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1.
Front Psychol ; 15: 1360260, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38524293

RESUMO

Introduction: The purpose of this study is to provide an overview of extant research regarding XR technology and its effect on consumer wellbeing. With the hopes of informing marketing practitioners on XR consumer psychology, in preparation for the Metaverse. Methods: To achieve the above aim, two types of analysis took place. Firstly, a bibliometric analysis was conducted which was then followed by a framework-based structured literature review. The latter entailed an analysis of 81 articles evaluated from a positive psychological approach. Findings: Following the TCCM framework, the analysis revealed the most common psychological theories demonstrating potential avenues for XR to impact consumer wellbeing. Moreover, researchers found preliminary links between, theory, characteristics, and contexts. Giving a preliminary description of how theory manifests into reality. Finally, the overview of extant literature was used to propose new avenues for future research pertaining to marketing, the Metaverse, and consumer effects. Conclusion: In conclusion, the paper provides stakeholder insights which can ensure minimal consumer risk and sustainable use of the XR technology and Metaverse. While addressing the need for more research that uncovers the psychological effects of emerging technologies, so to prepare for the Metaverse. This is especially important when considering the current upsurge of these technologies and the uncertainties associated with their novelty and the idea of an 'always on' consumer.

2.
Arthrosc Sports Med Rehabil ; 6(1): 100854, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38169826

RESUMO

Purpose: To evaluate online, self-reported pudendal nerve or perineal injuries related to the use of a perineal post during hip arthroscopy. Methods: Public posts on Reddit and the Health Organization for Pudendal Education were searched to identify anonymous individuals reporting symptoms of pudendal nerve or perineal injury following hip arthroscopy. Included posts were by any individual with a self-reported history of hip arthroscopy who developed symptoms of pudendal nerve injury or damage to the perineal soft tissues. Demographic information and details about a person's symptoms and concerns were collected from each post. Descriptive statistics were used to analyze the data. Results: Twenty-three online posts reported on a perineal post-related complication following hip arthroscopy. Sex information was available in 16 (70%) posts (8 male, 8 female). Twenty-two posts reported a sensory injury, and 4 posts reported a motor injury with sexual consequences (sexual dysfunction, dyspareunia, impotence). Symptom duration was available in 15 (65%) posts (8 temporary, 7 permanent). Permanent symptoms included paresthesia of the perineum or genitals (7) and sexual complaints (5). Two posts stated they were counseled preoperatively about the possibility of this injury. Zero patients reported that a postless hip arthroscopy alternative was an option made available to them before surgery. Conclusions: A high incidence of permanent pudendal nerve, perineal skin, and genitourinary/sexual complications are self-reported and discussed online by patients who have undergone post-assisted hip arthroscopy. These patients report being uninformed and undereducated about the possibility of sustaining a post-related complication. No patient reported being informed of postless hip arthroscopy preoperatively. Clinical Relevance: Identifying and evaluating self-reported patient information in online medical forums can provide important information about patient experiences and outcomes.

3.
Stem Cells Transl Med ; 13(2): 177-190, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38016184

RESUMO

Stroke is a leading cause of death in the US and around the world but with limited treatment options. Survivors often present with long-term cognitive and neurological deficits. Stem cell-based therapy has emerged as a potential treatment for stroke. While stem cell transplantation in stroke has reached clinical trials, mostly safety outcomes have been reported with efficacy readouts warranting more studies. In an effort to optimize the stem cell regimen for stroke, here we conducted vis-a-vis comparison of different routes of transplantation, namely, intracerebral, intraarterial, and intranasal delivery of expanded human CD34 + stem cells, called ProtheraCytes, in the established stroke model of transient middle cerebral artery occlusion (MCAO) using adult Sprague-Dawley rats. After adjusting for the dose and subacute timing of cell delivery, animals were randomly assigned to receive either ProtheraCytes or vehicle. Motor and neurological assays from days 7 to 28 post-stroke revealed significant functional recovery across all 3 delivery routes of ProtheraCytes compared to vehicle-treated stroke rats. Additionally, ProtheraCytes-transplanted stroke rats displayed significantly reduced infarct size and cell loss in the peri-infarct area coupled with enhanced neurogenesis and angiogenesis compared to vehicle-treated stroke rats. These results highlight the safety and efficacy of transplanting ProtheraCytes, including via the minimally invasive intranasal route, in conferring robust and stable behavioral and histological positive outcomes in experimental stroke.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Humanos , Animais , Ratos Sprague-Dawley , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/patologia , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/patologia , Células-Tronco/patologia , Neurogênese , Isquemia Encefálica/terapia , Modelos Animais de Doenças , Recuperação de Função Fisiológica
4.
Cell Transplant ; 31: 9636897221102898, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35726847

RESUMO

Mesenchymal stem cell-derived exosomes (MSC-Exos) have been shown to promote angiogenesis. Treating MSCs with ischemic rat brain extracts was sufficient to augment their benefits in stroke. However, no similar analyses of ischemic heart extracts have been performed to date. We aim to determine whether MSC-Exos derived from MSCs pretreated with ischemic rat heart extract were able to promote angiogenesis and to clarify underlying mechanisms. ELISA (enzyme-linked immunosorbent assay) of heart extracts revealed a significant increase of vascular endothelial growth factor (VEGF) at 24 h post-MI (myocardial infarction) modeling, and time-dependent decreases in hypoxia inducible factor-1α (HIF-1α). MTT and wound healing assays revealed human umbilical vein endothelial cells (HUVECs) migration and proliferation increased following MSCE-Exo treatment (exosomes derived from MSC pretreated with ischemic heart extracts of 24 h post-MI) relative to MSCN-Exo treatment (exosomes derived from MSC pretreated with normal heart extracts). Proteomic analyses of MSCE-Exo and MSCN-Exo were conducted to screen for cargo proteins promoting angiogenesis. Result revealed several angiogenesis-related proteins were upregulated in MSCE-Exo, including DMBT1 (deleted in malignant brain tumors 1). When DMBT1 was silenced in MSCs, HUVECs with MSCDMBT1 RNAi-Exo treatment exhibited impaired proliferative and migratory activity and reductions of DMBT1, p-Akt, ß-catenin, and VEGF. To explore how ischemic heart extracts took effects, ELISA was conducted showing a significant increase of IL-22 at 24 h post-MI modeling. P-STAT3, IL22RA1, DMBT1, and VEGF proteins were increased in MSCE relative to MSCN, and VEGF and DMBT1 were increased in MSCE-Exos. Together, these suggest that IL-22 upregulation in ischemic heart extracts can increase DMBT1 in MSCs. Exosomes derived from those MSCs deliver DMBT1 to HUVECs, thereby enhancing their migratory and proliferative activity.


Assuntos
Exossomos , Células-Tronco Mesenquimais , Infarto do Miocárdio , Animais , Exossomos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Neovascularização Patológica , Neovascularização Fisiológica , Proteômica , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Cell Transplant ; 30: 9636897211035715, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34559583

RESUMO

Traumatic brain injury (TBI) is a pervasive and damaging form of acquired brain injury (ABI). Acute, subacute, and chronic cell death processes, as a result of TBI, contribute to the disease progression and exacerbate outcomes. Extended neuroinflammation can worsen secondary degradation of brain function and structure. Mesenchymal stem cell transplantation has surfaced as a viable approach as a TBI therapeutic due to its immunomodulatory and regenerative features. This article examines the role of inflammation and cell death in ABI as well as the effectiveness of bone marrow-derived mesenchymal stem/stromal cell (BM-MSC) transplants as a treatment for TBI. Furthermore, we analyze new studies featuring transplanted BM-MSCs as a neurorestorative and anti-inflammatory therapy for TBI patients. Although clinical trials support BM-MSC transplants as a viable TBI treatment due to their promising regenerative characteristics, further investigation is imperative to uncover innovative brain repair pathways associated with cell-based therapy as stand-alone or as combination treatments.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Inflamação/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Humanos
6.
Brain Circ ; 7(1): 29-32, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084974

RESUMO

Cholinergic efferent networks located from the medial septal nucleus to the hippocampus play a pivotal role in learning and memory outcomes by generating regular theta rhythms that enhance information retention. Hippocampal cholinergic neurostimulating peptide (HCNP), derived from the N-terminus of HCNP precursor protein (HCNP-pp), promotes the synthesis of acetylcholine in the medial septal nuclei. HCNP-pp deletion significantly reduced theta power in CA1 possibly due to lower levels of choline acetyltransferase-positive axons in CA1 stratum oriens, suggesting cholinergic disruptions in the septo-hippocampal system. This review also explores HCNP as a potent cholinergic regulator in the septo-hippocampal network while also examining the limitations of our understanding of the neurostimulating peptide.

7.
Antioxidants (Basel) ; 10(3)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33653014

RESUMO

Stroke is a life-threatening condition that is characterized by secondary cell death processes that occur after the initial disruption of blood flow to the brain. The inability of endogenous repair mechanisms to sufficiently support functional recovery in stroke patients and the inadequate treatment options available are cause for concern. The pathology behind oxidative stress in stroke is of particular interest due to its detrimental effects on the brain. The oxidative stress caused by ischemic stroke overwhelms the neutralization capacity of the body's endogenous antioxidant system, which leads to an overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and eventually results in cell death. The overproduction of ROS compromises the functional and structural integrity of brain tissue. Therefore, it is essential to investigate the mechanisms involved in oxidative stress to help obtain adequate treatment options for stroke. Here, we focus on the latest preclinical research that details the mechanisms behind secondary cell death processes that cause many central nervous system (CNS) disorders, as well as research that relates to how the neuroprotective molecular mechanisms of pituitary adenylate cyclase-activating polypeptides (PACAPs) could make these molecules an ideal candidate for the treatment of stroke.

8.
CNS Neurosci Ther ; 27(5): 505-514, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33464726

RESUMO

Various neurological disorders, such as stroke and Alzheimer's disease (AD), involve neuroinflammatory responses. The advent of the gut-brain axis enhances our understanding of neurological disease progression and secondary cell death. Gut microbiomes, especially those associated with inflammation, may reflect the dysbiosis of both the brain and the gut, opening the possibility to utilize inflammatory microbiomes as biomarkers and therapeutic targets. The gut-brain axis may serve as a contributing factor to disease pathology and offer innovative approaches in cell-based regenerative medicine for the treatment of neurological diseases. In reviewing the pathogenesis of stroke and AD, we also discuss the effects of gut microbiota on cognitive decline and brain pathology. Although the underlying mechanism of primary cell death from either disease is clearly distinct, both may be linked to gut-microbial dysfunction as a consequential aberration that is unique to each disease. Targeting peripheral cell death pathways that exacerbate disease symptoms, such as those arising from the gut, coupled with conventional central therapeutic approach, may improve stroke and AD outcomes.


Assuntos
Doença de Alzheimer/psicologia , Eixo Encéfalo-Intestino , Transtornos Cognitivos/etiologia , Disbiose/etiologia , Microbioma Gastrointestinal , Acidente Vascular Cerebral/complicações , Transtornos Cognitivos/microbiologia , Transtornos Cognitivos/psicologia , Disbiose/microbiologia , Disbiose/psicologia , Humanos , Acidente Vascular Cerebral/psicologia
9.
Adv Exp Med Biol ; 1312: 165-177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33159307

RESUMO

Stem cell-based therapy stands as a robust experimental treatment for ischemic stroke. Stem cells derived from fetal, embryonic, and adult tissues serve as potential sources for transplantable cells in the setting of ischemic stroke. However, the search continues for finding an optimal cell line for clinical use. Muse cells, a distinct subset of mesenchymal stem cells found sporadically in the connective tissue of nearly every organ, may be a suitable candidate due to its safety and accessibility. These cells have been investigated for therapeutic usage in chronic kidney disease, liver disease, acute myocardial infarction, and stroke. Muse cells display the ability to engraft and differentiate into the host neural network unlike many other cell lines which only display bystander immunomodulating effects. Taking advantage of this unique engraftment and differentiation mechanism behind Muse cells' therapeutic effects on the central nervous system, as well as other organ systems, will undoubtedly advance the cells' utility for cell-based regenerative medicine in stroke.


Assuntos
Células-Tronco Pluripotentes , Acidente Vascular Cerebral , Adulto , Alprostadil , Diferenciação Celular , Humanos , Museus , Medicina Regenerativa , Acidente Vascular Cerebral/terapia
10.
Stem Cell Rev Rep ; 17(1): 9-32, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32789802

RESUMO

The human population is in the midst of battling a rapidly-spreading virus- Severe Acute Respiratory Syndrome Coronavirus 2, responsible for Coronavirus disease 2019 or COVID-19. Despite the resurgences in positive cases after reopening businesses in May, the country is seeing a shift in mindset surrounding the pandemic as people have been eagerly trickling out from federally-mandated quarantine into restaurants, bars, and gyms across America. History can teach us about the past, and today's pandemic is no exception. Without a vaccine available, three lessons from the 1918 Spanish flu pandemic may arm us in our fight against COVID-19. First, those who survived the first wave developed immunity to the second wave, highlighting the potential of passive immunity-based treatments like convalescent plasma and cell-based therapy. Second, the long-term consequences of COVID-19 are unknown. Slow-progressive cases of the Spanish flu have been linked to bacterial pneumonia and neurological disorders later in life, emphasizing the need to reduce COVID-19 transmission. Third, the Spanish flu killed approximately 17 to 50 million people, and the lack of human response, overcrowding, and poor hygiene were key in promoting the spread and high mortality. Human behavior is the most important strategy for preventing the virus spread and we must adhere to proper precautions. This review will cover our current understanding of the pathology and treatment for COVID-19 and highlight similarities between past pandemics. By revisiting history, we hope to emphasize the importance of human behavior and innovative therapies as we wait for the development of a vaccine. Graphical Abstract.


Assuntos
COVID-19/terapia , Terapia Baseada em Transplante de Células e Tecidos , COVID-19/patologia , COVID-19/prevenção & controle , COVID-19/virologia , História do Século XX , Humanos , Imunização Passiva , Influenza Pandêmica, 1918-1919/história , Pandemias/história , Medicina Regenerativa/história , SARS-CoV-2/patogenicidade , Soroterapia para COVID-19
11.
Cells ; 9(9)2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32932814

RESUMO

Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood-brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke.


Assuntos
Barreira Hematoencefálica/patologia , Células Endoteliais/metabolismo , Células-Tronco/patologia , Acidente Vascular Cerebral/genética , Animais , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Acidente Vascular Cerebral/metabolismo
12.
Biomolecules ; 10(9)2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899709

RESUMO

Stroke serves as a life-threatening disease and continues to face many challenges in the development of safe and effective therapeutic options. The use of hyperbaric oxygen therapy (HBOT) demonstrates pre-clinical effectiveness for the treatment of acute ischemic stroke and reports reductions in oxidative stress, inflammation, and neural apoptosis. These pathophysiological benefits contribute to improved functional recovery. Current pre-clinical and clinical studies are testing the applications of HBOT for stroke neuroprotection, including its use as a preconditioning regimen. Mild oxidative stress may be able to prime the brain to tolerate full extensive oxidative stress that occurs during a stroke, and HBOT preconditioning has displayed efficacy in establishing such ischemic tolerance. In this review, evidence on the use of HBOT following an ischemic stroke is examined, and the potential for HBOT preconditioning as a neuroprotective strategy. Additionally, HBOT as a stem cell preconditioning is also discussed as a promising strategy, thus maximizing the use of HBOT for ischemic stroke.


Assuntos
Oxigenoterapia Hiperbárica/métodos , AVC Isquêmico/terapia , Fármacos Neuroprotetores/uso terapêutico , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Humanos , Precondicionamento Isquêmico/métodos , Óxido Nítrico/metabolismo , Respiração , Células-Tronco
13.
Antioxidants (Basel) ; 9(8)2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32731545

RESUMO

Secreted by the pineal gland to regulate the circadian rhythm, melatonin is a powerful antioxidant that has been used to combat oxidative stress in the central nervous system. Melatonin-based therapies have been shown to provide neuroprotective effects in the setting of ischemic stroke by mitigating neuroinflammation and accelerating brain tissue restoration. Melatonin treatment includes injection of exogenous melatonin, pineal gland grafting and melatonin-mediated stem cell therapy. This review will discuss the current preclinical and clinical studies investigating melatonin-based therapeutics to treat stroke.

14.
Pharmaceutics ; 12(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32630218

RESUMO

Stroke is a devastating condition characterized by widespread cell death after disruption of blood flow to the brain. The poor regenerative capacity of neural cells limits substantial recovery and prolongs disruptive sequelae. Current therapeutic options are limited and do not adequately address the underlying mitochondrial dysfunction caused by the stroke. These same mitochondrial impairments that result from acute cerebral ischemia are also present in retinal ischemia. In both cases, sufficient mitochondrial activity is necessary for cell survival, and while astrocytes are able to transfer mitochondria to damaged tissues to rescue them, they do not have the capacity to completely repair damaged tissues. Therefore, it is essential to investigate this mitochondrial transfer pathway as a target of future therapeutic strategies. In this review, we examine the current literature pertinent to mitochondrial repair in stroke, with an emphasis on stem cells as a source of healthy mitochondria. Stem cells are a compelling cell type to study in this context, as their ability to mitigate stroke-induced damage through non-mitochondrial mechanisms is well established. Thus, we will focus on the latest preclinical research relevant to mitochondria-based mechanisms in the treatment of cerebral and retinal ischemia and consider which stem cells are ideally suited for this purpose.

15.
J Clin Neuromuscul Dis ; 15(1): 28-33, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23965407

RESUMO

Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited autosomal dominant disorder that causes a polyneuropathy with predisposition for involvement at sites of compression and is often underdiagnosed or misdiagnosed due to its heterogeneity in clinical and electrophysiological presentation. We report 2 cases of HNPP, which were initially diagnosed and treated as either an acquired demyelinating disorder or alternative inherited demyelinating disorder. Thorough evaluation of repeat electrodiagnostic studies and genetic testing confirmed the diagnosis of HNPP in both cases. One case showed the classic peripheral myelin protein 22 (PMP22) deletion and the other case showed a previously reported single base pair deletion at Leu145 causing a frameshift mutation at the PMP22 gene. These cases underscore the difficulty of diagnosing HNPP, because of the variations in clinical and electrophysiological findings and reinforce the importance of a combination high index of clinical suspicion, electrodiagnostic testing, and genetic testing to make the diagnosis.


Assuntos
Artrogripose/diagnóstico , Erros de Diagnóstico , Eletrofisiologia , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Artrogripose/genética , Doenças Desmielinizantes/diagnóstico , Feminino , Neuropatia Hereditária Motora e Sensorial/genética , Humanos , Masculino , Mutação , Proteínas da Mielina/genética , Deleção de Sequência , Adulto Jovem
16.
Am J Surg Pathol ; 28(1): 1-30, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14707860

RESUMO

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive "grungy" calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.


Assuntos
Biomarcadores Tumorais/análise , Mesenquimoma/patologia , Osteomalacia/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/complicações , Neoplasias Ósseas/patologia , Criança , Diagnóstico Diferencial , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Imuno-Histoquímica , Masculino , Mesenquimoma/complicações , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias de Tecidos Moles/complicações , Neoplasias de Tecidos Moles/patologia
17.
Am J Hum Genet ; 73(2): 314-22, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12858292

RESUMO

Although the molecular basis of pseudohypoparathyroidism type 1b (PHP type 1b) remains unknown, a defect in imprinting at the GNAS1 locus has been suggested by the consistent finding of paternal-specific patterns of DNA methylation on maternally inherited GNAS1 alleles. To characterize the relationship between the genetic and epigenetic defects in PHP type 1b, we analyzed allelic expression and methylation of CpG islands within exon 1A of GNAS1 in patients with sporadic PHP type 1b and in affected and unaffected individuals from five multigenerational kindreds with PHP type 1b. All subjects with resistance to parathyroid hormone (PTH) showed loss of methylation of the exon 1A region on the maternal GNAS1 allele and/or biallelic expression of exon 1A-containing transcripts, consistent with an imprinting defect. Paternal transmission of the disease-associated haplotype was associated with normal patterns of GNAS1 methylation and PTH responsiveness. We found that affected and unaffected siblings in one kindred had inherited the same GNAS1 allele from their affected mother, evidence for dissociation between the genetic and epigenetic GNAS1 defects. The absence of the epigenetic defect in subjects who have inherited a defective maternal GNAS1 allele suggests that the genetic mutation may be incompletely penetrant, and it indicates that the epigenetic defect, not the genetic mutation, leads to renal resistance to PTH in PHP type 1b.


Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Impressão Genômica , Pseudo-Hipoparatireoidismo/genética , Alelos , Sequência de Bases , Ilhas de CpG , Metilação de DNA , DNA Complementar/química , DNA Complementar/genética , Éxons , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Pseudo-Hipoparatireoidismo/classificação
18.
J Bone Miner Res ; 18(3): 424-33, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12619926

RESUMO

Pseudohypoparathyroidism (PHP) is characterized by biochemical hypoparathyroidism with elevated parathyroid hormone levels owing to reduced target tissue responsiveness to parathyroid hormone. Patients with PHP la have somatic defects termed Albright's hereditary osteodystrophy (AHO) and exhibit resistance to additional hormones because of heterozygous mutations in the GNAS1 gene that lead to a generalized deficiency of the a subunit of Gs, the heterotrimeric G protein that couples receptors to adenylyl cyclase. By contrast, patients with PHP 1b lack AHO and have selective parathyroid hormone (PTH) resistance, presumably because of an imprinting defect that impairs expression of G(s)alpha in the proximal renal tubule. Although an epigenetic defect in GNAS1 has been identified in subjects with PHP1b, the genetic defect is unknown. To define the genetic defect in PHP 1b, we performed a genome-wide linkage analysis in five multi-generational PHP lb families. Of the 408 polymorphic microsatellite markers examined, markers located on chromosome 20q13.3, the region containing GNAS1, demonstrated linkage to PHP lb. Fine-mapping and multipoint linkage analysis of this region demonstrated linkage to a 5.7-cM region between 907rep2 and the telomere. Haplotype analysis established that affected individuals shared a 5-cM region including part of the GNAS1 gene to the telomere. Our data confirm that PHP1b is linked to a region that includes GNAS1, and further refine the locus, although the primary genetic mutation(s) that causes defective imprinting of GNAS1 remains undefined.


Assuntos
Cromossomos Humanos Par 20 , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Ligação Genética , Pseudo-Hipoparatireoidismo/genética , Sequência de Bases , Mapeamento Cromossômico , Primers do DNA , Feminino , Humanos , Masculino , Linhagem
19.
J Bone Miner Res ; 17(6): 1102-10, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12054166

RESUMO

Oncogenic osteomalacia (OOM) is associated with primitive mesenchymal tumors that secrete phosphaturic factors resulting in low serum concentrations of phosphate and calcitriol, phosphaturia, and defective bone mineralization. To identify overexpressed genes in these tumors, we compared gene expression profiles of tumors resected from patients with OOM and histologically similar control tumors using serial analysis of gene expression (SAGE). Three hundred and sixty-four genes were expressed at least twofold greater in OOM tumors compared with control tumors. A subset of 67 highly expressed genes underwent validation with an extended set of OOM and control tumors using array analysis or reverse-transcription polymerase chain reaction (RT-PCR). Ten of these validated genes were consistently overexpressed in all OOM tumors relative to control tumors. Strikingly, genes with roles in bone matrix formation, mineral ion transport, and bone mineralization were highly expressed in the OOM tumors.


Assuntos
Neoplasias Ósseas/genética , Osso e Ossos/metabolismo , Perfilação da Expressão Gênica , Osteomalacia/genética , Sequência de Bases , Neoplasias Ósseas/metabolismo , Calcitriol/metabolismo , Cálcio/metabolismo , Primers do DNA , Humanos , Osteomalacia/metabolismo , Hormônio Paratireóideo/metabolismo , Fósforo/metabolismo , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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