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1.
J Craniofac Surg ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34560740

RESUMO

BACKGROUND: Bilateral cleft lip and palate (BCLP) remains a difficult surgical problem due to the severely protruding premaxillary segment, with no consensus of optimal treatment sequence in older patients. A systematic review of the literature was performed to assess the current status of BCLP repair based on age. METHODS: A PRISMA systematic review of the PubMed, Web of Science, and Embase databases was performed using a series of search terms related to BCLP. Studies were categorized based on the age of presentation, repair sequence, and technique. RESULTS: The database search identified 381 articles. Of these, 72 manuscripts were ultimately included. The lip was repaired first in 1077 patients (86.0%), palate first in 161 patients (12.9%), and simultaneous lip and palate in 14 patients (1.1%). Patients less than 6 months old received lip repair first (n = 959, 98.6%), with complications of unaesthetic appearance (n = 86, 62.3%) and midface retrusion (n = 41, 34.1%) in younger patients and wound dehiscence (n = 8, 40%) in older patients. Primary lip repair was preceded by presurgical orthopedics (n = 760) or lip adhesion (n = 272) to reduce lip tension with nasoalveolar molding (n = 452, 62.9%) or the Latham device (n = 282, 37.1%). In older patients, the palate was repaired first or premaxillary setback (n = 222) was indicated in protruded premaxillae greater than 10 mm, but carried the risk of premaxilla mobility (n = 20, 37.7%) and midface retrusion (n = 10, 18.9%). CONCLUSION: In younger patients, lip repair is performed first with preoperative orthopedics or lip adhesion. In older patients, the palate is more commonly repaired first compared with the lip; however, there is no difference in complication rate.

2.
JAMA Neurol ; 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34459874

RESUMO

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

3.
Eur J Surg Oncol ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34454813

RESUMO

BACKGROUND: Female patients with pelvic/adnexal masses often undergo gynecologic operations due to presumed ovarian origin. The diagnosis of an appendiceal tumor is often only made postoperatively after suboptimal cytoreduction has been performed. We hypothesized that an index gynecological procedure increases the morbidity of definitive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in patients with appendiceal mucinous tumors. METHODS: A single-center retrospective review was performed to identify female patients undergoing CRS/HIPEC for appendiceal tumors from 2012 to 2020. RESULTS: During the 8-year period, CRS/HIPEC was performed in 36 female patients with appendiceal mucinous tumors. Eighteen patients (50.0%) had received a prior pelvic operation by gynecologists (PPO Group) for presumed ovarian origin before referral for definitive CRS/HIPEC. The median peritoneal cancer index (PCI) was higher in the PPO group (21 vs. 9, p = 0.04). The median number of days from gynecologic procedure to definitive CRS/HIPEC was 169 days. Compared to patients who did not undergo a prior gynecologic operation, those in the PPO group had higher intraoperative blood loss (650 vs 100 mL, p < 0.01) during CRS/HIPEC as well as longer length of stay (12 vs 8 days, p = 0.02) and higher overall morbidity (72.3% vs 33.3%, p = 0.02). After controlling for PCI, prior gynecologic operation increased risk of 30-day morbidity after definitive CRS/HIPEC (OR 11.6, p < 0.01). CONCLUSION: A multi-disciplinary approach is needed for the primary evaluation of patients with pelvic masses of undetermined origin. A gynecological resection is associated with increased morbidity during definitive cytoreduction and HIPEC for appendiceal mucinous tumors.

4.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
5.
Methods Cell Biol ; 162: 223-252, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33707014

RESUMO

Rapidly changing features in an intact biological sample are challenging to efficiently trap and image by conventional electron microscopy (EM). For example, the model organism C. elegans is widely used to study embryonic development and differentiation, yet the fast kinetics of cell division makes the targeting of specific developmental stages for ultrastructural study difficult. We set out to image the condensed metaphase chromosomes of an early embryo in the intact worm in 3-D. To achieve this, one must capture this transient structure, then locate and subsequently image the corresponding volume by EM in the appropriate context of the organism, all while minimizing a variety of artifacts. In this methodological advance, we report on the high-pressure freezing of spatially constrained whole C. elegans hermaphrodites in a combination of cryoprotectants to identify embryonic cells in metaphase by in situ cryo-fluorescence microscopy. The screened worms were then freeze substituted, resin embedded and further prepared such that the targeted cells were successfully located and imaged by focused ion beam scanning electron microscopy (FIB-SEM). We reconstructed the targeted metaphase structure and also correlated an intriguing punctate fluorescence signal to a H2B-enriched putative polar body autophagosome in an adjacent cell undergoing telophase. By enabling cryo-fluorescence microscopy of thick samples, our workflow can thus be used to trap and image transient structures in C. elegans or similar organisms in a near-native state, and then reconstruct their corresponding cellular architectures at high resolution and in 3-D by correlative volume EM.

6.
Exp Neurol ; 339: 113650, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33607079

RESUMO

Functional recovery following peripheral nerve injury worsens with increasing durations of delay prior to repair. From the time of injury until re-innervation occurs, denervated muscle undergoes progressive atrophy that limits the extent to which motor function can be restored. Similarly, Schwann cells (SC) in the distal nerve lacking axonal interaction progressively lose their capacity to proliferate and support regenerating axons. The relative contributions of these processes to diminished functional recovery is unclear. We developed a novel rat model to isolate the effects of SC vs. muscle denervation on functional recovery. Four different groups underwent the following interventions for 12 weeks prior to nerve transfer: 1) muscle denervation; 2) SC denervation; 3) muscle + SC denervation (negative control); 4) no denervation (positive control). Functional recovery was measured weekly using the stimulated grip strength testing (SGST). Animals were sacrificed 13 weeks post nerve transfer. Retrograde labeling was used to assess the number of motor neurons that regenerated their axons. Immunofluorescence was performed to evaluate target muscle re-innervation and atrophy, and to assess the phenotype of the SC within the distal nerve segment. Functional recovery in the muscle denervation and SC denervation groups mirrored that of the negative and positive control groups, respectively. The SC denervation group achieved better functional recovery, with a greater number of reinnervated motor endplates and less muscle atrophy, than the muscle denervation group. Retrograde labeling suggested a higher number of neurons contributing to muscle reinnervation in the muscle denervation group as compared to SC denervation (p > 0.05). The distal nerve segment in the muscle denervation group had a greater proportion of SCs expressing the proliferation marker Ki67 as compared to the SC denervation group (p < 0.05). Conversely, the SC denervation group had a higher percentage of senescent SCs expressing p16 as compared to the muscle denervation group (p < 0.05). The deleterious effects of muscle denervation are more consequential than the effects of SC denervation on functional recovery. The effects of 12 weeks of SC denervation on functional outcome were negligible. Future studies are needed to determine whether longer periods of SC denervation negatively impact functional recovery.


Assuntos
Nervo Mediano/fisiologia , Denervação Muscular/métodos , Regeneração Nervosa/fisiologia , Recuperação de Função Fisiológica/fisiologia , Células de Schwann/fisiologia , Nervo Ulnar/fisiologia , Animais , Força da Mão/fisiologia , Masculino , Nervo Mediano/transplante , Denervação Muscular/tendências , Atrofia Muscular , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/cirurgia , Ratos , Ratos Endogâmicos Lew , Nervo Ulnar/transplante
9.
Am J Med Genet A ; 185(1): 213-218, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33044030

RESUMO

Glycosylation is a critical post/peri-translational modification required for the appropriate development and function of the immune system. As an example, abnormalities in glycosylation can cause antibody deficiency and reduced lymphocyte signaling, although the phenotype can be complex given the diverse roles of glycosylation. Human MGAT2 encodes N-acetylglucosaminyltransferase II, which is a critical enzyme in the processing of oligomannose to complex N-glycans. Complex N-glycans are essential for immune system functionality, but only one individual with MGAT2-CDG has been described to have an abnormal immunologic evaluation. MGAT2-CDG (CDG-IIa) is a congenital disorder of glycosylation (CDG) associated with profound global developmental disability, hypotonia, early onset epilepsy, and other multisystem manifestations. Here, we report a 4-year old female with MGAT2-CDG due to a novel homozygous pathogenic variant in MGAT2, a 4-base pair deletion, c.1006_1009delGACA. In addition to clinical features previously described in MGAT2-CDG, she experienced episodic asystole, persistent hypogammaglobulinemia, and defective ex vivo mitogen and antigen proliferative responses, but intact specific vaccine antibody titers. Her infection history has been mild despite the testing abnormalities. We compare this patient to the 15 previously reported patients in the literature, thus expanding both the genotypic and phenotypic spectrum for MGAT2-CDG.

10.
JPEN J Parenter Enteral Nutr ; 45(2): 230-238, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33085788

RESUMO

BACKGROUND: Patients with severe long-chain fatty acid oxidation disorders (LC-FAODs) experience serious morbidity and mortality despite traditional dietary management including medium-chain triglyceride (MCT)-supplemented, low-fat diets. Triheptanoin is a triglyceride oil that is broken down to acetyl-coenzyme A (CoA) and propionyl-CoA, which replenishes deficient tricarboxylic acid cycle intermediates. We report the complex medical and nutrition management of triheptanoin therapy initiated emergently for 3 patients with LC-FAOD. METHODS: Triheptanoin (Ultragenyx Pharmaceutical, Inc, Novato, CA, USA) was administered to 3 patients with LC-FAOD on a compassionate-use basis. Triheptanoin was mixed with non-MCT-containing low-fat formula. Patients were closely followed with regular cardiac and laboratory monitoring. RESULTS: Cardiac ejection fraction normalized after triheptanoin initiation. Patients experienced fewer hospitalizations related to metabolic crises while on triheptanoin. Patient 1 has tolerated oral administration without difficulty since birth. Patients 2 and 3 experienced increased diarrhea. Recurrent breakdown of the silicone gastrostomy tube occurred in patient 3, whereas the polyurethane nasogastric tube for patient 2 remained intact. Patient 3 experiences recurrent episodes of elevated creatine kinase levels and muscle weakness associated with illness. Patient 3 had chronically elevated C10-acylcarnitines while on MCT supplementation, which normalized after initiation of triheptanoin and discontinuation of MCT oil. CONCLUSIONS: Triheptanoin can ameliorate acute cardiomyopathy and increase survival in patients with severe LC-FAOD. Substituting triheptanoin for traditional MCT-based treatment improves clinical outcomes. MCT oil might be less effective in carnitine-acylcarnitine translocase deficiency patients compared with other FAODs and needs further investigation.


Assuntos
Erros Inatos do Metabolismo Lipídico , Carnitina , Ácidos Graxos , Humanos , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Oxirredução , Triglicerídeos
11.
Am J Med Genet A ; 182(7): 1576-1591, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32500973

RESUMO

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.


Assuntos
Mesilato de Imatinib/uso terapêutico , Leucoencefalopatias/etiologia , Miofibromatose/congênito , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Adolescente , Adulto , Aneurisma/genética , Criança , Feminino , Estudos de Associação Genética , Humanos , Lactente , Leucoencefalopatias/tratamento farmacológico , Leucoencefalopatias/genética , Masculino , Miofibromatose/tratamento farmacológico , Miofibromatose/etiologia , Miofibromatose/genética , Linhagem , Inibidores de Proteínas Quinases/uso terapêutico
12.
Mol Genet Metab Rep ; 24: 100607, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32489882

RESUMO

Serine, a non-essential amino acid, has attracted clinical attention because of potential benefit in certain metabolic and neurological disorders. Despite the therapeutic potential, little is known about the pharmacokinetics of l-serine metabolism in humans. Here we present pharmacokinetic data at the time of treatment initiation as well as plasma serine levels during dose escalation from a single individual taking oral l-serine as part of a treatment regimen. Our results show that plasma serine levels rise and fall rapidly after oral l-serine intake, suggesting that the optimal dosing for oral l-serine supplementation is at least three times per day.

13.
Plast Reconstr Surg ; 146(4): 725-733, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32590526

RESUMO

BACKGROUND: The central mound technique offers a relatively less common approach for breast reduction. This study evaluated the expected safety and efficacy outcomes using this technique in a large patient series. METHODS: A retrospective review of all patients undergoing central mound breast reduction at the authors' institution between June of 1999 and November of 2018 was performed. Both bilateral macromastia and unilateral symmetrizing reduction patients were included but evaluated separately for some outcomes. Patient demographics and comorbidities, operative details, postoperative adverse events, and BREAST-Q scores were recorded. Associations between preoperative variables and outcomes were assessed with chi-square tests, Wilcoxon tests, and Kendall tau-b correlations. RESULTS: A total of 325 patients were identified for inclusion (227 bilateral and 98 unilateral; 552 breasts). The average patient age was 46 years, and the average body mass index was 27.4 kg/m. Among the bilateral macromastia patients, the average operative time was 3 hours 34 minutes, and average breast tissue removed was 533 g (right breast) and 560 g (left breast). Among all patients, average follow-up was 169 days. On a per-breast basis for all patients, the following complication rates were observed: seroma, 0.2 percent; hematoma, 1.1 percent; dehiscence, 2.9 percent; infection, 1.5 percent; hypertrophic scar, 4.6 percent; nipple necrosis, 0.4 percent; fat necrosis, 0.9 percent; and skin flap necrosis, 1.7 percent. Using the BREAST-Q Reduction/Mastopexy questions on a Likert scale ranging from 1 to 5, restricted to the bilateral macromastia patient population, all scores improved with statistical significance. CONCLUSION: The central mound pedicle is a safe and effective approach for reduction mammaplasty for both bilateral macromastia patients and unilateral symmetrizing operations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.


Assuntos
Mama/anormalidades , Hipertrofia/cirurgia , Mamoplastia/métodos , Adulto , Mama/cirurgia , Feminino , Humanos , Mamoplastia/efeitos adversos , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
14.
Mol Genet Genomic Med ; 8(4): e1172, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32067425

RESUMO

BACKGROUND: We report the first case of a family with co-occurrence of Wilson disease (WD), an autosomal recessive disorder of copper metabolism, and X-linked agammaglobulinemia (XLA), a primary immunodeficiency disorder (PIDD) that features marked reduction in circulating B lymphocytes and serum immunoglobulins. METHODS AND RESULTS: Through utilization of a multiplexed biomarker peptide quantification method known as the immuno-SRM assay, we were able to simultaneously and independently identify which family members are affected with WD and which are affected with XLA using dried blood spots (DBS). CONCLUSION: Being able to delineate multiple diagnoses using proteolytic analysis from a single DBS provides support for implementation of this methodology for clinical diagnostic use as well as large-scale population screening, such as newborn screening (NBS). This could allow for early identification and treatment of affected individuals with WD or XLA, which have been shown to reduce morbidity and decrease mortality in these two populations.


Assuntos
Agamaglobulinemia/sangue , Teste em Amostras de Sangue Seco/métodos , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Degeneração Hepatolenticular/sangue , Peptídeos/sangue , Proteólise , Adolescente , Adulto , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Biomarcadores/sangue , Criança , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/diagnóstico , Humanos , Testes Imunológicos/métodos , Masculino , Espectrometria de Massas/métodos , Linhagem
15.
Transfusion ; 60(3): 466-472, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31984520

RESUMO

BACKGROUND: Understanding factors that impact tissue oxygen extraction may guide red blood cell (RBC) transfusion decision making in preterm infants. Our objective was to assess the influence of enteral feeding and anemia on cerebral and mesenteric oxygen saturation (Csat and Msat) and fractional tissue oxygen extraction (cFTOE and mFTOE) over the entire time course of RBC transfusion. STUDY DESIGN AND METHODS: Preterm, very low-birth-weight infants receiving RBC transfusions at a single center were enrolled. Near-infrared spectroscopy sensors measured Csat and Msat levels from an hour before transfusion to 24 hours after. During this period, changes in Csat, Msat, cFTOE, and mFTOE were described, and their association with enteral feeding status and pretransfusion degree of anemia were assessed using generalized estimating equations. RESULTS: RBC transfusion data from 31 preterm infants were included. Infants receiving enteral feeds exhibited lower pretransfusion Msat. Infants with pretransfusion hematocrit greater than 30% exhibited higher pretransfusion Csat and lower pretransfusion cFTOE. Such differences in baseline measurements persisted through 24 hours after transfusion. However, no statistically significant differences in oxygenation measures over time by enteral feeding or anemia status were identified. CONCLUSION: Compared to NPO, enteral feeding was associated with lower Msat; anemia (hematocrit ≤30%) was associated with lower Csat and higher cFTOE. Over the time course of RBC transfusion, trajectories of Csat, Msat, cFTOE and mFTOE did not differ by enteral feeding or anemia status.


Assuntos
Anemia/terapia , Transfusão de Eritrócitos , Peso ao Nascer/fisiologia , Nutrição Enteral , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Espectroscopia de Luz Próxima ao Infravermelho
16.
Aesthet Surg J ; 40(5): 493-498, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-31784736

RESUMO

BACKGROUND: Machine learning represents a new frontier in surgical innovation. The ranking Convolutional Neural Network (CNN) is a novel machine learning algorithm that helps elucidate patterns and features of aging that are not always appreciable with the human eye. OBJECTIVES: The authors sought to determine the impact of aesthetic rhinoplasty on facial aging employing a multidimensional facial recognition and comparison software. METHODS: A retrospective chart review and subsequent analysis was carried out on all female patients who underwent open rhinoplasty with the senior author from 2014 through 2018 and had postoperative photos at 12 or more weeks follow-up. All photos were analyzed with Microsoft Azure Face API (Redmond, WA), which estimates patients' age by cropping the face from a photograph and then extracting a CNN-based prediction through multiple deep neural networks. RESULTS: A total of 100 patients ultimately met full inclusion criteria. The average post-surgical follow up for this cohort was 29 weeks (median, 14 weeks; range, 12-64 weeks). Patients ranged from 16 to 72 years old (mean, 32.75 years; median, 28.00 years; standard deviation, 12.79 years). The ranking CNN algorithm on average estimated patients preoperatively to be 0.03 years older than their actual age. The correlation coefficient between actual age and predicted preoperative age was r = 0.91. On average, patients were found to look younger post-open rhinoplasty (-3.10 vs 0.03 years, P < 0.0001). CONCLUSIONS: The ranking CNN algorithm is both accurate and precise in estimating human age before and after cosmetic rhinoplasty. Given the resulting data, the effects of open rhinoplasty on reversing signs of facial aging should be revisited.


Assuntos
Rinoplastia , Adolescente , Adulto , Idoso , Estética , Face/cirurgia , Feminino , Humanos , Aprendizado de Máquina , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
17.
J Cell Biol ; 219(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31834351

RESUMO

After fertilization, parental genomes are enclosed in two separate pronuclei. In Caenorhabditis elegans, and possibly other organisms, when the two pronuclei first meet, the parental genomes are separated by four pronuclear membranes. To understand how these membranes are breached to allow merging of parental genomes we used focused ion beam scanning electron microscopy (FIB-SEM) to study the architecture of the pronuclear membranes at nanometer-scale resolution. We find that at metaphase, the interface between the two pronuclei is composed of two membranes perforated by fenestrations ranging from tens of nanometers to several microns in diameter. The parental chromosomes come in contact through one of the large fenestrations. Surrounding this fenestrated, two-membrane region is a novel membrane structure, a three-way sheet junction, where the four membranes of the two pronuclei fuse and become two. In the plk-1 mutant, where parental genomes fail to merge, these junctions are absent, suggesting that three-way sheet junctions are needed for formation of a diploid genome.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Membrana Celular/genética , Núcleo Celular/genética , Mitose/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/ultraestrutura , Membrana Celular/ultraestrutura , Núcleo Celular/ultraestrutura , Cromossomos/genética , Fertilização/genética , Genoma/genética , Microscopia Eletrônica de Varredura
18.
Dev Cogn Neurosci ; 41: 100737, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31786477

RESUMO

Empirical and theoretical work suggests that early postnatal experience may inform later developing synaptic connectivity to adapt the brain to its environment. We hypothesized that early maternal experience may program the development of synaptic density on long range frontal cortex projections. To test this idea, we used maternal separation (MS) to generate environmental variability and examined how MS affected 1) maternal care and 2) synapse density on virally-labeled long range axons of offspring reared in MS or control conditions. We found that MS and variation in maternal care predicted bouton density on dorsal frontal cortex axons that terminated in the basolateral amygdala (BLA) and dorsomedial striatum (DMS) with more, fragmented care associated with higher density. The effects of maternal care on these distinct axonal projections of the frontal cortex were manifest at different ages. Maternal care measures were correlated with frontal cortex → BLA bouton density at mid-adolescence postnatal (P) day 35 and frontal cortex → DMS bouton density in adulthood (P85). Meanwhile, we found no evidence that MS or maternal care affected bouton density on ascending orbitofrontal cortex (OFC) or BLA axons that terminated in the dorsal frontal cortices. Our data show that variation in early experience can alter development in a circuit-specific and age-dependent manner that may be relevant to understanding the effects of early life adversity.


Assuntos
Lobo Frontal/anormalidades , Privação Materna , Animais , Modelos Animais de Doenças , Masculino , Camundongos
19.
Am J Hum Genet ; 104(5): 936-947, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982608

RESUMO

Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia. The second individual had a homozygous missense mutation (c.1929C>A [p.His643Gln]) and presented with developmental delay and epilepsy in childhood. We analyzed a zebrafish model (csf1rDM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor. CUX1+ neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1+ neurons. Since a large fraction of CUX1+ neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1+ neurons. Our results suggest that CSF1R is required for human brain development and establish the csf1rDM fish as a model for microgliopathies. In addition, our results exemplify an under-recognized form of phenotypic expansion, in which genes associated with well-recognized, dominant conditions produce different phenotypes when biallelically mutated.


Assuntos
Anormalidades Congênitas/etiologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Microglia/patologia , Mutação , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Animais , Criança , Anormalidades Congênitas/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Homozigoto , Humanos , Lactente , Recém-Nascido , Microglia/metabolismo , Linhagem , Fenótipo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adulto Jovem , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
20.
J Inherit Metab Dis ; 42(2): 325-332, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30701557

RESUMO

STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation disorder characterized by seizures, developmental delay, intellectual disability, and a type I carbohydrate deficient transferrin pattern. All previously reported cases (n = 6) have been attributed to a homozygous pathogenic missense variant c.1877C>T (p.Val626Ala) in STT3A. We describe a patient with a novel homozygous likely pathogenic missense variant c.1079A>C (p.Tyr360Ser) who presents with chronically low Factor VIII (FVIII) and von Willebrand Factor (vWF) levels and activities in addition to the previously reported symptoms of developmental delay and seizures. VWF in our patient's plasma is present in a mildly hypoglycosylated form. FVIII antigen levels were too low to quantify in our patient. Functional studies with STT3A-/- HEK293 cells showed severely reduced FVIII antigen and activity levels in conditioned media <10% expected, but normal intracellular levels. We also show decreased glycosylation of STT3A-specific acceptors in fibroblasts from our patient, providing a mechanistic explanation for how STT3A deficiency leads to a severe defect in FVIII secretion. Our results suggest that certain STT3A-dependent N-glycans are required for efficient FVIII secretion, and the decreased FVIII level in our patient is a combined effect of both severely impaired FVIII secretion and lower plasma VWF level. Our report expands both the genotype and phenotype of STT3A-CDG; demonstrating, as in most types of CDG, that there are multiple disease-causing variants in STT3A.


Assuntos
Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Hemofilia A/etiologia , Hexosiltransferases/genética , Proteínas de Membrana/genética , Doenças de von Willebrand/etiologia , Idade de Início , Pré-Escolar , Defeitos Congênitos da Glicosilação/complicações , Feminino , Glicosilação , Células HEK293 , Homozigoto , Humanos , Lactente , Recém-Nascido , Mutação de Sentido Incorreto
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