RESUMO
Limb-girdle muscular dystrophy type 2G/R7 (LGMD2G/R7) is an ultra-rare condition initially identified within the Brazilian population. We aimed to expand clinical and genetic information about this disease, including its worldwide distribution. A multicenter historical cohort study was performed at 13 centers in Brazil in which data from index cases and their affected relatives from consecutive families with LGMD2G/R7 were reviewed from July 2017 to August 2023. Additionally, a systematic literature review was conducted to identify case reports and series of the disease worldwide. Forty-one LGMD2G/R7 cases were described in the Brazilian cohort, being all subjects homozygous for the c.157C>T/(p.Gln53*) variant in TCAP. Survival curves showed that the median disease duration before individuals required walking aids was 21 years. Notably, women exhibited a slower disease progression, requiring walking aids 13 years later than men. LGMD2G/R7 was frequently reported not only in Brazil but also in China and Bulgaria, with 119 cases identified globally, with possible founder effects in the Brazilian, Eastern European, and Asian populations. These findings are pivotal in raising awareness of LGMD2G/R7, understanding its progression, and identifying potential modifiers. This can significantly contribute to the development of future natural history studies and clinical trials for this disease.
RESUMO
BACKGROUND: While extensive research has explored why women undergo labiaplasty, little attention has been paid to societal and professional abilities to distinguish between altered and unaltered labia, impacting both patient concerns and broader societal perceptions. OBJECTIVES: This study aimed to evaluate the accuracy of the general public and healthcare professionals in identifying labiaplasty and to pinpoint the misconceptions driving their perceptions. The goal was to inform more effective patient counseling strategies and challenge existing stigmas around cosmetic genital surgery. METHODS: We conducted an online survey with 511 lay adults and a group of 21 gynecologists and aesthetic vulvar surgeons, assessing their ability to detect labiaplasty from images, focusing on aesthetic appearance, hair patterns, and size. The analysis involved Pearson correlation and Z-tests to compare perceptions against actual operative status. RESULTS: Our analysis revealed a pronounced difficulty among participants in accurately discerning labiaplasty, with neither group showing a significant ability to identify surgical alterations. Misinterpretations were notably influenced by expectations of aesthetic appearance, with 49% associating an "odd" or "fake" look with surgery, and hair and size misconceptions also misleading respondents. Additionally, 20% of participants mistakenly related surgical changes to gender affirming surgery or female genital mutilation. CONCLUSIONS: The study highlights a gap in the ability of both the general public and medical professionals to accurately identify labiaplasty, pointing to a broad misunderstanding of cosmetic genital surgery's visual outcomes. Addressing these misconceptions through targeted education could substantially improve patient counseling and help dismantle the stigmas associated with labiaplasty.
RESUMO
BACKGROUND: Facilitatory and inhibitory conditioned pain modulation (CPM) responses are observed in healthy volunteers and chronic pain patients, but the clinical implications for phenotyping are unknown. This study aimed to subgroup and compare chronic knee pain patients according to their CPM responses. METHODS: This explorative, cross-sectional study included 127 patients with chronic knee pain (osteoarthritis or following total knee arthroplasty). Individual CPM responses were categorized as facilitatory (test stimuli pain intensity increased when conditioning stimuli were applied), as inhibitory (test stimuli pain intensity decreased) or as no change (defined as less than 5.3% change in pain intensity). Outcomes were clinical pain intensities, temporal summation, widespread pain, self-reported physical function, PainDETECT questionnaire and Pain Quality Assessment Scale. Data were analysed as comparisons between the inhibitory and the facilitatory groups and using multivariate linear regression models. RESULTS: Fifty-four patients had facilitatory CPM responses, 49 had inhibitory CPM responses, and 24 showed no change in CPM response. A between-group difference was observed for self-reported physical function, with the facilitatory CPM group reporting better function (54.4 vs. 46.0, p = 0.028) and the facilitatory CPM group reported more deep pain sensations (3.2 vs. 2.0, p = 0.021). The remaining outcomes showed no between-group differences. Higher clinical pain intensity and facilitated temporal summation were associated in the facilitated CPM group but not in the inhibitory CPM group. CONCLUSION: These explorative findings indicated that quantitative clinical and experimental differences exist between facilitatory or inhibitory CPM responses in a chronic knee pain patient population. Differences in patients' CPM responses should be further investigated to unravel possible clinical importance. SIGNIFICANCE: Our findings confirm that conditioned pain modulation consist of inhibitory and facilitatory responders among a patient population with chronic knee pain. This explorative study indicates that patients with either facilitatory or inhibitory conditioned pain modulation could exhibit differences in pain outcomes. Subgrouping of chronic pain patients depending on individual conditioned pain modulation responses could be considered in phenotyping patients prior to inclusion in clinical trials or used for personalizing the management regime.
Assuntos
Dor Crônica , Osteoartrite do Joelho , Humanos , Estudos Transversais , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/tratamento farmacológico , Medição da Dor , Limiar da Dor/fisiologia , Estudos Multicêntricos como AssuntoRESUMO
Tissue interactions are essential for guiding organ development and regeneration. Hair follicle formation relies on inductive signalling between two tissues, the embryonic surface epithelium and the adjacent mesenchyme. Although previous research has highlighted the hair-inducing potential of the mesenchymal component of the hair follicle - the dermal papilla and its precursor, the dermal condensate - the source and nature of the primary inductive signal before dermal condensate formation have remained elusive. Here, we performed epithelial-mesenchymal tissue recombination experiments using hair-forming back skin and glabrous plantar skin from mouse embryos to unveil that the back skin mesenchyme is inductive even before dermal condensate formation. Moreover, the naïve, unpatterned mesenchyme was sufficient to trigger hair follicle formation even in the oral epithelium. Building on previous knowledge, we explored the hair-inductive ability of the Wnt agonist R-spondin 1 and a Bmp receptor inhibitor in embryonic skin explants. Although R-spondin 1 instigated precocious placode-specific transcriptional responses, it was insufficient for hair follicle induction, either alone or in combination with Bmp receptor inhibition. Our findings pave the way for identifying the hair follicle-inducing cue.
Assuntos
Folículo Piloso , Cabelo , Camundongos , Animais , Folículo Piloso/fisiologia , Pele , Mesoderma/fisiologia , Receptores de Proteínas Morfogenéticas ÓsseasRESUMO
BACKGROUND: A new selective preventive spinal immobilization (PSI) protocol was introduced in the Netherlands. This may have led to an increase in non-immobilized spinal fractures (NISFs) and consequently adverse patient outcomes. AIM: A pilot study was conducted to describe the adverse patient outcomes in NISF of the PSI protocol change and assess the feasibility of a larger effect study. METHODS: Retrospective comparative cohort pilot study including records of trauma patients with a presumed spinal injury who were presented at the emergency department of a level 2 trauma center by the emergency medical service (EMS). The pre-period 2013-2014 (strict PSI protocol), was compared to the post-period 2017-2018 (selective PSI protocol). Primary outcomes were the percentage of records with a NISF who had an adverse patient outcome such as neurological injuries and mortality before and after the protocol change. Secondary outcomes were the sample size calculation for a larger study and the feasibility of data collection. RESULTS: 1,147 records were included; 442 pre-period, and 705 post-period. The NISF-prevalence was 10% (95% CI 7-16, n = 19) and 8% (95% CI 6-11, n = 33), respectively. In both periods, no neurological injuries or mortality due to NISF were found, by which calculating a sample size is impossible. Data collection showed to be feasible. CONCLUSIONS: No neurological injuries or mortality due to NISF were found in a strict and a selective PSI protocol. Therefore, a larger study is discouraged. Future studies should focus on which patients really profit from PSI and which patients do not.
RESUMO
Connexin 43 (Cx43), the predominate gap junction protein in bone, is essential for intercellular communication and skeletal homeostasis. Previous work suggests that osteocyte-specific deletion of Cx43 leads to increased bone formation and resorption; however, the cell-autonomous role of osteocytic Cx43 in promoting increased bone remodeling is unknown. Recent studies using three-dimensional (3D) culture substrates in OCY454 cells suggest that 3D cultures may offer increased bone remodeling factor expression and secretion, such as sclerostin and receptor activator of nuclear factor-κB ligand (RANKL). In this study, we compared culturing OCY454 osteocytes on 3D Alvetex scaffolds with traditional 2D tissue culture, both with [wild-type (WT)] and without Cx43 (Cx43 KO). Conditioned media from OCY454 cell cultures were used to determine soluble signaling to differentiate primary bone marrow cells into osteoblasts and osteoclasts. OCY454 cells cultured on 3D portrayed a mature osteocytic phenotype, relative to cells on 2D, shown by increased osteocytic gene expression and reduced cell proliferation. In contrast, OCY454 differentiation based on these same markers was not affected by Cx43 deficiency in 3D. Interestingly, increased sclerostin secretion was found in 3D cultured WT cells compared with that of Cx43 KO cells. Conditioned media from Cx43 KO cells promoted increased osteoblastogenesis and osteoclastogenesis, with maximal effects from 3D cultured Cx43 KO cells. These results suggest that Cx43 deficiency promotes increased bone remodeling in a cell-autonomous manner with minimal changes in osteocyte differentiation. Finally, 3D cultures appear better suited to study mechanisms from Cx43-deficient OCY454 osteocytes in vitro due to their ability to promote osteocyte differentiation, limit proliferation, and increase bone remodeling factor secretion.NEW & NOTEWORTHY 3D cell culture of OCY454 cells promoted increased differentiation compared with traditional 2D culture. Although Cx43 deficiency did not affect OCY454 differentiation, it resulted in increased signaling, promoting osteoblastogenesis and osteoclastogenesis. Our results suggest that Cx43 deficiency promotes increased bone remodeling in a cell-autonomous manner with minimal changes in osteocyte differentiation. Also, 3D cultures appear better suited to study mechanisms in Cx43-deficient OCY454 osteocytes.
Assuntos
Conexina 43 , Osteócitos , Osteócitos/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Meios de Cultivo Condicionados/metabolismo , Diferenciação Celular , Técnicas de Cultura de CélulasRESUMO
Graft-versus-host disease (GvHD) is a serious complication of allogeneic haematopoietic stem cell transplantation (HSCT). Both anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) are used as lymphocyte-depleting strategies, yet a systematic comparison of transplantation outcomes between these two methods in matched unrelated donors (MUD) transplantations with non-myeloablative conditioning (NMC) is lacking. Adult patients with haematological malignancies who had undergone MUD HSCT with NMC regimens between 2014 and 2021 at 2 centres in Amsterdam (ATG: n = 95, PTCy: n = 90), were included in this retrospective study. Patient characteristics were comparable between the groups. The cumulative incidence of acute GvHD grade II-IV was 48% in the ATG group compared to 21% in the PTCy group (p < 0.001). The 3-year moderate/severe chronic GvHD was similar in both groups (p = 0.69). While the relapse rate was comparable between the groups (ATG 31% vs. PTCy 34%, p = 0.94), non-relapse mortality tended to be higher in the ATG group (17% vs. 9%, p = 0.069). Overall survival was similar in both groups (p = 0.12). In conclusion, PTCy-based regimens resulted in a significantly lower rate of acute GvHD than ATG-containing regimens in MUD transplantations with NMC. Whether PTCy results in improved overall survival as compared to ATG needs to be elucidated in larger prospective studies.
RESUMO
Connexin 43 (Cx43), the predominate gap junction protein in bone, is essential for intercellular communication and skeletal homeostasis. Previous work suggests osteocyte-specific deletion of Cx43 leads to increased bone formation and resorption, however the cell-autonomous role of osteocytic Cx43 in promoting increased bone remodeling is unknown. Recent studies using 3D culture substrates in OCY454 cells suggest 3D cultures may offer increased bone remodeling factor expression and secretion, such as sclerostin and RANKL. In this study, we compared culturing OCY454 osteocytes on 3D Alvetex scaffolds to traditional 2D tissue culture, both with (WT) and without Cx43 (Cx43 KO). Conditioned media from OCY454 cell cultures was used to determine soluble signaling to differentiate primary bone marrow stromal cells into osteoblasts and osteoclasts. OCY454 cells cultured on 3D portrayed a mature osteocytic phenotype, relative to cells on 2D, shown by increased osteocytic gene expression and reduced cell proliferation. In contrast, OCY454 differentiation based on these same markers was not affected by Cx43 deficiency in 3D. Interestingly, increased sclerostin secretion was found in 3D cultured WT cells compared to Cx43 KO cells. Conditioned media from Cx43 KO cells promoted increased osteoblastogenesis and increased osteoclastogenesis, with maximal effects from 3D cultured Cx43 KO cells. These results suggest Cx43 deficiency promotes increased bone remodeling in a cell autonomous manner with minimal changes in osteocyte differentiation. Finally, 3D cultures appear better suited to study mechanisms from Cx43-deficient OCY454 osteocytes in vitro due to their ability to promote osteocyte differentiation, limit proliferation, and increase bone remodeling factor secretion. New and Noteworthy: 3D cell culture of OCY454 cells promoted increased differentiation compared to traditional 2D culture. While Cx43 deficiency did not affect OCY454 differentiation, it resulted in increased signaling, promoting osteoblastogenesis and osteoclastogenesis. Our results suggest Cx43 deficiency promotes increased bone remodeling in a cell autonomous manner with minimal changes in osteocyte differentiation. Also, 3D cultures appear better suited to study mechanisms in Cx43-deficient OCY454 osteocytes.
RESUMO
Genital self-image describes the perception of one's genital appearance as being "normal" or "abnormal," and a disharmonious image leads to an increasing number of women seeking esthetic genital surgery each year. The concept of what constitutes "normal" is strongly influenced by the media, cultural norms, and sexual relations. In reality, the extent of normalcy is highly variable and overall patient education regarding extremes of size and shape should be provided to all patients considering surgery. When performed with appropriate training, expertise, and attention to detail in a properly selected patient, esthetic genital surgery is associated with minimal complications or sequelae.
Assuntos
Imagem Corporal , Cirurgia Plástica , Estética , Feminino , Genitália , Humanos , AutoimagemRESUMO
PURPOSE: Preclinical and clinical data suggest a potential benefit in the addition of radiotherapy (RT) to immune-checkpoint inhibitors (ICI) during the treatment of advanced cancers. Nevertheless, the ideal patients for this approach and the optimal RT regimen is still debated. MATERIAL AND METHODS: The aim of this study was to determine the effect RT schedule has on survival for advanced non-small cell lung cancer and melanoma patients (pts) treated with ICI (anti-PD1 or anti-CTLA4) and concomitant RT. RESULTS: A total of 58 pts were identified, of which 26 received RT concomitantly with ICI while the remaining 32 pts were treated with RT at the time of progression under ICI. The RT parameters associated with outcome include dose per fraction, biological effective dose, RT to all targets and lung irradiation. Independent predictors of improved progression-free survival were lung irradiation, melanoma histology, oligometastatic status (<6 metastasis), presence of liver metastasis, PNN<7000/mm3 and normal LDH. Independent predictors of improved overall survival were melanoma histology and normal LDH. Among pts who were irradiated at progression, 68.7% had an overall clinical benefit and had a median extension of ICI use by 2.3 months (range: 0-29.1), among which 2 presented with an abscopal effect. CONCLUSIONS: The irradiation of lung metastases may increase survival in patients under ICI. RT at progression could prolong the use of ICI, and neutrophilia and LDH should be considered during patient selection of this combined RT/ICI approach.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Humanos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Imunoterapia/efeitos adversos , Melanoma/tratamento farmacológico , Melanoma/radioterapia , Estudos RetrospectivosRESUMO
The highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant led to increased hospitalizations, staffing shortages, and increased school closures. To reduce spread in school-aged children during the Omicron peak, the District of Columbia implemented a test-to-return strategy in public and public charter schools after a 2-week break from in-person learning.
Assuntos
COVID-19 , Criança , District of Columbia , Humanos , SARS-CoV-2 , Instituições AcadêmicasRESUMO
Alcohol and tobacco are the most commonly used addictive substances, with high comorbidity rates between alcohol use disorder and tobacco use disorder. Risk for alcohol and nicotine addiction is highly heritable, and they share common genetic factors. A GWAS in over 1 million individuals has revealed 566 genetic variants in 406 loci associated with multiple stages of alcohol and tobacco use. Three novel genes-SLC39A8, GRK4 and HGFAC-within loci associated with altered alcoholic drinks per week (ADW) or cigarettes per day (CPD) were selected to further study their role in alcohol and tobacco use disorder. The role of these genes was assessed using the two-bottle choice addiction paradigm in transgenic mice for each of the genes. We found significant decreases in chronic alcohol consumption and preference in female Hgfac knockout (KO) mice, and decreased nicotine preference in male Hgfac KO compared with wild-type (WT) mice. Additionally, male Slc39a8 hypomorph mice showed greater overall nicotine preference compared with WT mice, while no differences were detected for Grk4 KO mice in alcohol or nicotine consumption and preference in either sex. Thus, this study implicates Hgfac and Slc39a8 in alcohol and tobacco use in a sex-specific manner.
Assuntos
Proteínas de Transporte de Cátions , Tabagismo , Consumo de Bebidas Alcoólicas/genética , Animais , Proteínas de Transporte de Cátions/genética , Etanol , Feminino , Estudo de Associação Genômica Ampla , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Nicotina , Tabagismo/genéticaRESUMO
INTRODUCTION: ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) is a rare lung cancer with limited treatment options. Phase I-II studies with ROS1-tyrosine kinase inhibitors (TKIs) included small numbers of patients and real-world data are lacking. We investigate the efficacy and safety of lorlatinib, a third-generation TKI targeting ALK and ROS1, in patients with ROS1+ NSCLC treated through an expanded access program. METHODS: Consecutive patients with advanced ROS1+ NSCLC treated with lorlatinib between October 2015 and June 2019 were included. Data were collected from medical records. The primary endpoint was progression-free survival. RESULTS: Out of the 80 patients included, 47(59%) were female, 49(62%) never smokers (less than 100 cigarettes over the lifetime), and 68(85%) had stage IV NSCLC at diagnosis. Most frequent histology was adenocarcinoma (95%) and median age was 58.2 years. At the time of lorlatinib initiation, 51(64%) patients had brain metastases and 55(81%) were PS 0-1. Lorlatinib was administered as second/third/fourth/fifth+ line in 29%/28%/18%/26% of patients. All patients previously received at least one ROS1 TKI, and 55(69%) previously received chemotherapy. Median follow-up from lorlatinib initiation was 22.2 months. Median progression-free survival and overall survival from lorlatinib initiation were 7.1 months [95% confidence interval (CI) 5.0-9.9 months] and 19.6 months (95% CI 12.3-27.5 months). Median duration of treatment with lorlatinib was 7.4 months (95% CI 6.5-13.1 months). Overall response and disease control rates were 45% and 82%, respectively. The central nervous system response rate was 72%. Treatment was stopped due to toxicity in 10 patients (13%). The safety profile was consistent with previously published data. CONCLUSIONS: Lorlatinib is a major treatment option for advanced refractory ROS1+ NSCLC in treatment strategy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Aminopiridinas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Lactamas , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Tirosina Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/uso terapêutico , PirazóisAssuntos
Coreia , Acidente Vascular Cerebral , Infarto Cerebral/complicações , Infarto Cerebral/diagnóstico por imagem , Coreia/diagnóstico por imagem , Coreia/etiologia , Humanos , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagemRESUMO
The mechanism by which substrate surface characteristics are transduced by osteoblastic cells and their progenitors is not fully known. Data from previous studies by our group suggest the involvement of ß-catenin in the mechanism by which substrate surface characteristics are transduced. This focal adhesion and ß-catenin mediated mechanism functions through the liberation of ß-catenin from focal adhesion complexes in response to pro-osteogenic substrate (POS) characteristics. After liberation, ß-catenin translocates and facilitates upregulation of genes associated with osteogenesis. It is not known whether the observed correlation between focal adhesion turnover and ß-catenin translocation directly results from focal adhesion turnover. In this study we inhibited focal adhesion turnover using a focal adhesion kinase inhibitor PF-573228. We found that inhibition of focal adhesion turnover resulted in an abrogation of the more rapid translocation and increased transcriptional activity of ß-catenin induced by POS. In addition, inhibition of focal adhesion turnover mitigated the increase in osteoblastic differentiation induced by a POS as measured by alkaline phosphatase enzymatic activity and osteogenic gene and protein expression. Together, these data, coupled with previous findings, suggest that the observed ß-catenin translocation is a result of focal adhesion turnover, providing evidence for a focal adhesion initiated, ß-catenin mediated mechanism of substrate surface signal transduction.