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Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.
Assuntos
Hérnia Inguinal , Herniorrafia , Recém-Nascido Prematuro , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Asiático/estatística & dados numéricos , Teorema de Bayes , Idade Gestacional , Hérnia Inguinal/epidemiologia , Hérnia Inguinal/etnologia , Hérnia Inguinal/cirurgia , Herniorrafia/efeitos adversos , Herniorrafia/métodos , Herniorrafia/estatística & dados numéricos , Alta do Paciente , Fatores Etários , Hispânico ou Latino/estatística & dados numéricos , Brancos/estatística & dados numéricos , Estados Unidos/epidemiologia , Negro ou Afro-Americano/estatística & dados numéricosRESUMO
PURPOSE: Distribution and outcomes of traumatic injury of the esophagus (TIE) in pediatric versus adult populations are unknown. Our study sought to perform a descriptive analysis of TIE in children and adults. METHODS: We reviewed the National Trauma Data Bank (NTDB) for the years 2010-2015. Demographics, characteristics, and outcomes of pediatric (age < 16 years) and adult TIE patients were described and compared. RESULTS: Among 526,850 pediatric and 3,838,895 adult trauma patients, 90 pediatric (0.02%) and 1,411 (0.04%) adult TIE patients were identified. Demographics and esophageal injury severity did not differ. Children were more likely to sustain blunt trauma (63% versus 37%), with the most common mechanism being transportation-related accidents, were less-severely injured (median ISS 14 versus 22), and had fewer associated injuries (79% versus 95%) and complications (30% versus 51%) (all p < 0.001). Children had shorter hospitalizations (median 5 versus 10 days) and were more likely to be discharged home (84% versus 64%) (both p = 0.01). In-hospital mortality did not differ significantly between children and adults (10% versus 19%, p = 0.09). CONCLUSION: TIE in the pediatric population has unique characteristics compared to adults: it is more likely to be a result of blunt trauma, has lower injury burden, and has more favorable clinical outcomes.
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Traumatismos Abdominais/epidemiologia , Esôfago/lesões , Traumatismo Múltiplo , Sistema de Registros , Traumatismos Torácicos/epidemiologia , Centros de Traumatologia/estatística & dados numéricos , Ferimentos não Penetrantes/epidemiologia , Traumatismos Abdominais/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Mortalidade Hospitalar/tendências , Humanos , Incidência , Lactente , Recém-Nascido , Escala de Gravidade do Ferimento , Tempo de Internação/tendências , Masculino , Traumatismos Torácicos/diagnóstico , Estados Unidos/epidemiologia , Ferimentos não Penetrantes/diagnóstico , Adulto JovemRESUMO
Controlling the activation of platelets is a key strategy to mitigate cardiovascular disease. Previous studies have suggested that the ATP-binding cassette (ABC) transporter, ABCC4, functions in platelet-dense granules. Using plasma membrane biotinylation and super-resolution microscopy, we demonstrate that ABCC4 is primarily expressed on the plasma membrane of both mouse and human platelets. Platelets lacking ABCC4 have unchanged dense-granule function, number, and volume, but harbor a selective impairment in collagen-induced aggregation. Accordingly, Abcc4 knockout (KO) platelet attachment to a collagen substratum was also faulty and associated with elevated intracellular cyclic AMP (cAMP) and reduced plasma membrane localization of the major collagen receptor, GPVI. In the ferric-chloride vasculature injury model, Abcc4 KO mice exhibited markedly impaired thrombus formation. The attenuation of platelet aggregation by the phosphodiesterase inhibitor EHNA (a non-ABCC4 substrate), when combined with Abcc4 deficiency, illustrated a crucial functional interaction between phosphodiesterases and ABCC4. This was extended in vivo where EHNA dramatically prolonged the bleeding time, but only in Abcc4 KO mice. Further, we demonstrated in human platelets that ABCC4 inhibition, when coupled with phosphodiesterase inhibition, strongly impaired platelet aggregation. These findings have important clinical implications because they directly highlight an important relationship between ABCC4 transporter function and phosphodiesterases in accounting for the cAMP-directed activity of antithrombotic agents.
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Plaquetas/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Agregação Plaquetária , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Plaquetas/patologia , AMP Cíclico/genética , AMP Cíclico/metabolismo , Humanos , Camundongos , Camundongos Knockout , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Trombose/genética , Trombose/metabolismo , Trombose/patologiaRESUMO
BACKGROUND: Foregut duplication cysts are rare congenital anomalies that require surgical intervention with approximately 10%-15% of all gastrointestinal duplication cysts originating from the esophagus. Consensus is lacking among surgeons regarding closure of the esophageal muscle layer after resection of an esophageal duplication cyst and long-term outcomes are poorly documented. Therefore, we conducted the first study comparing complication rates in patients undergoing closure versus nonclosure of the esophageal muscle layer after esophageal duplication cyst resection. MATERIALS AND METHODS: A retrospective cohort study at Boston Children's Hospital, Massachusetts General Hospital, Brigham and Women's Hospital, and the Floating Hospital for Children at Tufts Medical Center was conducted. Patients undergoing resection of esophageal duplication cysts between 1990 and 2012 were classified according to whether the esophageal muscle layer was closed or left open. Demographic data, surgical technique, preoperative symptoms, and both short-term (<30 d) and long-term (≥30 d) complication rates were abstracted from patient medical records. RESULTS: Twenty-five patients were identified with a median age of 15-y old (range, 2 mo to 68-y old) and an average follow-up of 1 y. Eleven patients had the esophageal muscle layer closed after surgical resection (44%). Of those 11 patients, one developed a short-term complication, dysphagia (9%, 95% CI: 2%, 38%). Only one patient returned to the operating room, after 30 d, for an upper endoscopy after developing symptoms of gastroesophageal reflux disease. Of the 14 patients who had their muscle layer left open, three patients (21%, 95% CI: 8%, 48%) developed short-term complications, two of whom required surgical intervention within 30 d. Furthermore, two additional patients required surgical intervention after 30 d for a long-term complication (diverticulum and cyst recurrence). CONCLUSIONS: Surgical complications occurred more frequently in patients who had the muscle layer left open after resection of an esophageal duplication cyst. In addition, most patients requiring reoperation for both short-term and long-term complications occurred in this group. Though small, this study is the first to evaluate the complications after resecting esophageal duplication cysts. Our results suggest that closing the esophageal muscle layer after removal of an esophageal duplication cyst may be indicated to prevent both complications and the need for reoperations.
Assuntos
Cisto Esofágico/congênito , Cisto Esofágico/cirurgia , Esofagoplastia/métodos , Esôfago/anormalidades , Esôfago/cirurgia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
The performance of an 8 × 8 array of 6.0 × 6.0 mm2 (active area) SiPMs was evaluated for PET applications using crystal arrays with different pitch sizes (3.4 mm, 1.5 mm, 1.35 mm and 1.2 mm) and custom designed five-channel front-end readout electronics (four channels for position information and one channel for timing information). The total area of this SiPM array is 57.4 × 57.4 mm2, and the pitch size is 7.2 mm. It was fabricated using enhanced blue sensitivity SiPMs (MicroFB-60035-SMT) with peak spectral sensitivity at 420 nm. The performance of the SiPM array was characterized by measuring flood histogram decoding quality, energy resolution, timing resolution and saturation at several bias voltages (from 25.0 V to 30.0 V in 0.5 V intervals) and two different temperatures (5 °C and 20 °C). Results show that the best flood histogram was obtained at a bias voltage of 28.0 V and 5 °C and an array of polished LSO crystals with a pitch as small as 1.2 mm can be resolved. No saturation was observed up to a bias voltage of 29.5 V during the experiments, due to adequate light sharing between SiPMs. Energy resolution and timing resolution at 5 °C ranged from 12.7 ± 0.8% to 14.6 ± 1.4 % and 1.58 ± 0.13 ns to 2.50 ± 0.44 ns, for crystal array pitch sizes of 3.4 mm and 1.2 mm respectively. Superior flood histogram quality, energy resolution and timing resolution were obtained with larger crystal array pitch sizes and at lower temperature. Based on our findings, we conclude that this large-area SiPM array can serve as a suitable photodetector for high-resolution small-animal PET or dedicated human brain PET scanners.
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BACKGROUND: Fetal alcohol spectrum disorder (FASD) is associated with a large number of cognitive and sensory-motor deficits. In particular, the accurate assessment of sensory-motor deficits in children with FASD is not always simple and relies on clinical assessment tools that may be coarse and subjective. Here we present a new approach: using robotic technology to accurately and objectively assess motor deficits of children with FASD in a center-out reaching task. METHODS: A total of 152 typically developing children and 31 children with FASD, all aged between 5 and 18 were assessed using a robotic exoskeleton device coupled with a virtual reality projection system. Children made reaching movements to 8 peripheral targets in a random order. Reach trajectories were subsequently analyzed to extract 12 parameters that had been previously determined to be good descriptors of a reaching movement, and these parameters were compared for each child with FASD to a normative model derived from the performance of the typically developing population. RESULTS: Compared with typically developing children, the children with FASD were found to be significantly impaired on most of the parameters measured, with the greatest deficits found in initial movement direction error. Also, children with FASD tended to fail more parameters than typically developing children: 95% of typically developing children failed fewer than 3 parameters compared with 69% of children with FASD. These results were particularly pronounced for younger children. CONCLUSIONS: The current study has shown that robotic technology is a sensitive and powerful tool that provides increased specificity regarding the type of motor problems exhibited by children with FASD. The high frequency of motor deficits in children with FASD suggests that interventions aimed at stimulating and/or improving motor development should routinely be considered for this population.
Assuntos
Transtornos do Espectro Alcoólico Fetal/diagnóstico , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologia , Robótica/métodos , Terapia de Exposição à Realidade Virtual/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Humanos , Masculino , Estimulação Luminosa/métodosRESUMO
BACKGROUND: Ceftolozane/tazobactam, a cephalosporin-ß-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed. METHODS: This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (<18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points. RESULTS: The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol. CONCLUSION: Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious.
Assuntos
Infecções Intra-Abdominais , Metronidazol , Adulto , Humanos , Criança , Meropeném/efeitos adversos , Metronidazol/efeitos adversos , Antibacterianos/efeitos adversos , Ácido Penicilânico/efeitos adversos , Cefalosporinas/efeitos adversos , Tazobactam/efeitos adversos , Infecções Intra-Abdominais/tratamento farmacológico , Escherichia coliRESUMO
We show here that a zinc finger transcriptional repressor, Slug, which is aberrantly upregulated by the E2A-HLF oncoprotein in pro-B cell acute leukemia, functions as an antiapoptotic factor in normal hematopoietic progenitor cells. Slug(-/-) mice were much more radiosensitive than wild-type mice, dying earlier and showing accentuated decreases in peripheral blood cell counts, as well as abundant microhemorrhages and widely disseminated bacterial microabscesses throughout the body. Slug expression was detected in diverse subsets of hematopoietic progenitors, but not in more differentiated B and T lymphoid cells, and there was a significant increase in apoptotic (TUNEL-positive) bone marrow progenitor cells in irradiated Slug(-/-) mice compared to wild-type controls. These results implicate Slug in a novel survival pathway that protects hematopoietic progenitors from apoptosis after DNA damage.
Assuntos
Apoptose/efeitos da radiação , Células-Tronco Hematopoéticas/citologia , Fatores de Transcrição/fisiologia , Dedos de Zinco/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica , Contagem de Células Sanguíneas , Plaquetas/metabolismo , Medula Óssea/metabolismo , Linhagem da Célula , Transformação Celular Neoplásica , Citoproteção , Dano ao DNA , Primers do DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Raios gama , Regulação Neoplásica da Expressão Gênica , Hematopoese/fisiologia , Hematopoese/efeitos da radiação , Células-Tronco Hematopoéticas/efeitos da radiação , Hemoglobinas/metabolismo , Homozigoto , Marcação In Situ das Extremidades Cortadas , Leucemia de Células B/genética , Leucemia de Células B/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Reação em Cadeia da Polimerase , Recombinação Genética , Fatores de Transcrição da Família Snail , Baço/metabolismo , Taxa de Sobrevida , Timo/efeitos da radiação , Proteína Supressora de Tumor p53/metabolismo , Irradiação Corporal TotalAssuntos
Abdome/parasitologia , Dor Abdominal/diagnóstico , Anisaquíase/diagnóstico , Abdome/patologia , Abdome/cirurgia , Dor Abdominal/parasitologia , Dor Abdominal/patologia , Dor Abdominal/cirurgia , Animais , Anisaquíase/parasitologia , Anisaquíase/patologia , Anisaquíase/cirurgia , Anisakis/anatomia & histologia , Anisakis/crescimento & desenvolvimento , Criança , Amarelo de Eosina-(YS) , Hematoxilina , Humanos , Larva/anatomia & histologia , Larva/crescimento & desenvolvimento , Masculino , MicroscopiaRESUMO
We generated mice expressing a full-length Mpl transgene under the control of a 2-kb Mpl promoter in an Mpl(-/-) background, effectively obtaining mice that express full-length Mpl in the absence of other Mpl isoforms. These mice developed thrombocytosis with platelet levels approximately 5-fold higher than wild-type controls and markedly increased megakaryocyte numbers. The reintroduction of one wild-type Mpl allele restored normal platelet counts. We excluded the deletion of Mpl-tr, a dominant-negative isoform, as the underlying molecular cause for thrombocytosis. Instead, we found that transgene expression driven by the 2-kb Mpl promoter fragment was decreased during late megakaryocyte maturation, resulting in strongly diminished Mpl protein expression in platelets. Because platelets exert a negative feedback on thrombopoiesis by binding and consuming Tpo in the circulation through Mpl, we propose that the severe reduction of Mpl protein in platelets in Mpl-transgenic Mpl(-/-) mice shifts the equilibrium of this feedback loop, resulting in markedly elevated levels of megakaryocytes and platelets at steady state. Although the mechanism causing decreased expression of Mpl protein in platelets from patients with myeloproliferative disorders differs from this transgenic model, our results suggest that lowering Mpl protein in platelets could contribute to raising the platelet count.
Assuntos
Receptores de Trombopoetina/genética , Receptores de Trombopoetina/metabolismo , Trombocitose/patologia , Trombocitose/fisiopatologia , Trombopoese/fisiologia , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , DNA Complementar , Dosagem de Genes , Células-Tronco Hematopoéticas/citologia , Megacariócitos/citologia , Megacariócitos/fisiologia , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Contagem de Plaquetas , Regiões Promotoras Genéticas/fisiologia , Trombopoetina/metabolismo , Transgenes/fisiologiaRESUMO
Human spermatozoa interact with a complex biochemical environment in the female reproductive tract en route to the site of fertilisation. Ovarian follicular fluid contributes to this complex milieu and is known to contain steroids such as progesterone, whose effects on sperm physiology have been widely characterised. We have previously reported that progesterone stimulates intracellular calcium concentration ([Ca2+]i) signalling and acrosome reaction in human spermatozoa. To characterise the effects of the unified complete follicular fluid steroid hormone complement on human spermatozoa, a comprehensive, data-based, 'physiological standard' steroid hormone balance of follicular fluid (shFF) was created from individual constituents. shFF induced a rapid biphasic [Ca2+]i elevation in human spermatozoa. Using population fluorimetry, we compared [Ca2+]i signal amplitude in cells exposed to serial applications of shFF (6 steps from 10-5X up to 1X shFF) with responses to the equivalent progesterone component alone (6 steps from 135 pM - 13.5µM). Threshold for the response to shFF was right-shifted (≈10-fold) compared to progesterone alone, but the maximum response to shFF was greatly enhanced. An acrosome reaction assay was used to assess functional effects of shFF-induced sperm calcium signalling. shFF as well as progesterone-treated spermatozoa showed a significant increase in % acrosome reaction (P < 0.01). All of this evidence suggests the modulation of progesterone-mediated responses by other follicular fluid steroids.
Assuntos
Líquido Folicular/química , Hormônios/fisiologia , Espermatozoides/fisiologia , Reação Acrossômica , Cálcio/metabolismo , Feminino , Hormônios/análise , Humanos , MasculinoRESUMO
OBJECTIVE: Unintentional window falls represent a preventable source of injury and death in children. Despite major campaigns in some larger cities, there continue to be unintentional falls from windows throughout the United States. We aimed to identify risk factors and trends in unintentional window falls in the pediatric population in a national and regional sample. METHODS: A retrospective analysis of annual emergency department (ED) visits from the National Electronic Injury Surveillance System using product codes specific to windows, as well as patient encounters for unintentional window falls from January 2007 to August 2017 using site-specific trauma registries from 10 tertiary care children's hospitals in New England. National and state-specific census population estimates were used to compute rates per 100,000 population. RESULTS: There were 38,840 ED visits and 496 regional patients who unintentionally fell from a window across the study period between 0 and 17 years old. The majority of falls occurred in children under the age of 6 and were related to falls from a second story or below. A decreased trend in national ED visits was seen, but no change in rates over time for regional trauma center encounters. A high number of falls was found to occur in smaller cities surrounding metropolitan areas and from single family residences. CONCLUSIONS: Falls from windows represent a low proportion of overall types of unintentional sources of injury in children but are a high risk for severe disability. These results provide updated epidemiologic data for targeted intervention programs, as well as raise awareness for continued education and advocacy.
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Serviço Hospitalar de Emergência , Ferimentos e Lesões , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia , Ferimentos e Lesões/epidemiologiaRESUMO
Using an expression gene trapping strategy, we recently identified a novel gene, hematopoietic zinc finger (Hzf), which encodes a protein containing three C(2)H(2)-type zinc fingers that is predominantly expressed in megakaryocytes. Here, we have examined the in vivo function of Hzf by gene targeting and demonstrated that Hzf is essential for megakaryopoiesis and hemostasis in vivo. Hzf-deficient mice exhibited a pronounced tendency to rebleed and had reduced alpha-granule substances in both megakaryocytes and platelets. These mice also had large, faintly stained platelets, whereas the numbers of both megakaryocytes and platelets were normal. These results indicate that Hzf plays important roles in regulating the synthesis of alpha-granule substances and/or their packing into alpha-granules during the process of megakaryopoiesis.
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Proteínas Sanguíneas/fisiologia , Hemostasia , Megacariócitos/fisiologia , Proteínas , Animais , Tempo de Sangramento , Proteínas Sanguíneas/deficiência , Proteínas Sanguíneas/genética , Clonagem Molecular , DNA/sangue , DNA/genética , Primers do DNA , Hemorragia/genética , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase , Proteínas Recombinantes/metabolismo , Dedos de ZincoRESUMO
Vision and proprioception are the main sensory modalities that convey hand location and direction of movement. Fusion of these sensory signals into a single robust percept is now well documented. However, it is not known whether these modalities also interact in the spatial allocation of attention, which has been demonstrated for other modality pairings. The aim of this study was to test whether proprioceptive signals can spatially cue a visual target to improve its detection. Participants were instructed to use a planar manipulandum in a forward reaching action and determine during this movement whether a near-threshold visual target appeared at either of two lateral positions. The target presentation was followed by a masking stimulus, which made its possible location unambiguous, but not its presence. Proprioceptive cues were given by applying a brief lateral force to the participant's arm, either in the same direction (validly cued) or in the opposite direction (invalidly cued) to the on-screen location of the mask. The d' detection rate of the target increased when the direction of proprioceptive stimulus was compatible with the location of the visual target compared to when it was incompatible. These results suggest that proprioception influences the allocation of attention in visual space.
Assuntos
Sinais (Psicologia) , Propriocepção/fisiologia , Detecção de Sinal Psicológico/fisiologia , Percepção Espacial/fisiologia , Adulto , Análise de Variância , Movimentos Oculares , Feminino , Lateralidade Funcional/fisiologia , Humanos , Masculino , Modelos Psicológicos , Estimulação Luminosa/métodos , Tempo de Reação/fisiologia , Adulto JovemRESUMO
Transcription of immediate-early genes--as well as multiple genes affecting muscle function, cytoskeletal integrity, apoptosis control, and wound healing/angiogenesis--is regulated by serum response factor (Srf). Extracellular signals regulate Srf in part via a pathway involving megakaryoblastic leukemia 1 (Mkl1, also known as myocardin-related transcription factor A [Mrtf-a]), which coactivates Srf-responsive genes downstream of Rho GTPases. Here we investigate Mkl1 function using gene targeting and show the protein to be essential for the physiologic preparation of the mammary gland during pregnancy and the maintenance of lactation. Lack of Mkl1 causes premature involution and impairs expression of Srf-dependent genes in the mammary myoepithelial cells, which control milk ejection following oxytocin-induced contraction. Despite the importance of Srf in multiple transcriptional pathways and widespread Mkl1 expression, the spectrum of abnormalities associated with Mkl1 absence appears surprisingly restricted.
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Lactação/fisiologia , Glândulas Mamárias Animais/anatomia & histologia , Glândulas Mamárias Animais/fisiologia , Transativadores/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Criança , Insuficiência de Crescimento , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Marcação de Genes , Coração/anatomia & histologia , Coração/embriologia , Humanos , Lactente , Leucemia Megacarioblástica Aguda , Masculino , Glândulas Mamárias Animais/anormalidades , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Leite , Miócitos Cardíacos/patologia , Miócitos Cardíacos/ultraestrutura , Análise de Sequência com Séries de Oligonucleotídeos , Ocitocina/metabolismo , Gravidez , Prolactina/metabolismo , Fator de Transcrição STAT3 , Fator de Resposta Sérica/genética , Fator de Resposta Sérica/metabolismo , Transativadores/genéticaRESUMO
OBJECTIVE: Our objective was to determine a mechanism for the thrombocytopenia of murine Wiskott-Aldrich syndrome (WAS). MATERIALS AND METHODS: Consumption rates of WAS protein (WASP)(-) and wild-type (WT) platelets were measured by injection of 5-chloromethylfluorescein diacetate (CMFDA)-labeled platelets into WT or WASP(-) recipients, and by in vivo biotinylation. Platelet and reticulated platelet counts were performed using quantitative flow cytometry. Bone marrow megakaryocyte number and ploidy was assessed by flow cytometry. Phagocytosis of CMFDA-labeled, opsonized platelets was assessed using bone marrow-derived macrophages. Serum antiplatelet antibodies were assayed via their binding to WT platelets. RESULTS: CMFDA-labeled WASP(-) platelets are consumed more rapidly than WT platelets in either WT or WASP(-) recipients. In vivo biotinylation studies corroborate these findings and show a normal consumption rate for WASP(-) reticulated platelets. The number of reticulated platelets is reduced in WASP(-) mice, but a significant number of the mice show an increased proportion of reticulated platelets and more severe thrombocytopenia. Sera from some of the latter group contain antiplatelet antibodies. Compared to WT platelets, WASP(-) platelets opsonized with anti-CD61 or 6A6 antibody are taken up more rapidly by bone marrow-derived macrophages. In vivo consumption rates of WASP(-) platelets are more accelerated by opsonization than are those of WT platelets. CONCLUSION: Both rapid clearance and impaired production contribute to the thrombocytopenia of murine WAS. Increased susceptibility of opsonized WASP(-) platelets to phagocytosis leads to increased in vivo clearance. This correlates with a higher incidence of individuals with an elevated fraction of reticulated platelets, a more severe thrombocytopenia, and antiplatelet antibodies.
Assuntos
Plaquetas/imunologia , Fagocitose/imunologia , Trombocitopenia/imunologia , Proteína da Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/imunologia , Animais , Anticorpos/sangue , Anticorpos/imunologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Fluoresceínas/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Opsonizantes/imunologia , Contagem de Plaquetas , Fatores de Tempo , Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/deficiência , Proteína da Síndrome de Wiskott-Aldrich/genéticaRESUMO
Sex differences in human spatial navigation are well known. However, the exact strategies that males and females employ in order to navigate successfully around the environment are unclear. While some researchers propose that males prefer environment-centred (allocentric) and females prefer self-centred (egocentric) navigation, these findings have proved difficult to replicate. In the present study we examined eye movements and physiological measures of memory (pupillometry) in order to compare visual scanning of spatial orientation using a human virtual analogue of the Morris Water Maze task. Twelve women and twelve men (average age=24 years) were trained on a visible platform and had to locate an invisible platform over a series of trials. On all but the first trial, participants' eye movements were recorded for 3s and they were asked to orient themselves in the environment. While the behavioural data replicated previous findings of improved spatial performance for males relative to females, distinct sex differences in eye movements were found. Males tended to explore consistently more space early on while females demonstrated initially longer fixation durations and increases in pupil diameter usually associated with memory processing. The eye movement data provides novel insight into differences in navigational strategies between the sexes.
Assuntos
Comportamento Exploratório/fisiologia , Movimentos Oculares/fisiologia , Aprendizagem em Labirinto/fisiologia , Percepção Espacial/fisiologia , Adulto , Aprendizagem por Discriminação/fisiologia , Feminino , Humanos , Masculino , Memória/fisiologia , Orientação/fisiologia , Desempenho Psicomotor/fisiologia , Pupila/fisiologia , Tempo de Reação/fisiologia , Caracteres SexuaisRESUMO
A 14-year-old male presented with a T4 sigmoid adenocarcinoma, <10 colonic adenomas and multiple café-au-lait macules. Family history was not suggestive of a dominant hereditary form of colorectal cancer. Evaluation of the tumor revealed abnormal immunohistochemical staining of the PMS2 protein and high frequency microsatellite instability. Germline analysis identified biallelic PMS2 missense mutations. A new cancer syndrome caused by biallelic mutations in the mismatch repair genes, including PMS2, is now emerging and is characterized by café-au-lait macules, colonic polyps and a distinctive tumor spectrum.
Assuntos
Adenosina Trifosfatases/genética , Manchas Café com Leite/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Mutação de Sentido Incorreto , Adolescente , Alelos , Manchas Café com Leite/complicações , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Humanos , Masculino , Endonuclease PMS2 de Reparo de Erro de Pareamento , LinhagemRESUMO
It is not yet clear how the temporal structure of a voluntary action is coded allowing coordinated bimanual responses. This study focuses on the adaptation to and compensation for a force profile presented to one stationary arm which is proportional to the velocity of the other moving arm. We hypothesised that subjects would exhibit predictive coordinative responses which would co-vary with the state of the moving arm. Our null hypothesis is that they develop a time-dependent template of forces appropriate to compensate for the imposed perturbation. Subjects were trained to make 500 ms duration reaching movements with their dominant right arm to a visual target. A force generated with a robotic arm that was proportional to the velocity of the moving arm and perpendicular to movement direction acted on their stationary left hand, either at the same time as the movement or delayed by 250 or 500 ms. Subjects rapidly learnt to minimise the final end-point error. In the delay conditions, the left hand moved in advance of the onset of the perturbing force. In test conditions with faster or slower movement of the right hand, the predictive actions of the left hand co-varied with movement speed. Compensation for movement-related forces appeared to be predictive but not based on an accurate force profile that was equal and opposite to the imposed perturbation.
Assuntos
Adaptação Fisiológica/fisiologia , Braço/fisiologia , Lateralidade Funcional/fisiologia , Movimento/fisiologia , Músculo Esquelético/fisiologia , Desempenho Psicomotor/fisiologia , Adulto , Fenômenos Biomecânicos , Sistema Nervoso Central/fisiologia , Retroalimentação/fisiologia , Feminino , Humanos , Aprendizagem/fisiologia , Masculino , Testes Neuropsicológicos , Estimulação Física , Tempo de Reação/fisiologia , Fatores de Tempo , Percepção do Tempo/fisiologiaRESUMO
INTRODUCTION: Colostomy morbidity has been reported to be as high as 50%. Laparoscopic-assisted colostomy (LAC) is associated with decreased colostomy complication. LAC is recommended for stoma formation in adults but has not been previously reported in children. In this paper, we report on our initial experience with LAC in children. MATERIALS AND METHODS: Using a two- to four-port (3.5-mm) technique, LAC was performed in a female with an imperforate anus and 2 male patients with complicated Hirschsprung's disease (HD), respectively. Data collected included operative time, time to recover bowel function, and morbidity. Close follow-up was done until stoma closure. RESULTS: The operative time was 144 minutes in the HD patients (including concomitant laparoscopic biopsies and a leveling colostomy) and 40 minutes in the imperforate anus patient. Median time to passage of both flatus and stool was 40 hours (range, 24-48). Time to commence feeds postop was 40 hours (range, 24-48). The median time of follow-up was 3 months (range, 2-9) until the stoma was taken down. No complications have occurred to date. CONCLUSIONS: LAC is safe and easily performed in neonates and infants. It facilitates accurate stoma placement and orientation. It allows additional bowel mobilization, especially in HD. In accordance with the adult experience, LAC seems to obviate stoma-related complications. Encouraged by our initial low morbidity rate, a prospective evaluation of this technique is planned.