating primary hypertension. The majority of participants achieved BP control on novel doses, and with personalization of dose there were no trial discontinuations due to drug intolerance. App-assisted remote clinician dose titration may better balance BP control and adverse effects and help optimize long-term care. REGISTRATION: URL: clinicaltrials.gov. Identifier: NCT04559074.
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COVID-19 , Hipertensión , Adolescente , Adulto , Humanos , Amlodipino/uso terapéutico , Antihipertensivos/uso terapéutico , Presión Sanguínea , Hipertensión Esencial/tratamiento farmacológico , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/inducido químicamente , Pandemias , Proyectos Piloto , Teléfono Inteligente , Resultado del TratamientoRESUMEN
Intraovarian factors play important roles in coordinating germ cell and somatic cell growth in the ovary. Prior to the onset of gonadotropin stimulation and reproductive cyclicity, follicle development is dependent upon locally produced growth factors, such as the transforming growth factor beta family members inhibin, activin, and GDF9. In the absence of inhibin in prepubertal mice (Inha(-/-)), there are marked alterations in preantral follicle growth, but no evidence of ovarian tumors characteristic of adult Inha-null mice. To ascertain the contribution of GDF9 to the Inha-null phenotype, we analyzed folliculogenesis in postnatal Inha Gdf9 double knockout mice. Deletion of Gdf9 from Inha(-/-) rescues the initial growth defects found at early follicle stages in Inha(-/-) ovaries, but surprisingly enhances the onset of pretumor lesions. The normalization of growth dynamics between granulosa cells and oocytes of Inha Gdf9 double knockout mice is also accompanied by a reduction in levels of the activin/inhibin beta B subunit, Inhbb, which is upregulated in Inha(-/-) ovaries. However, at later ages, Inha Gdf9 double knockout ovaries are similar to Inha(-/-) ovaries, and show upregulation of the activin/inhibin subunits and downregulation of the growth factor, kit ligand, thus resulting in a local environment that is growth-promoting for granulosa cells but growth-inhibitory for oocytes. These data suggest a sequential mechanism of action initiated by GDF9 in the Inha knockout mouse that promotes defective folliculogenesis. These studies thus provide a novel role for GDF9 in causing reproductive defects and suppressing tumor initiation in the Inha(-/-) mouse model.
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Factor 9 de Diferenciación de Crecimiento/fisiología , Inhibinas/genética , Neoplasias/genética , Reproducción/genética , Animales , Transformación Celular Neoplásica/genética , Femenino , Factor 9 de Diferenciación de Crecimiento/genética , Factor 9 de Diferenciación de Crecimiento/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/patología , Tamaño de los Órganos , Folículo Ovárico/metabolismo , Folículo Ovárico/fisiología , Ovario/anatomía & histología , Ovario/metabolismo , FenotipoRESUMEN
Although rare in the USA, vesicovaginal fistulae are usually associated with postoperative complications. Even more rarely seen, vesicoperitoneal fistulae can also present postoperatively. Both types of fistulae pose as diagnostically challenging and can be difficult to manage. We describe a case report of a patient with both vesicovaginal and vesicoperitoneal fistulae after a laparoscopic-assisted vaginal hysterectomy who presented with abdominal pain and anuria. Cystogram and outpatient cystoscopy were imperative in the diagnosis. She was conservatively managed with continuous bladder drainage via indwelling catheter resulting in an ideal recovery without requiring reoperation.