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PURPOSE: To compare ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL) rates of change (RoC) in eyes with central or moderate to advanced glaucoma. DESIGN: Prospective cohort study. PARTICIPANTS: 918 matched macular and RNFL OCT scan pairs from 109 eyes (109 patients) enrolled in the Advanced Glaucoma Progression Study with ≥2 years of follow-up and ≥4 OCT scans. METHODS: We exported GCC and RNFL thickness measurements in 49 central macular superpixels and 12 RNFL clock-hour sectors, respectively. We applied our latest Bayesian hierarchical longitudinal model to estimate population and subject-specific baseline thickness (intercepts) and rates of change (RoC) in macular superpixels and RNFL sectors. Global RNFL and GCC RoC were analyzed in a single bivariate longitudinal model to properly compare them accounting for the correlation between their RoC. MAIN OUTCOME MEASURES: Proportion of significant negative (deteriorating) and positive (improving) RoC expressed in µm/year. Standardized RoC were calculated by dividing RoC by the corresponding population SD. Analyses were repeated in eyes with visual field mean deviation (MD) ≤-6 and >-6 dB. RESULTS: Average (SD) 24-2 visual field MD and follow-up length were -8.6 (6.3) dB and 4.2 (0.5) years, respectively. Global RNFL RoC (-0.70 µm/year) were faster than GCC (-0.44 µm/year) (p<.001); corresponding normalized RoC were not significantly different (p=0.052). In bivariate analysis, patients with a significant negative global RNFL RoC (n=63, 57%) or GCC (n=56, 51%) frequently did so for both outcomes (n=49, 45%). The average proportion of significantly decreasing RNFL sectors within an eye was 30.7% in eyes with MD >-6 dB compared to 20.5% in those with MD ≤-6 dB (p=0.014); the proportions for GCC superpixels were 21.1% vs. 18.7%, respectively (p=0.63). CONCLUSIONS: Both GCC and RNFL measures can detect structural progression in glaucoma patients with central damage or moderate to advanced glaucoma. The clinical utility of RNFL imaging decreases with worsening severity of glaucoma.
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This paper presents a new approach for quantitatively modeling the resilience of a system that has been disrupted by a sudden-impact event. It introduces a new theoretical model that explicitly incorporates representations of the enabling and inhibiting forces that are inherent within postdisruption recovery behavior. Based on a new, more comprehensive measure of resilience that is able to capture both negative and positive deviations in performance, a generic mass-spring system is then used to illustrate the applicability of the theoretical model. The interplay between the enabling and inhibiting forces that is revealed by the new model provides a new theoretical basis for understanding the complexity of resilience and disaster recovery. With the addition of the new resilience measure, it lends support for defining and characterizing a new type of resilient behavior: unstable resilience.
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Many organic dyes are fluorescent in solution. In the solid state, however, quenching processes often dominate, hampering material science applications such as light filters, light-emitting devices, or coding tags. We show that the dimethylene-cyclopropanide scaffold can be used to form two structurally different types of chromophores, which feature fluorescence quantum yields up to 0.65 in dimethyl sulfoxide and 0.53 in solids. The increased fluorescence in the solid state for compounds bearing malonate substituents instead of dicyanomethid ones is rationalized by the induced twist between the planes of the cyclopropanide core and a pyridine ligand.
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Purpose: This study aims to examine predisposing anatomic factors and subsequent post-decompression functional outcomes among high-intensity athletes with thoracic outlet syndrome (TOS). Materials and Methods: A single-institution retrospective review was performed on a prospective database of patients with TOS from 2018 to 2023 who had undergone operative decompression for TOS. Demographics, TOS characteristics, predisposing anatomy, operative details, and postoperative outcomes were examined. The primary outcome was postoperative return to sport. Secondary outcomes included vascular patency. Results: A total of 13 patients who were engaged in high-demand athletic activity at the time of their diagnosis were included. Diagnoses included 8 (62%) patients with venous TOS, 4 (31%) patients with neurogenic TOS, and 1 (8%) patient with arterial TOS. Mixed vascular and neurogenic TOS was observed in 3 (23%) patients. The mean age of the cohort was 30 years. Abnormal scalene structure was observed in 12 (92%) patients, and abnormal bone structures were noted in 4 (27%) patients; 2 (15%) with cervical ribs and 3 (23%) patients with clavicular abnormalities. Prior ipsilateral upper extremity trauma was reported in 4 (27%) patients. Significant joint hypermobility was observed in 8 (62%) patients with a median Beighton score of 6. Supraclavicular cervical and/or first rib resection with scalenectomy was performed in all patients. One case of postoperative pneumothorax was treated non-operatively. Ten (77%) patients returned to sport. Duplex ultrasonography showed subclavian vein patency in all 8 patients with venous TOS and wide patency with no drop in perfusion indices in the patient with arterial TOS. Conclusion: Athletes with TOS who required operative intervention had a high incidence of musculoskeletal aberrations and joint hypermobility. Supraclavicular decompression was associated with a high success rate, with overall good functional outcomes and good likelihood of patients returning to preoperative high-intensity athletics.
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Evolution results from the interaction of stochastic and deterministic processes that create a web of historical contingency, shaping gene content and organismal function. To understand the scope of this interaction, we examine the relative contributions of stochasticity, determinism, and contingency in shaping gene inactivation in 34 lineages of endosymbiotic bacteria, Sodalis, found in parasitic lice, Columbicola, that are independently undergoing genome degeneration. Here we show that the process of genome degeneration in this system is largely deterministic: genes involved in amino acid biosynthesis are lost while those involved in providing B-vitamins to the host are retained. In contrast, many genes encoding redundant functions, including components of the respiratory chain and DNA repair pathways, are subject to stochastic loss, yielding historical contingencies that constrain subsequent losses. Thus, while selection results in functional convergence between symbiont lineages, stochastic mutations initiate distinct evolutionary trajectories, generating diverse gene inventories that lack the functional redundancy typically found in free-living relatives.
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Evolução Molecular , Genoma Bacteriano , Filogenia , Processos Estocásticos , Simbiose , Simbiose/genética , Genoma Bacteriano/genética , Animais , Enterobacteriaceae/genética , Enterobacteriaceae/metabolismo , MutaçãoRESUMO
Maintaining the structure of cardiac membranes and membrane organelles is essential for heart function. A critical cardiac membrane organelle is the transverse tubule system (called the t-tubule system) which is an invagination of the surface membrane. A unique structural characteristic of the cardiac muscle t-tubule system is the extension of the extracellular matrix (ECM) from the surface membrane into the t-tubule lumen. However, the importance of the ECM extending into the cardiac t-tubule lumen is not well understood. Dystroglycan (DG) is an ECM receptor in the surface membrane of many cells, and it is also expressed in t-tubules in cardiac muscle. Extensive posttranslational processing and O-glycosylation are required for DG to bind ECM proteins and the binding is mediated by a glycan structure known as matriglycan. Genetic disruption resulting in defective O-glycosylation of DG results in muscular dystrophy with cardiorespiratory pathophysiology. Here, we show that DG is essential for maintaining cardiac t-tubule structural integrity. Mice with defects in O-glycosylation of DG developed normal t-tubules but were susceptible to stress-induced t-tubule loss or severing that contributed to cardiac dysfunction and disease progression. Finally, we observed similar stress-induced cardiac t-tubule disruption in a cohort of mice that solely lacked matriglycan. Collectively, our data indicate that DG in t-tubules anchors the luminal ECM to the t-tubule membrane via the polysaccharide matriglycan, which is critical to transmitting structural strength of the ECM to the t-tubules and provides resistance to mechanical stress, ultimately preventing disruptions in cardiac t-tubule integrity.
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Distroglicanas , Miocárdio , Animais , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Glicosilação , Distroglicanas/metabolismo , Matriz Extracelular/metabolismo , Camundongos KnockoutRESUMO
BACKGROUND: With aging, repetitive contraction of the platysma leads to an increase in platysma prominence (PP) characterized by the accentuation of vertical neck bands and blunting of the jawline's contour. METHODS: This multicenter, double-blind, phase 2 study evaluated onabotulinumtoxinA (onabotA) treatment in adults with Moderate to Severe PP. Participants were randomized to receive 1 treatment of onabotA low dose (LD), onabotA high dose (HD), or placebo, and were followed for 4 months. Efficacy endpoints were the achievement of a ≥ 1-grade improvement on both the left and right sides at Day 14 at maximum contraction as assessed by the investigator (primary) or by participants (secondary) using validated scales. Safety was evaluated throughout. RESULTS: Participants in the modified intent-to-treat population (N = 164) had a mean age of 50 years; 95.1% were female and 93.9% were White. The primary endpoint was met for both onabotA groups, with investigator-assessed ≥ 1-grade improvement in 77.8% (LD) and 88.2% (HD) vs 12.0% (placebo) of participants on Day 14 (P < 0.0001 vs placebo). Based on participant self-assessment, 75.9% (LD) and 88.2% (HD) vs 18.0% (placebo) achieved ≥ 1-grade improvement on Day 14 (P < 0.0001 vs placebo). Most treatment-related adverse events (AEs) were procedure-related, transient, and mild in severity. The most frequent onabotA-related AE was neck muscle weakness, reported in the HD group. CONCLUSIONS: OnabotA was effective in improving the appearance of PP based on both investigators' and participants' ratings. Treatment was well tolerated.
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We describe the case of a 62-year-old man presenting 2 months after a reversed great saphenous vein femoropopliteal bypass performed for critical limb ischemia. He was found to have early, high-grade bypass graft stenosis on duplex ultrasound. Subsequent angiography demonstrated flow limitations secondary to two areas of retained venous valves in the proximal and mid-portions of the vein graft. The culprit valve lesions were successfully lysed endovascularly with a HawkOne (Medtronic) directional atherectomy device. This case demonstrates a safe, novel use of a directional atherectomy device for treatment of remnant valves causing hemodynamically significant flow problems in peripheral vein grafts.
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Meiotic sex chromosome inactivation (MSCI) is a critical feature of meiotic prophase I progression in males. While the ATR kinase and its activator TOPBP1 are key drivers of MSCI within the specialized sex body (SB) domain of the nucleus, how they promote silencing remains unclear given their multifaceted meiotic functions that also include DNA repair, chromosome synapsis, and SB formation. Here we report a novel mutant mouse harboring mutations in the TOPBP1-BRCT5 domain. Topbp1B5/B5 males are infertile, with impaired MSCI despite displaying grossly normal events of early prophase I, including synapsis and SB formation. Specific ATR-dependent events are disrupted, including phosphorylation and localization of the RNA:DNA helicase Senataxin. Topbp1B5/B5 spermatocytes initiate, but cannot maintain ongoing, MSCI. These findings reveal a non-canonical role for the ATR-TOPBP1 signaling axis in MSCI dynamics at advanced stages in pachynema and establish the first mouse mutant that separates ATR signaling and MSCI from SB formation.
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Infertilidade Masculina , Meiose , Animais , Humanos , Masculino , Camundongos , Alelos , Proteínas de Transporte/genética , Reparo do DNA , Proteínas de Ligação a DNA/genética , Infertilidade Masculina/genética , Proteínas Nucleares/genética , Cromossomos SexuaisRESUMO
Purpose: Demonstrate that a novel Bayesian hierarchical spatial longitudinal (HSL) model improves estimation of local macular ganglion cell complex (GCC) rates of change compared to simple linear regression (SLR) and a conditional autoregressive (CAR) model. Methods: We analyzed GCC thickness measurements within 49 macular superpixels in 111 eyes (111 patients) with four or more macular optical coherence tomography scans and two or more years of follow-up. We compared superpixel-patient-specific estimates and their posterior variances derived from the latest version of a recently developed Bayesian HSL model, CAR, and SLR. We performed a simulation study to compare the accuracy of intercept and slope estimates in individual superpixels. Results: HSL identified a significantly higher proportion of significant negative slopes in 13/49 superpixels and a significantly lower proportion of significant positive slopes in 21/49 superpixels than SLR. In the simulation study, the median (tenth, ninetieth percentile) ratio of mean squared error of SLR [CAR] over HSL for intercepts and slopes were 1.91 (1.23, 2.75) [1.51 (1.05, 2.20)] and 3.25 (1.40, 10.14) [2.36 (1.17, 5.56)], respectively. Conclusions: A novel Bayesian HSL model improves estimation accuracy of patient-specific local GCC rates of change. The proposed model is more than twice as efficient as SLR for estimating superpixel-patient slopes and identifies a higher proportion of deteriorating superpixels than SLR while minimizing false-positive detection rates. Translational Relevance: The proposed HSL model can be used to model macular structural measurements to detect individual glaucoma progression earlier and more efficiently in clinical and research settings.
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Glaucoma , Humanos , Teorema de Bayes , Glaucoma/diagnóstico , Olho , Nonoxinol , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: Demonstrate that a novel Bayesian hierarchical spatial longitudinal (HSL) model identifies macular superpixels with rapidly deteriorating ganglion cell complex (GCC) thickness more efficiently than simple linear regression (SLR). DESIGN: Prospective cohort study. SETTING: Tertiary Glaucoma Center. SUBJECTS: One hundred eleven eyes (111 patients) with moderate to severe glaucoma at baseline and ≥4 macular optical coherence tomography scans and ≥2 years of follow-up. OBSERVATION PROCEDURE: Superpixel-patient-specific GCC slopes and their posterior variances in 49 superpixels were derived from our latest Bayesian HSL model and Bayesian SLR. A simulation cohort was created with known intercepts, slopes, and residual variances in individual superpixels. MAIN OUTCOME MEASURES: We compared HSL and SLR in the fastest progressing deciles on (1) proportion of superpixels identified as significantly progressing in the simulation study and compared to SLR slopes in cohort data; (2) root mean square error (RMSE), and SLR/HSL RMSE ratios. RESULTS: Cohort- In the fastest decile of slopes per SLR, 77% and 80% of superpixels progressed significantly according to SLR and HSL, respectively. The SLR/HSL posterior SD ratio had a median of 1.83, with 90% of ratios favoring HSL. Simulation- HSL identified 89% significant negative slopes in the fastest progressing decile vs 64% for SLR. SLR/HSL RMSE ratio was 1.36 for the fastest decile of slopes, with 83% of RMSE ratios favoring HSL. CONCLUSION: The Bayesian HSL model improves the estimation efficiency of local GCC rates of change regardless of underlying true rates of change, particularly in fast progressors.
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Glaucoma , Pressão Intraocular , Humanos , Modelos Lineares , Estudos Prospectivos , Teorema de Bayes , Campos Visuais , Fibras Nervosas , Células Ganglionares da Retina , Glaucoma/diagnóstico , Tomografia de Coerência Óptica/métodosRESUMO
Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylases regulating metabolism and stress responses; however, characterization of the removed acyl groups and their downstream metabolic fates remains incomplete. Here we employed untargeted comparative metabolomics to reinvestigate mitochondrial sirtuin biochemistry. First, we identified N-glutarylspermidines as metabolites downstream of the mitochondrial sirtuin SIR-2.3 in Caenorhabditis elegans and demonstrated that SIR-2.3 functions as a lysine deglutarylase and that N-glutarylspermidines can be derived from O-glutaryl-ADP-ribose. Subsequent targeted analysis of C. elegans, mouse and human metabolomes revealed a chemically diverse range of N-acylspermidines, and formation of N-succinylspermidines and/or N-glutarylspermidines was observed downstream of mammalian mitochondrial sirtuin SIRT5 in two cell lines, consistent with annotated functions of SIRT5. Finally, N-glutarylspermidines were found to adversely affect C. elegans lifespan and mammalian cell proliferation. Our results indicate that N-acylspermidines are conserved metabolites downstream of mitochondrial sirtuins that facilitate annotation of sirtuin enzymatic activities in vivo and may contribute to sirtuin-dependent phenotypes.
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Caenorhabditis elegans , Mitocôndrias , Sirtuínas , Sirtuínas/metabolismo , Caenorhabditis elegans/metabolismo , Animais , Mitocôndrias/metabolismo , Humanos , Camundongos , Proliferação de Células , MetabolômicaRESUMO
BACKGROUND: Elevated inflammatory cytokines in the periphery have been identified as active contributors to neuroinflammation and sympathetic overactivity in heart failure (HF). Yet, the exact mechanisms by which these cytokines breach the blood-brain barrier (BBB) to exert their effects on the brain remain elusive. Interleukin 17A has been linked to BBB disruption in various neurologic disorders, and its levels were significantly augmented in circulation and the brain in HF. The present study aimed to determine whether the BBB integrity was compromised within the hypothalamic paraventricular nucleus (PVN), and if so, whether interleukin 17A contributes to BBB disruption in myocardial infarction-induced HF. METHODS AND RESULTS: Male Sprague-Dawley rats underwent coronary artery ligation to induce HF or sham surgery. Some HF rats received bilateral PVN microinjections of an interleukin 17 receptor A small interfering RNA or a scrambled small interfering RNA adeno-associated virus. Four weeks after coronary artery ligation, the permeability of the BBB was evaluated by intracarotid injection of fluorescent dyes (fluorescein isothiocyanate-dextran 10 kDa+rhodamine-dextran 70 kDa). Compared with sham-operated rats, HF rats exhibited an elevated extravasation of fluorescein isothiocyanate-dextran 10 kDa within the PVN but not in the brain cortex. The plasma interleukin 17A levels were positively correlated with fluorescein isothiocyanate 10 kDa extravasation in the PVN. The expression of caveolin-1, a transcytosis marker, was augmented, whereas the expression of tight junction proteins was diminished in HF rats. Interleukin 17 receptor A was identified within the endothelium of PVN microvessels. Treatment with interleukin 17 receptor A small interfering RNA led to a significant attenuation of fluorescein isothiocyanate 10 kDa extravasation in the PVN and reversed expression of caveolin-1 and tight junction-associated proteins in the PVN. CONCLUSIONS: Collectively, these data indicate that BBB permeability within the PVN is enhanced in HF and is likely attributable to increased interleukin 17A/interleukin 17 receptor A signaling in the BBB endothelium, by promoting caveolar transcytosis and degradation of tight junction complexes.
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Barreira Hematoencefálica , Fluoresceína-5-Isotiocianato , Interleucina-17 , Infarto do Miocárdio , Núcleo Hipotalâmico Paraventricular , Transdução de Sinais , Animais , Masculino , Ratos , Barreira Hematoencefálica/metabolismo , Caveolina 1/metabolismo , Citocinas/metabolismo , Dextranos/metabolismo , Dextranos/farmacologia , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceínas/metabolismo , Fluoresceínas/farmacologia , Insuficiência Cardíaca , Interleucina-17/metabolismo , Isotiocianatos/metabolismo , Isotiocianatos/farmacologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Ratos Sprague-Dawley , Receptores de Interleucina-17/metabolismo , RNA Interferente Pequeno/metabolismoRESUMO
BACKGROUND: The use of tissue fillers to treat age-related deepening of the nasolabial fold (NLF) has increased and become the standard clinical approach, creating a need for evidence-based, objective evaluation for pre- and post-procedure assessment of the NLF. METHODS: A 5-point rating scale was developed to assess the NLF, specifically the presence of depression and shadowing. Live validation of the scale was performed with a total of 73 participants representing the full range of NLF severities. Physicians board-certified in a core aesthetic specialty (3 trained raters) performed the scale validation over 2 rounds, 2 weeks apart. Training was carried out, and test-retest reliability was quantitated through the determination of intra- and inter-rater reliability by percentage of agreement, weighted kappa statistic with 95% confidence interval (CI), and intraclass correlation coefficient with 95% CI. To evaluate the clinical relevance of a 1-grade difference, rater assessments of 90 photo pairs were compared with previous designations of clinically different or not clinically different. RESULTS: The NLF scale achieved near-perfect intra- and inter-rater reliability when utilized by trained raters to assess a diverse group of live participants. Furthermore, clinically relevant differences between grades were established, and a 1-point difference was detectable by trained evaluators using the NLF scale. CONCLUSION: The clinically relevant and highly reliable validated NLF scale provides a standardized grading system with a user-friendly design for objectively assessing NLF in clinical practice and as a research tool for clinical approval studies of new aesthetic products and technologies. J Drugs Dermatol. 2024;23(1):1284-1291. doi:10.36849/JDD.7316.
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Relevância Clínica , Médicos , Humanos , Sulco Nasogeniano , Reprodutibilidade dos Testes , EstéticaRESUMO
PURPOSE: To confirm that CrCEST in muscle exhibits a slow-exchanging process, and to obtain high-resolution amide, creatine (Cr), and phosphocreatine (PCr) maps of skeletal muscle using a POlynomial and Lorentzian Line-shape Fitting (PLOF) CEST at 3T. METHODS: We used dynamic changes in PCr/CrCEST of mouse hindlimb before and after euthanasia to assign the Cr and PCr CEST peaks in the Z-spectrum at 3T and to obtain the optimum saturation parameters. Segmented 3D EPI was employed to obtain multi-slice amide, PCr, and Cr CEST maps of human skeletal muscle. Subsequently, the PCrCEST maps were calibrated using the PCr concentrations determined by 31 P MRS. RESULTS: A comparison of the Z-spectra in mouse hindlimb before and after euthanasia indicated that CrCEST is a slow-exchanging process in muscle (<150.7 s-1 ). This allowed us to simultaneously extract PCr/CrCEST signals at 3T using the PLOF method. We determined optimal B1 values ranging from 0.3 to 0.6 µT for CrCEST in muscle and 0.3-1.2 µT for PCrCEST. For the study on human calf muscle, we determined an optimum saturation time of 2 s for both PCr/CrCEST (B1 = 0.6 µT). The PCr/CrCEST using 3D EPI were found to be comparable to those obtained using turbo spin echo (TSE). (3D EPI/TSE PCr: (2.6 ± 0.3) %/(2.3 ± 0.1) %; Cr: (1.3 ± 0.1) %/(1.4 ± 0.07) %). CONCLUSIONS: Our study showed that in vivo CrCEST is a slow-exchanging process. Hence, amide, Cr, and PCr CEST in the skeletal muscle can be mapped simultaneously at 3T by PLOF CEST.
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Creatina , Imageamento por Ressonância Magnética , Humanos , Animais , Camundongos , Fosfocreatina , Imageamento por Ressonância Magnética/métodos , Músculo Esquelético/diagnóstico por imagem , AmidasRESUMO
INTRODUCTION: AUA Guidelines do not support the routine use of ultrasound (US) in evaluation of boys with an undescended testicle (UDT) prior to urology referral. Multiple studies have demonstrated that real time US is inferior to a physical examination by a pediatric urologist in detecting an UDT. However, improved US technology, which now permits detection of the non-palpable testis located just proximal to the internal ring, may aid in guiding the surgical approach to the non-palpable testis. We evaluated US findings of boys deemed to have a non-palpable UDT and compared them to surgical findings. OBJECTIVE: To assess the role of pre-operative ultrasonography in guiding surgical management in boys deemed to have a non-palpable testis by a pediatric urologist. STUDY DESIGN: US of boys with a non-palpable UDT, as reported by a pediatric urologist on physical exam, during a 3-year period, were reviewed. All US were performed jointly by a technician and pediatric radiologist. Patient demographics, laterality, and intra-operative findings were assessed. RESULTS: Thirty-one boys with a non-palpable testicle on physical exam underwent scrotal/inguinal/pelvis US at a median age of 7.5 months (IQR 2.5-12.3 months). Two patients had bilateral non-palpable testicles, 21 had a non-palpable left sided testicle and 8 had a non-palpable right sided testicle. Of the 33 non-palpable testes, 5 (15.2%) were identified in the inguinal canal. Sixteen (48.5%) were visualized in the lower pelvis just proximal to the internal ring and graded as intra-abdominal. Four (12.1%) nubbins or very atrophic testes were identified in the inguinal region or scrotum and 5 (15.2%) testes were not identified on US. Three (9.1%) testes were observed to be mobile between the lower pelvis just proximal to the internal ring and the inguinal canal. Of the 8 patients with testes that were identified in the inguinal canal, or mobile between the lower pelvis and inguinal canal, 7 avoided a diagnostic laparoscopy and underwent an inguinal orchiopexy. Of the 16 testicles located in the lower pelvis proximal to the internal ring, only 2 underwent laparoscopy/laparoscopic orchiopexy. DISCUSSION: In cases of a non-palpable testicle following a physical examination by a urologist, an ultrasound can impact the operative plan, and allow for patients to avoid laparoscopy. In our cohort, 87.5% of non-palpable testes avoided laparoscopic surgery after ultrasound identification of a viable testis. CONCLUSIONS: US in the evaluation of cryptorchidism can guide surgical management in select cases in which a testis is non-palpable following careful examination by a urologist.
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Criptorquidismo , Laparoscopia , Masculino , Humanos , Criança , Lactente , Criptorquidismo/diagnóstico por imagem , Criptorquidismo/cirurgia , Ultrassonografia , OrquidopexiaRESUMO
Oral delivery, while a highly desirable form of nanoparticle-drug administration, is limited by challenges associated with overcoming several biological barriers. Here, the authors study how fluorescent and poly(ethylene glycol)-coated (PEGylated) core-shell silica nanoparticles sized 5 to 50 nm interact with major barriers including intestinal mucus, intestinal epithelium, and stomach acid. From imaging fluorescence correlation spectroscopy studies using quasi-total internal reflection fluorescence microscopy, diffusion of nanoparticles through highly scattering mucus is progressively hindered above a critical hydrodynamic size around 20 nm. By studying Caco-2 cell monolayers mimicking the intestinal epithelia, it is observed that ultrasmall nanoparticles below 10 nm diameter (Cornell prime dots, [C' dots]) show permeabilities correlated with high absorption in humans from primarily enhanced passive passage through tight junctions. Particles above 20 nm diameter exclusively show active transport through cells. After establishing C' dot stability in artificial gastric juice, in vivo oral gavage experiments in mice demonstrate successful passage through the body followed by renal clearance without protein corona formation. Results suggest C' dots as viable candidates for oral administration to patients with a proven pathway towards clinical translation and may generate renewed interest in examining silica as a food additive and its effects on nutrition and health.
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Portadores de Fármacos , Nanopartículas , Humanos , Ratos , Camundongos , Animais , Portadores de Fármacos/química , Células CACO-2 , Ratos Sprague-Dawley , Dióxido de Silício/química , Nanopartículas/químicaRESUMO
Facioscapulohumeral dystrophy (FSHD) has a unique genetic aetiology resulting in partial chromatin relaxation of the D4Z4 macrosatellite repeat array on 4qter. This D4Z4 chromatin relaxation facilitates inappropriate expression of the transcription factor DUX4 in skeletal muscle. DUX4 is encoded by a retrogene that is embedded within the distal region of the D4Z4 repeat array. In the European population, the D4Z4 repeat array is usually organized in a single array that ranges between 8 and 100 units. D4Z4 chromatin relaxation and DUX4 derepression in FSHD is most often caused by repeat array contraction to 1-10 units (FSHD1) or by a digenic mechanism requiring pathogenic variants in a D4Z4 chromatin repressor like SMCHD1, combined with a repeat array between 8 and 20 units (FSHD2). With a prevalence of 1.5% in the European population, in cis duplications of the D4Z4 repeat array, where two adjacent D4Z4 arrays are interrupted by a spacer sequence, are relatively common but their relationship to FSHD is not well understood. In cis duplication alleles were shown to be pathogenic in FSHD2 patients; however, there is inconsistent evidence for the necessity of an SMCHD1 mutation for disease development. To explore the pathogenic nature of these alleles we compared in cis duplication alleles in FSHD patients with or without pathogenic SMCHD1 variant. For both groups we showed duplication-allele-specific DUX4 expression. We studied these alleles in detail using pulsed-field gel electrophoresis-based Southern blotting and molecular combing, emphasizing the challenges in the characterization of these rearrangements. Nanopore sequencing was instrumental to study the composition and methylation of the duplicated D4Z4 repeat arrays and to identify the breakpoints and the spacer sequence between the arrays. By comparing the composition of the D4Z4 repeat array of in cis duplication alleles in both groups, we found that specific combinations of proximal and distal repeat array sizes determine their pathogenicity. Supported by our algorithm to predict pathogenicity, diagnostic laboratories should now be furnished to accurately interpret these in cis D4Z4 repeat array duplications, alleles that can easily be missed in routine settings.