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Point of care ultrasound (POCUS) represents an exciting tool for current and future acute care practitioners. POCUS has come a long way in a short space of time and its widespread implementation may well be one of the biggest changes seen in acute medicine across the next decade. This narrative review explores the increasing evidence base for the accuracy of POCUS use in various acute scenarios, whilst also addressing current gaps in the evidence and areas for potential future POCUS development.
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Medicina , Sistemas de Atención de Punto , Humanos , Cuidados Críticos , Pruebas en el Punto de AtenciónRESUMEN
Patient reported experience measures (PREMS) are a key part of measured quality. There is no tool currently used in the UK in Acute Medicine. On the 8th of September 2022 10 units based in England, Scotland and Wales collected data for the validated PREM, alongside the EQ-5D and variables from the Society for Acute Medicine's Benchmarking Audit (SAMBA) dataset. 365 patients were screened, 200 were included (55%): 159 patients from AMUs and 41 from SDEC units. Overall experience of patients was rated 8.5/10, patients rated their experience of safety, trust and listening highly. Collection of PREMS was feasible. Further research is required to link experience to clinical outcome and explore tools that capture experience of patients with altered mental status.
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Benchmarking , Mejoramiento de la Calidad , Humanos , Estudios de Factibilidad , Recolección de Datos , Medición de Resultados Informados por el PacienteRESUMEN
BACKGROUND: The advent of laparoscopy has been a notable landmark in surgery; however, there is a slow progress to widespread utilization in West Africa. AIMS: To study the awareness and practice of laparoscopic surgery among trainee surgeons in Nigerian tertiary hospitals while highlighting measures to mitigate challenges. MATERIALS AND METHODS: A cross-sectional study conducted during a 2-week West African College of Surgeons update course in September 2018 at Ilorin, Kwara State, Nigeria. A structured questionnaire was distributed to registered trainee surgeons for completion. Data collated included demographics, cognitive knowledge, common procedures in centres, referrals, routine practice, performing laparoscopic surgeon, and routine practice. Statistical analysis was done using IBM SPSS Statistics for Windows version 20 Armonk NY USA. RESULTS: There were 184 registered trainee surgeons with 80 respondents from 26 Nigerian tertiary health facilities. The age range was 29 -51 years (mean 35.0 ± 4.4) and a mean training duration of 3.3 years (R2= 0.12). Seven (63.6%) senior registrars and 54(76.3%) registrars were reported as first assistants in laparoscopic surgeries performed but no unassisted surgery. Four (15.4%) represented centres had no laparoscopy equipment or expertise. A non-referral rate of 52/80(65.0%) for laparoscopic surgery was recorded. CONCLUSION: Laparoscopic surgery is practiced in some Nigerian tertiary hospitals with trainee surgeons actively involved in performing these surgeries. However, there is limited unassisted experience by trainee surgeons in the basic laparoscopic surgeries predominantly performed.
CONTEXTE: L'avènement de la laparoscopie a été un jalon notable en chirurgie; cependant, il y a un lent progrès vers une utilisation généralisée en Afrique de l'Ouest. OBJECTIFS: Étudier la sensibilisation et la pratique de la chirurgie laparoscopique chez les chirurgiens stagiaires dans les hôpitaux tertiaires nigérians tout en mettant en évidence les mesures visant à atténuer les défis. MATÉRIEL ET MÉTHODES: Une étude transversale menée au cours d'un cours de mise à jour de 2 semaines du Collège ouest-africain des chirurgiens en septembre 2018 à Ilorin, État de Kwara, Nigéria. Un questionnaire structuré a été distribué aux chirurgiens stagiaires enregistrés pour qu'il le remplisse. Les données rassemblées comprenaient les données démographiques, les connaissances cognitives, les procédures courantes dans les centres, les références, la pratique de routine, le chirurgien laparoscopique en exercice et la pratique de routine. L'analyse statistique a été effectuée à l'aide d'IBM SPSS Statistics pour Windows version 200 Armonk NY USA. RÉSULTATS: Il y avait 184 chirurgiens stagiaires enregistrés avec 80 répondants de 26 établissements de santé tertiaires nigérians. La tranche d'âge était de 29 à 51 ans (moyenne 35,0 ± 4,4) et une durée moyenne de formation de 3,3 ans (R2 = 0,12). Sept (63,6%) registraires principaux et 54 registraires (76,3%) ont été signalés comme premiers assistants dans les chirurgies laparoscopiques effectuées mais pas de chirurgie non assistée. Quatre (15,4%) centres représentés n'avaient ni équipement ni expertise de laparoscopie. Un taux de non-référence de 52/80 (65,0%) pour la chirurgie laparoscopique a été enregistré. CONCLUSION: La chirurgie laparoscopique est pratiquée dans certains hôpitaux tertiaires nigérians avec des chirurgiens stagiaires activement impliqués dans la réalisation de ces chirurgies. Cependant, l'expérience non assistée des chirurgiens stagiaires est limitée dans les chirurgies laparoscopiques de base principalement pratiquées. MOTS CLÉS: Chirurgie, laparoscopie, formation.
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Laparoscopía , Cirujanos , Adulto , África Occidental , Estudios Transversales , Humanos , Persona de Mediana Edad , Nigeria , Centros de Atención TerciariaRESUMEN
OBJECTIVE: The objective is to assess the reasoning by families in deciding between a home vs. facility delivery and vaginal vs. caesarean. STUDY DESIGN: The authors selected a convenience sample of 16 villages in Sathkira district in southwest Bangladesh. Evidence was drawn from detailed in-home post-delivery interviews with all mothers in these villages who delivered in 2015 or 2016. METHODS: Local family health workers and paramedics used a structured questionnaire that enabled gathering of relevant quantitative and qualitative evidence. Mothers' reasons for selection of delivery location and type were categorized, and regression analysis was conducted to assess significance of variables that proxy supply and demand factors. RESULTS: Among 492 completed interviews, 48% were home deliveries, 52% facility deliveries; two-thirds of facility deliveries in private clinics. Overall, sample caesarean rate is 39%, public hospital rate 53%, private clinic rate 86%. Over half of reasons for home delivery refer to pregnancy without complication or access to trusted birth attendant. Over half of reasons for facility delivery refer to medical complications allegedly precluding home delivery, or requiring home-to-facility transfer during labour for reasons not clear to the mother. The decision depends on both 'demand' factors originating with the family (proxied by family income, birth order and education levels) and 'supply' factors originating with obstetric care providers (proxied by number of antenatal visits and variation of caesarean rate by village). In a regression controlling for both demand and supply variables, the above proxy variables are all significant. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Bangladesh has inadequate nursing support for vaginal delivery in either home or facility. Hence, physicians frequently recommend that women deliver in a facility (usually a physician's clinic). Physicians are reluctant to hire adequate nurses to attend vaginal deliveries. Hence, families with some discretionary income are increasingly opting for a caesarean over vaginal delivery. Facility deliveries reduce incidence of obstructed labour fistula, but probably contribute to rising incidence of iatrogenic fistula. Reducing caesarean rates requires a large increase in numbers of nurses and midwives, and acceptance by physicians of a broad scope of practice for nurses/midwives in vaginal deliveries.
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Cesárea/psicología , Cesárea/estadística & datos numéricos , Parto Obstétrico/psicología , Parto Obstétrico/estadística & datos numéricos , Familia/psicología , Parto Domiciliario/psicología , Prioridad del Paciente/psicología , Prioridad del Paciente/estadística & datos numéricos , Adulto , Femenino , Parto Domiciliario/estadística & datos numéricos , Humanos , Masculino , Embarazo , Investigación CualitativaRESUMEN
BACKGROUND: Chromosomal instability (CIN) has been shown to be associated with drug resistance and poor clinical outcome in several cancer types. However, in oestrogen receptor (ER)-negative breast cancer we have previously demonstrated that extreme CIN is associated with improved clinical outcome, consistent with a negative impact of CIN on tumour fitness and growth. The aim of this current study was to validate this finding using previously defined CIN thresholds in a much larger prospective cohort from a randomised, controlled, clinical trial. PATIENTS AND METHODS: As a surrogate measurement of CIN, dual centromeric fluorescence in situ hybridisation was performed for both chromosomes 2 and 15 on 1173 tumours from the breast cancer TACT trial (CRUK01/001). Each tumour was scored manually and the mean percentage of cells deviating from the modal centromere number was used to define four CIN groups (MCD1-4), where tumours in the MCD4 group were defined as having extreme CIN. RESULTS: In a multivariate analysis of disease-free survival, with a median follow-up of 91 months, increasing CIN was associated with improved outcome in patients with ER-negative cancer (P trend = 0.03). A similar pattern was seen in ER-negative/HER2-negative cancers (Ptrend = 0.007). CONCLUSIONS: This prospective validation cohort study further substantiated the association between extreme CIN and improved outcome in ER-negative breast cancers. Identifying such patients with extreme CIN may help distinguish good from poor prognostic groups, and therefore support treatment and risk stratification in this aggressive breast cancer subtype.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Inestabilidad Cromosómica , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antraciclinas/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Taxoides/administración & dosificación , Adulto JovenRESUMEN
Amelogenesis mperfecta is an inherited disorder of enamel development, which results n morphological defects of both the primary and secondary dentition, usually in the absence of systemic involvement. Mutational defects involving the genes that encode for enamel matrix proteins and proteinases are mplicated in this disorder. The phenotypic expression is variable, spanning a spectrum from barely discernible changes to severe aesthetic and functional enamel defects. The specific type and location of the genetic mutation, as well as the mode of inheritance, determine the clinical presentation Clinical recognition and early therapeutic intervention are required for the most successful outcome. An essentia component of the treatment process includes patient counselling and education. Patient management requires a dedicated multi-disciplinary approach. The disorder is reviewed here with emphasis on the clinical significance for the oral healthcare worker. In addition, a case is presented in order to provide an example of treatment panning and dental management.
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Amelogénesis Imperfecta , Amelogénesis Imperfecta/patología , Amelogénesis Imperfecta/terapia , Alargamiento de Corona , Porcelana Dental , Restauración Dental Permanente , Femenino , Humanos , Persona de Mediana Edad , Desbridamiento Periodontal , Bolsa Periodontal/terapia , Dimensión VerticalRESUMEN
This study examined the correlation between intestinal protozoans and the bacterial microbiome in faecal samples collected from 463 patients in New Zealand who were diagnosed with gastroenteritis. In comparison to traditional microscopic diagnosis methods, Multiplexed-tandem PCR proved to be more effective in detecting intestinal parasites. Among the identified protozoans, Blastocystis sp. and Dientamoeba fragilis were the most prevalent. Notably, D. fragilis was significantly associated with an increase in the alpha-diversity of host prokaryotic microbes. Although the exact role of Blastocystis sp. and D. fragilis as the primary cause of gastroenteritis remains debatable, our data indicates a substantial correlation between these protozoans and the prokaryote microbiome of their hosts, particularly when compared to other protists or patients with gastroenteritis but no detectable parasitic cause. These findings underscore the significance of comprehending the contributions of intestinal protozoans, specifically D. fragilis, to the development of gastroenteritis and their potential implications for disease management.
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Blastocystis , Gastroenteritis , Parasitosis Intestinales , Parásitos , Animales , Humanos , Dientamoeba , Parasitosis Intestinales/parasitología , Blastocystis/genética , Gastroenteritis/parasitología , Heces/parasitologíaRESUMEN
We have developed a radioluminescence-based survey meter for use in industries in which there is involvement in naturally occurring radioactive material (NORM), also in support of those needing to detect other weak emitters of radiation. The functionality of the system confronts particular shortcomings of the handheld survey meters that are currently being made use of. The device couples a LYSO:Ce scintillator with a photodetector via a polymer optical fibre waveguide, allowing for "intrinsically safe" inspection within pipework, separators, valves and other such component pieces. The small-diameter optical fibre probe is electrically passive, immune to electromagnetic interference, and chemically inert. The readout circuit is entirely incorporated within a handheld casing housing a silicon photomultiplier (SiPM) detection circuit and a microprocessor circuit connected to an LCD display. A 15 m long flexible PMMA optical fibre waveguide is butt coupled to an ABS plastic probe that retains the LYSO:Ce scintillator. Initial tests have included the use of lab-based mixed gamma-ray sources, measurements being made in concert with a reference conventional GM survey-meter. Characterization, via NORM sources at a decontamination facility, has shown useful sensitivity, covering the dose-rate range 0.10- to 28 µSv h-1 (R-squared 0.966), extending to 80 µSv/h as demonstrated in use of a Cs-137 source. The system is shown to provide an effective tool for detection of radioactivity within hard to access locations, in particular for sources emitting at low radiation levels, down to values that approach background.
RESUMEN
BACKGROUND: Orofacial clefts are the most common malformations of the head and neck, with a worldwide prevalence of 1 in 700 births. They are commonly divided into CL(P) and CP based on anatomic, genetic, and embryologic findings. A Nigerian craniofacial anomalies study (NigeriaCRAN) was set up in 2006 to investigate the role of gene-environment interaction in the origin of orofacial clefts in Nigeria. SUBJECTS AND METHODS: DNA isolated from saliva from Nigerian probands was used for genotype association studies and direct sequencing of cleft candidate genes: MSX1 , IRF6 , FOXE1, FGFR1 , FGFR2 , BMP4 , MAFB, ABCA4 , PAX7, and VAX1 , and the chromosome 8q region. RESULTS: A missense mutation A34G in MSX1 was observed in nine cases and four HapMap controls. No other apparent causative variations were identified. Deviation from Hardy Weinberg equilibrium (HWE) was observed in these cases (p = .00002). A significant difference was noted between the affected side for unilateral CL (p = .03) and bilateral clefts and between clefts on either side (p = .02). A significant gender difference was also observed for CP (p = .008). CONCLUSIONS: Replication of a mutation previously implicated in other populations suggests a role for the MSX1 A34G variant in the development of CL(P).
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Población Negra/genética , Labio Leporino/genética , Fisura del Paladar/genética , Factor de Transcripción MSX1/genética , Mutación Missense/genética , Estudios de Casos y Controles , Niño , Preescolar , Labio Leporino/epidemiología , Fisura del Paladar/epidemiología , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Nigeria/epidemiología , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
Traumatic diaphragmatic rupture (TDR) is rare in children and can be easily overlooked because of lack of awareness of late presentation and concomitant injuries. A 4-year-old girl presented with respiratory distress 2 months after a road traffic accident. The initial differential diagnosis was pneumonia or pulmonary tuberculosis with associated pleural effusion. On further assessment, a diaphragmatic hernia was suspected. The initial radiograph showed left hydropneumothorax. Fluoroscopy, follow-up chest radiographs and barium swallow confirmed the diagnosis of left TDR. Surgery was undertaken but unfortunately she did not survive. Awareness of delayed presentation of TDR is essential for prompt management.
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Hernia Diafragmática Traumática/diagnóstico , Hernia Diafragmática Traumática/patología , Hidroneumotórax/diagnóstico , Hidroneumotórax/patología , Preescolar , Diagnóstico Diferencial , Resultado Fatal , Femenino , Hernia Diafragmática Traumática/cirugía , Humanos , Radiografía TorácicaRESUMEN
Pyogenic liver abscess [PLA] is a rare and life-threatening disease in children. Appendicitis was the leading source of PLA in the pre-antibiotic era, but it essentially has been eliminated in recent times. Most patients with persistent fever after exploratory laparatomy for perforated appendicitis are often found to have residual abdominal collection. We report a 12-year old girl with PLA after laparotomy for perforated appendix. She developed persistent fever and respiratory distress post operatively. Physicians had an impression of pneumonia but abdominal ultrasound showed cystic mass with mobile internal echoes within the right lobe of the liver suggesting an abscess. Patient was successfully managed by percutaneous drainage under ultrasound guidance. Culture of the pus yielded no growth. She was discharged after 7 weeks of hospital stay. Aetiology, evaluation and treatment modalities were reviewed.
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Apendicitis/cirugía , Drenaje , Perforación Intestinal/cirugía , Absceso Piógeno Hepático/diagnóstico por imagen , Apendicectomía , Apendicitis/complicaciones , Apendicitis/diagnóstico , Niño , Drenaje/métodos , Femenino , Humanos , Perforación Intestinal/complicaciones , Laparoscopía , Absceso Piógeno Hepático/etiología , Absceso Piógeno Hepático/terapia , Complicaciones Posoperatorias , Radiografía , Rotura Espontánea , Resultado del TratamientoRESUMEN
OBJECTIVES: Efficient pre-hospital transport (emergency medical services, EMS) is associated with improved outcomes in road traffic injuries (RTI). This study aims to discover possible interventions in the existing mode of transport. METHODS: Persons bringing all RTI victims to the Emergency room (ER) over a 4-year period and the injury arrival intervals were noted prospectively. FINDINGS: There were 2,624 patients (1,886 males and 738 females); only 2,046 (78%) had clear documentations of three categories of persons bringing victims to ER: Relatives (REL, 1,081, 52.83%); Police/Federal Road Safety Corps (P/F, 827, 40.42%) and Bystanders (BS, 138, 6.74%). No intervention was provided during transport: Within 1 hour, 986 victims (48.2% of 2,046) arrived ERbrought by P/F (448, 21.9%), REL (439, 21.5% of 2,046), and BS (99, 4.8%). These figures, in each instance, represent 40.6 % of total victims brought by REL; 54.2% by P/F and 71.7% by BS. However, after 6 hours, REL were the main active group as they brought 94.5% (359 of 380) patients of this period. In 91 victims (4.4%) the injury arrival time was not captured. CONCLUSION: This study has identified three groups of persons involved in pre-hospital transport with nearly 50% getting to ER within 1 hour without any intervention or prior notification of ER. Absence of EMS obscures pre-hospital death records. The P/F responsible for only 40% of transport should be trained and equipped to offer basic trauma life support (BTLS). The REL and BS (both responsible for 60% of transport) represent a pool of volunteers for BTLS to be trained.
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Accidentes de Tránsito/estadística & datos numéricos , Países en Desarrollo , Servicios Médicos de Urgencia/organización & administración , Heridas y Lesiones/epidemiología , Heridas y Lesiones/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Femenino , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Nigeria , Estudios Retrospectivos , Adulto JovenRESUMEN
Thymidylate synthase (TS) is an essential enzyme for DNA synthesis and repair and elevated levels of TS have been identified as an important prognostic biomarker for colorectal cancer and several other common human malignancies. In addition, TS gene expression has been linked with cell-cycle regulation and cell proliferation through the ability of retinoblastoma protein to repress the transcriptional activation of E2F target genes such as TS. Therefore, overproduction of TS could participate in the progression to a neoplastic phenotype. Consistent with this model, a recent study has suggested that ectopic TS expression can induce a transformed phenotype in mammalian cells. To investigate the role of deregulated TS activity in tumor development, we generated transgenic mice that express high levels of catalytically active human TS (hTS) exclusively in the pancreas and low levels of hTS in multiple other tissues. Analyses of pancreatic tissue in TS transgenic mice revealed abnormalities within the endocrine pancreas, ranging from pancreatic islet hyperplasia to the detection of islet cell tumors. Overexpression of hTS in murine islets provides a new model to study genetic alterations associated with the progression from normal cells to hyperplasia to islet cell tumors, and suggests that this mouse model may be useful for regulating TS activity in vivo for development of cancer prevention and new therapies.
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Adenoma de Células de los Islotes Pancreáticos/patología , Islotes Pancreáticos/patología , Neoplasias Pancreáticas/patología , Timidilato Sintasa/metabolismo , Adenoma de Células de los Islotes Pancreáticos/enzimología , Adenoma de Células de los Islotes Pancreáticos/genética , Animales , Humanos , Hiperplasia , Immunoblotting , Inmunohistoquímica , Islotes Pancreáticos/enzimología , Islotes Pancreáticos/metabolismo , Ratones , Ratones Transgénicos , Células 3T3 NIH , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/genética , Timidilato Sintasa/genética , Factores de TiempoRESUMEN
Typhoid intestinal perforation is a common complication of typhoid fever in our environment. The occurrence of multiple intestinal perforations that involves both small and large bowel is increasingly being seen in our practice. We report a case of 32 intestinal perforations in a child. This is the highest number of perforations seen in any 1 patient in our search of the English literature. This article details our approach to management of this type of patient.
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Perforación Intestinal/etiología , Perforación Intestinal/cirugía , Fiebre Tifoidea/complicaciones , Fiebre Tifoidea/tratamiento farmacológico , Antiinfecciosos/uso terapéutico , Antiprotozoarios/uso terapéutico , Preescolar , Ciprofloxacina/uso terapéutico , Colectomía , Femenino , Gentamicinas/uso terapéutico , Humanos , Metronidazol/uso terapéutico , NigeriaRESUMEN
In aesthetic sites, the integrity of the facial bone wall dimension in the anterior maxilla is jeopardized by physiologic and structural changes postextraction. An effective regenerative protocol is key to reestablish and maintain the hard and soft tissue dimensions over time. The present prospective case series study examined the effectiveness of early implant placement with simultaneous contour augmentation through guided bone regeneration with a 2-layer composite graft in postextraction single-tooth sites over an observation period of 10 y among 20 patients. The median peri-implant bone loss was 0.35 mm between the 1- and 10-y examination. A success rate of 95% was obtained, with pleasing aesthetic outcomes and a high median Pink Esthetic Score (8). Implant crowns (ICs) revealed significant median facial recession between IC10y and IC1y (0.17 mm). The facial bone wall dimensions were assessed by preoperative cone beam computed tomography and 2 subsequent scans taken at 6 and 10 y. The median facial bone wall thickness increased significantly from 0 mm at surgery to 1.67 mm at the 10-y examination. The facial vertical bone wall peak (DIC) was located at a median distance of 0.16 mm coronal to the implant shoulder. The facial vertical bone loss of DIC amounted to 0.02 mm between 6 and 10 y. Equivalence testing was performed for the null hypothesis of a difference of >0.2 mm per year between 2 respective time points, showing stable bone conditions. Modulating factors influencing the regenerative outcomes at 10 y were the preoperative proximal crest width and soft tissue thickness. In conclusion, the present study confirmed the long-term effectiveness of early implant placement with simultaneous contour augmentation through guided bone regeneration with a 2-layer composite graft in postextraction single-tooth sites offering stable bone conditions with low risks of mucosal recessions over an observation period of 10 y ( ClinicalTrials.gov NCT03252106).
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Aumento de la Cresta Alveolar/métodos , Implantación Dental Endoósea/métodos , Implantes Dentales de Diente Único , Regeneración Tisular Guiada Periodontal , Adulto , Anciano , Regeneración Ósea/fisiología , Sustitutos de Huesos/uso terapéutico , Tomografía Computarizada de Haz Cónico , Estética Dental , Femenino , Humanos , Masculino , Maxilar , Persona de Mediana Edad , Oseointegración/fisiología , Estudios Prospectivos , Extracción Dental , Alveolo Dental/cirugía , Resultado del Tratamiento , Dimensión VerticalRESUMEN
In contrast to the progress that has been made toward understanding the genetic etiology of cleft lip with or without cleft palate, relatively little is known about the genetic etiology for cleft palate only (CPO). A common coding variant of grainyhead like transcription factor 3 ( GRHL3) was recently shown to be associated with risk for CPO in Europeans. Mutations in this gene were also reported in families with Van der Woude syndrome. To identify rare mutations in GRHL3 that might explain the missing heritability for CPO, we sequenced GRHL3 in cases of CPO from Africa. We recruited participants from Ghana, Ethiopia, and Nigeria. This cohort included case-parent trios, cases and other family members, as well as controls. We sequenced exons of this gene in DNA from a total of 134 nonsyndromic cases. When possible, we sequenced them in parents to identify de novo mutations. Five novel mutations were identified: 2 missense (c.497C>A; p.Pro166His and c.1229A>G; p.Asp410Gly), 1 splice site (c.1282A>C p.Ser428Arg), 1 frameshift (c.470delC; p.Gly158Alafster55), and 1 nonsense (c.1677C>A; p.Tyr559Ter). These mutations were absent from 270 sequenced controls and from all public exome and whole genome databases, including the 1000 Genomes database (which includes data from Africa). However, 4 of the 5 mutations were present in unaffected mothers, indicating that their penetrance is incomplete. Interestingly, 1 mutation damaged a predicted sumoylation site, and another disrupted a predicted CK1 phosphorylation site. Overexpression assays in zebrafish and reporter assays in vitro indicated that 4 variants were functionally null or hypomorphic, while 1 was dominant negative. This study provides evidence that, as in Caucasian populations, mutations in GRHL3 contribute to the risk of nonsyndromic CPO in the African population.
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Población Negra/genética , Fisura del Paladar/genética , Proteínas de Unión al ADN/genética , Mutación con Pérdida de Función/genética , Factores de Transcripción/genética , Animales , Codón sin Sentido/genética , Mutación del Sistema de Lectura/genética , Estudio de Asociación del Genoma Completo , Humanos , Mutagénesis Sitio-Dirigida , Mutación Missense/genética , Sitios de Empalme de ARN/genética , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
The overexpression or mutation of tyrosine kinases (TKs), such as the epidermal growth factor receptor (EGFR), can lead to the development of cancer. The most common mutation of the EGFR in glioblastomas is the deletion of exons 2-7 known as the EGFRvIII. This mutant receptor cannot bind EGF but, instead, is constitutively active. The Cbl family of ubiquitin ligases (Cbl, Cbl-b, and Cbl-c) targets the activated EGFR for degradation. As the EGFRvIII is transforming, we investigated whether it could be downregulated by the Cbl proteins. The overexpression of all three Cbl proteins resulted in the ubiquitination and degradation of the EGFRvIII. As with the wild-type EGFR, the TK-binding domain and the RING finger of Cbl-b are sufficient for the downregulation of the EGFRvIII. Also, we found that Cbl-b is recruited to the EGFRvIII and inhibits the transformation of NIH 3T3 cells by the EGFRvIII. Mutation of the Cbl-binding site (Y1045F) in the EGFRvIII inhibits its ubiquitination and downregulation by Cbl-b and enhances its ability to transform. Furthermore, the EGFR TK inhibitor, AG 1478, prevents the downregulation of the EGFRvIII by the Cbl proteins and antagonizes the ability of an immunotoxin directed against the EGFRvIII to kill cells expressing this receptor. In conclusion, the EGFRvIII does not transform by escaping regulation by Cbl proteins and this activation-induced downregulation of the EGFRvIII has an important role in mediating the toxicity of anti-EGFRvIII immunotoxins.
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Receptores ErbB/metabolismo , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Células CHO , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica , Células Cultivadas , Cricetinae , Regulación hacia Abajo , Humanos , Ratones , Células 3T3 NIH , Unión Proteica , Procesamiento Proteico-Postraduccional , Quinazolinas , Transfección , Tirfostinos/farmacología , Ubiquitina/metabolismoRESUMEN
BACKGROUND: Oral premedication for paediatric age group is an uncommon practice amongst anaesthetists in Nigeria. Both parents and the child suffer some form of emotional or psychological distress. AIM: To determine the efficacy and safety of oral formulated ketamine for premedication in children scheduled for ambulatory surgeries. METHODS: Seventy three children aged 1 - 6 years with American Society of Anesthesiologists (ASA) physical status I-II were prospectively studied. They were assigned randomly to receive either 5 mg/kg (Group A), 10 mg/kg (Group B), or no ketamine (Group C).The children were observed for acceptance of premedication, sedation and anxiolysis at 10, 20 and 30 minutes after drug administration. Behavior/response of each child at the time of separation from parents, intravenous access, and acceptance of facemask for induction, postanaesthetic arousal state and complications were also recorded. RESULTS: There were 73 children in this study with a mean age of 37.4±18.0 months. The groups were comparable in age. The studied agent was tolerated by both groups that received premedication with no significant difference (P 0.73). Adequate sedation and anxiolysis were observed in groups A and B, (52%, 84%) and (68%, 88%) respectively. However, more children in group B (82.6%) had satisfactory behaviour at separation from parents and a better acceptance of anaesthetic face mask (64%) at induction than those in groups A and C (33.3%, 21.7%, respectively). No side effect was recorded in either of the premedication groups or the control group. CONCLUSION: Oral ketamine is acceptable and safe premedication for children. It provided good sedation, relieved anxiety and had no side effect in the children at the studied doses.