RESUMEN
The aim of the present prospective study was to evaluate periodontal health and subgingival microbiological alterations in adolescents treated with fixed self ligating orthodontic brackets in comparison to subject without any orthodontic appliance. A total of 40 adolescents (23 females and 17 males; mean age: 13.2 ± 3.2 years) were included: 30 subjects with self ligating brackets (test group) and 10 patients without orthodontic appliances (control group). Follow-ups were as follows: T1 (1 month), T2 (3 months), T3 (6 months) from the beginning of the orthodontic therapy. Clinical parameters (plaque index, gingival index and clinical attachment level) were measured for every patient and a microbiological analysis was performed. Mann Whitney test was performed to evaluate clinical parameters between test and control group and Friedman test and Fisher test were adopted to evaluate intra group differences at different follow-ups. Student T-test was performed to compare clinical attachment level between the two groups. Significance level was set at p<0.05. No periodontal pathogens and no clinical attachment loss were found in the whole sample. A slightly higher plaque index and gingival inflammation were recorded in the test group in comparison to the controls.
Asunto(s)
Gingivitis , Soportes Ortodóncicos , Adolescente , Biopelículas , Niño , Índice de Placa Dental , Femenino , Humanos , Masculino , Índice Periodontal , Estudios ProspectivosRESUMEN
It is well known that greenish pigmentation of the teeth is seen in children following remission of severe jaundice and clinical and serum bilirubin, a degradation product of haemoglobin, may be permanently trapped in forming dental hard tissues causing discolouration and enamel and dentine hypoplasia. Neonatal jaundice is the most common cause of hyperbilirubinemia and pigmentation of the deciduous teeth is the consequence of this condition. Various hepatobiliary pathologies may have a clinical finding in the oral cavity; furthermore, oral manifestations of hepatic pathologies are not just limited to the pigmentation of the deciduous teeth but also the permanent dentition and the mucous membranes can be affected.
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Enfermedades del Sistema Digestivo , Trastornos de la Pigmentación , Decoloración de Dientes , Niño , Humanos , Recién Nacido , Diente PrimarioRESUMEN
Serial muscle biopsies within clinical trials for Duchenne muscular dystrophy (DMD) are critical to document therapeutic responses. Less invasive means of sampling muscle are needed. We analyzed a retrospective consecutive case-series cohort of vacuum-assisted core needle muscle biopsy procedures performed on healthy and dystrophic individuals at a single institution assessing for safety and reliability of obtaining sufficient high-quality biopsy tissue for histologic assessment in adult and pediatric subjects. Of 471 muscle cores from 128 biopsy procedures, 377-550 mg of total muscle tissue was obtained per procedure with mean core weight of 129 mg (SD, 25.1 mg). All biopsies were adequate for histological assessment. There were no significant adverse events. This core needle biopsy approach, when combined with improved sample processing, provides a safe means to consistently obtain muscle samples for diagnostic and clinical trial applications.
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Biopsia con Aguja Gruesa/métodos , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/patología , Adolescente , Adulto , Anciano , Anestésicos Locales/uso terapéutico , Biopsia con Aguja Gruesa/instrumentación , Estudios de Casos y Controles , Niño , Preescolar , Sedación Consciente , Femenino , Humanos , Biopsia Guiada por Imagen , Masculino , Persona de Mediana Edad , Dolor Asociado a Procedimientos Médicos/prevención & control , Reproducibilidad de los Resultados , Manejo de Especímenes/métodos , Conservación de Tejido/métodos , Ultrasonografía , Vacio , Adulto JovenRESUMEN
Sjögren's Syndrome is a complex disease, due to an autoimmune physiopathology, that strongly impacts both patients' primary needs (nutrition and speaking), and patients' relationship life related factors (psychological health and quality of life). In Literature, few studies had investigated oral health status in Sjögren's syndrome and its impact on patients' quality of life, so the aim of this study was to analyse that issue. 30 patients were enrolled, within the Department of Rheumatology (University of Pisa), both first diagnosis patients' and both patients who had been diagnosed with Sjögren's syndrome in the past. For each patient, a medical record was filled out together with the compilation of the Oral Health Impact Profile questionnaire. Then, during a specialistic rheumatologic visit, Sjögren's Syndrome Disease Damage Index Score (SSDDI) was determined. Results showed a direct proportion between years from diagnosis and severity of oral health issues. It was found that these issues were related to soft tissue damage and an overall worse, reported quality of life and psychological health.
Asunto(s)
Salud Bucal , Síndrome de Sjögren , Estudios Transversales , Humanos , Calidad de Vida , Síndrome de Sjögren/epidemiología , Encuestas y CuestionariosRESUMEN
Antisense oligonucleotide (AON)-mediated exon skipping is an emerging therapeutic for individuals with Duchenne muscular dystrophy (DMD). Skipping of exons adjacent to common exon deletions in DMD using AONs can produce in-frame transcripts and functional protein. Targeted skipping of DMD exons 8, 44, 45, 50, 51, 52, 53, and 55 is predicted to benefit 47% of affected individuals. We observed a correlation between mutation subgroups and age at loss of ambulation in the Duchenne Registry, a large database of phenotypic and genetic data for DMD (N = 765). Males amenable to exon 44 (N = 74) and exon 8 skipping (N = 18) showed prolonged ambulation compared to other exon skip groups and nonsense mutations (P = 0.035 and P < 0.01, respectively). In particular, exon 45 deletions were associated with prolonged age at loss of ambulation relative to the rest of the exon 44 skip amenable cohort and other DMD mutations. Exon 3-7 deletions also showed prolonged ambulation relative to all other exon 8 skippable mutations. Cultured myotubes from DMD patients with deletions of exons 3-7 or exon 45 showed higher endogenous skipping than other mutations, providing a potential biological rationale for our observations. These results highlight the utility of aggregating phenotypic and genotypic data for rare pediatric diseases to reveal progression differences, identify potentially confounding factors, and probe molecular mechanisms that may affect disease severity.
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Distrofina/genética , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Oligodesoxirribonucleótidos Antisentido/genética , Adolescente , Adulto , Factores de Edad , Biopsia , Codón sin Sentido/genética , Distrofina/antagonistas & inhibidores , Exones/genética , Femenino , Fibroblastos/patología , Genotipo , Humanos , Estimación de Kaplan-Meier , Tiempo de Internación , Masculino , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/patología , Distrofia Muscular de Duchenne/terapia , Mioblastos/patología , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Cultivo Primario de Células , Sistema de Registros , Eliminación de Secuencia/genética , Caracteres Sexuales , Adulto JovenRESUMEN
Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129∗]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024∗]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.
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Codón sin Sentido/genética , Discapacidades del Desarrollo/genética , Histona Acetiltransferasas/genética , Microcefalia/genética , Anomalías Múltiples/genética , Acetilación , Preescolar , Exoma , Femenino , Heterocigoto , Histona Acetiltransferasas/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Mutación , LinajeRESUMEN
The effect of oral hygiene education measures and professional tooth cleaning on the salivary levels of microbial species with high cariogenic potential (i.e. Streptococcus mutans, Lactobacillus spp. and Candida albicans) was evaluated at different time points. At time 0, high salivary carriage rates were recorded in the study group (n=30). Fifty percent of the subjects harbored all three species in their saliva, 27% harbored 2 species, and 23% only one species. At 3 months after oral hygiene measures, a statistically significant reduction was observed in salivary count of S. mutans and Lactobacillus spp. The percentage of subjects harboring all three species was also highly reduced, along with an overall improvement of clinical and risk factors parameters. At 8 months after oral hygiene measures, S. mutans and Lactobacillus spp. load was still statistically lower than that recorded at time 0, although an increment in bacterial load and a partial worsening of clinical and risk factors parameters were observed. S. mutans count in saliva inversely correlated with salivary pH, while it positively correlated with C. albicans salivary levels. The results obtained suggest that strengthening of the motivation and administration of oral hygiene instructions and professional tooth cleaning every 6-8 months, might be necessary to control salivary levels of cariogenic species.
Asunto(s)
Candida albicans/aislamiento & purificación , Caries Dental/microbiología , Lactobacillus/aislamiento & purificación , Higiene Bucal , Saliva/microbiología , Streptococcus mutans/aislamiento & purificación , Humanos , Estudios LongitudinalesRESUMEN
Our understanding of muscle glycosylation to date has derived from studies in mouse models and a limited number of human lectin histochemistry studies. As various therapeutic approaches aimed at treating patients with muscular dystrophies are being translated from rodent models to human, it is critical to better understand human muscle glycosylation and relevant disease-specific differences between healthy and dystrophic muscle. Here, we report the first quantitative characterization of human muscle glycosylation, and identify differentiation- and disease-specific differences in human muscle glycosylation. Utilizing a panel of 13 lectins with varying glycan specificities, we surveyed lectin binding to primary and immortalized myoblasts and myotubes from healthy and dystrophic sources. Following differentiation of primary and immortalized healthy human muscle cells, we observed increased binding of Narcissus pseudonarcissus agglutinin (NPA), PNA, MAA-II and WFA to myotubes compared to myoblasts. Following differentiation of immortalized healthy and dystrophic human muscle cells, we observed disease-specific differences in binding of NPA, Jac and Tricosanthes japonica agglutinin-I (TJA-I) to differentiated myotubes. We also observed differentiation- and disease-specific differences in binding of NPA, Jac, PNA, TJA-I and WFA to glycoprotein receptors in muscle cells. Additionally, Jac, PNA and WFA precipitated functionally glycosylated α-DG, that bound laminin, while NPA and TJA-I did not. Lectin histochemistry of healthy and dystrophic human muscle sections identified disease-specific differences in binding of O-glycan and sialic acid-specific lectins between healthy and dystrophic muscle. These results indicate that specific and discrete changes in glycosylation occur following differentiation, and identify specific lectins as potential biomarkers sensitive to changes in healthy human muscle glycosylation.
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Glicoproteínas/metabolismo , Proteínas Musculares/metabolismo , Distrofias Musculares/metabolismo , Mioblastos Esqueléticos/metabolismo , Narcissus/química , Lectinas de Plantas/farmacología , Línea Celular Transformada , Glicoproteínas/química , Humanos , Proteínas Musculares/química , Distrofias Musculares/patología , Mioblastos Esqueléticos/química , Mioblastos Esqueléticos/patología , Lectinas de Plantas/químicaRESUMEN
Noise coming from urban traffic, household appliances or discotheques might be as hazardous to the health of exposed people as occupational noise, because may likewise cause hearing loss, changes in hormonal, cardiovascular and immune systems and behavioral alterations. Besides, noise can affect sleep, work performance and productivity as well as communication skills. Moreover, exposure to noise can trigger an oxidative imbalance between reactive oxygen species (ROS) and the activity of antioxidant enzymes in different structures, which can contribute to tissue damage. In this review we systematized the information from reports concerning noise effects on cell oxidative balance in different tissues, focusing on auditory and non-auditory structures. We paid specific attention to in vivo studies, including results obtained in adult and developing subjects. Finally, we discussed the pharmacological strategies tested by different authors aimed to minimize the damaging effects of noise on living beings.
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Envejecimiento/fisiología , Oído/fisiología , Ruido/efectos adversos , Estrés Oxidativo , Animales , Especies Reactivas de Oxígeno/metabolismoRESUMEN
CD8(+) T cells respond to TCR stimulation by producing proinflammatory cytokines, and destroying infected or malignant cells through the production and release of cytotoxic granules. Scaffold protein Discs large homolog 1 (Dlg1) specifies TCR-dependent functions by channeling proximal signals toward the activation of p38-dependent proinflammatory cytokine gene expression and/or p38-independent cytotoxic granule release. Two Dlg1 variants are expressed in CD8(+) T cells via alternative splicing, Dlg1AB and Dlg1B, which have differing abilities coordinate TCR-dependent functions. Although both variants facilitate p38-independent cytotoxicity, only Dlg1AB coordinates p38-dependent proinflammatory cytokine expression. In this study, we identify TCR-induced Dlg1 tyrosine phosphorylation as a key regulatory step required for Dlg1AB-mediated p38-dependent functions, including proinflammatory cytokine expression. We find that Dlg1AB but not Dlg1B is tyrosine phosphorylated by proximal tyrosine kinase Lck in response to TCR stimulation. Furthermore, we identify Dlg1 tyrosine 222 (Y222) as a major site of Dlg1 phosphorylation required for TCR-triggered p38 activation and NFAT-dependent expression of proinflammatory cytokines, but not for p38-independent cytotoxicity. Taken together, our data support a model where TCR-induced phosphorylation of Dlg1 Y222 is a key point of control that endows Dlg1AB with the ability to coordinate p38 activation and proinflammatory cytokine production. We propose blocking Dlg1AB phosphorylation as a novel therapeutic target to specifically block proinflammatory cytokine production but not cytotoxicity.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Citocinas/biosíntesis , Proteínas del Tejido Nervioso/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Comunicación Celular/inmunología , Homólogo 1 de la Proteína Discs Large , Activación Enzimática/inmunología , Inflamación/inmunología , Activación de Linfocitos/inmunología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Fosforilación , Isoformas de Proteínas/inmunología , Proteínas Asociadas a SAP90-PSD95 , Alineación de Secuencia , Transducción de Señal/inmunología , Tirosina/químicaRESUMEN
OBJECTIVES: Fibroblast growth factor-23 (FGF-23) and vitamin D are hormones involved in phosphate homoeostasis. They also directly influence cardiomyocyte hypertrophy. We examined whether the relationships between levels of vitamin D or FGF-23, cardiac phenotype and outcome were independent of established cardiac biomarkers in a large cohort of community-dwelling elderly subjects. DESIGN AND SETTING: Plasma levels of FGF-23 and vitamin D were measured in 1851 men and women (65-84 years) resident in the Lazio region of Italy. Participants were referred to eight cardiology centres for clinical examination, electrocardiography, comprehensive Doppler echocardiography and blood sampling. All-cause mortality or hospitalizations were available after a median follow-up of 47 months with record linkage of administrative data. RESULTS: Vitamin D deficiency (<20 ng mL(-1) ) was found in 72.3% of subjects, but FGF-23 levels were normal [74 (58-97) RU per mL]. After adjustment for cardiovascular risk factors and morbidities, low concentrations of vitamin D and high levels of FGF-23 were associated with a higher left ventricular (LV) mass index. Levels of FGF-23 [hazard ratio (HR) (95% confidence interval (CI)) 1.71 (1.28-2.28), P < 0.0001] but not vitamin D [0.76 (0.57-1.01), P = 0.08] were independently associated with mortality after adjustment for clinical risk factors and two cardiac markers together (N-terminal pro-brain natriuretic peptide and high-sensitivity cardiac troponin T), but did not predict hospital admission. People with above median values of FGF-23 and below median values of vitamin D had greater LV hypertrophy and higher mortality. CONCLUSIONS: In community-dwelling elderly individuals with highly prevalent vitamin D deficiency, FGF-23 levels were associated with LV hypertrophy and predicted mortality independently of two robust cardiac biomarkers. A causal relationship was not demonstrated, but the hormones involved in mineral metabolism emerged as nontraditional risk factors and may affect cardiovascular risk.
Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Hipertrofia Ventricular Izquierda/etiología , Vitamina D/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Estudios Transversales , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Hipertrofia Ventricular Izquierda/sangre , Masculino , Fenotipo , Pronóstico , Factores de Riesgo , Deficiencia de Vitamina D/complicacionesRESUMEN
Donors not meeting standard criteria, such as those with bacteremia, are now being used in response to the increasing need for organs for transplantation. Recommended strategies to prevent the occurrence of donor-derived bacteremia include the use of directed antibiotic prophylaxis. However, this approach does not eliminate the risk of infection transmission. Similarly, the management of organ recipients from donors with infective endocarditis (IE) remains uncharacterized. We report 2 cases of donor-derived bacterial infections in liver transplant recipients despite pathogen-specific antibiotic prophylaxis. In both instances, the donors had documented IE treated with appropriate antimicrobial therapy and clearance of bacteremia. Recipients had very distinctive clinical outcomes likely related to pathogen virulence and the extent of donor infection. Persistent infection in the transplanted liver should be suspected in organ recipients of a liver from donors with IE, despite the absence of bacteremia at the time of death and organ procurement. For eradication, recipients may require prolonged pathogen-directed antimicrobial therapy, such as is used for endovascular infections. Prompt recognition of donors with IE, appropriate notification, and prolonged antibiotic prophylaxis are key to reducing the risk of such donor-derived infections.
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Antibacterianos/uso terapéutico , Profilaxis Antibiótica , Endocarditis Bacteriana/transmisión , Infecciones por Bacterias Grampositivas/transmisión , Infecciones Estafilocócicas/transmisión , Adulto , Bacteriemia , Endocarditis Bacteriana/prevención & control , Enterococcus faecalis/efectos de los fármacos , Femenino , Infecciones por Bacterias Grampositivas/prevención & control , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Persona de Mediana Edad , Infecciones Estafilocócicas/prevención & control , Staphylococcus aureus/efectos de los fármacos , Donantes de Tejidos , Obtención de Tejidos y Órganos , Receptores de TrasplantesRESUMEN
OBJECTIVES: To estimate the influence of educational level and oral hygiene behaviours on the prevalence and severity of dental caries and periodontal disease in an adult Italian population attending the Oral Hygiene department of a public Dental Clinic. METHODS: Dental caries was diagnosed according to the World Health Organization criteria. The DMFT index (decayed, missing, filled tooth) was used to record the dental caries' experience. The periodontal status was assessed using the community periodontal index of treatment needs (CPITN). Questionnaires on educational level and oral hygiene behaviours were also collected. RESULTS: A total of 350 patients were enrolled. The mean DMFT value reported was 4.37 ± 3.06, and higher values were observed for male patients (P < 0.05). Increased CPITN scores and DMFT values were significantly correlated with lower level of education (P < 0.05). Subjects of high educational status showed significantly better oral hygiene habits (P < 0.05). CONCLUSIONS: The oral health status, in terms of periodontal disease and dental caries, appears correlated with patients' educational level.
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Índice CPO , Escolaridad , Conductas Relacionadas con la Salud , Higiene Bucal/estadística & datos numéricos , Índice Periodontal , Adulto , Estudios Transversales , Atención Odontológica/estadística & datos numéricos , Caries Dental/epidemiología , Dispositivos para el Autocuidado Bucal/estadística & datos numéricos , Restauración Dental Permanente/estadística & datos numéricos , Estudios Epidemiológicos , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Enfermedades Periodontales/epidemiología , Prevalencia , Factores Sexuales , Fumar/epidemiología , Pérdida de Diente/epidemiología , Cepillado Dental/estadística & datos numéricosRESUMEN
Clostridium difficile infection (CDI) occurs in 3-7% of liver transplant recipients (LTR). However, few data exist on the recent epidemiology, predictors and outcomes of CDI in LTR. A cohort study was performed including LTR from 2000 to 2010 at a tertiary care hospital in Detroit. CDI was defined as diarrhea with a stool C. difficile positive test. Data analyzed included demographics, comorbidities, length of stay (LOS), severity of CDI, rates of recurrence (<12 weeks), relapse (<4 weeks) and overall mortality. Predictors of CDI were calculated using Cox proportional hazard model; 970 LTR were followed for years. Overall prevalence of CDI was 18.9%. Incidence of CDI within 1 year of transplant was 12.4%. Severe CDI occurred in 29.1%. CDI recurrence and relapse rates were 16.9% and 9.7%, respectively. Independent predictors of CDI were year of transplant (hazard ratio [HR] 1.137, 95% confidence interval [CI] 1.06-1.22; p < 0.001), white race (105/162 whites, HR 1.47, 95% CI 1.03-2.1; p = 0.035), Model for End-Stage Liver Disease score (HR 1.03, 95% CI 1.01-1.045, p = 0.003) and LOS (HR 1.01, 95% CI 1.005-1.02, p < 0.001). Significant mortality was observed among LTR with CDI compared to those without CDI (p = 0.003). We concluded that CDI is common among LTR and is associated with higher mortality.
Asunto(s)
Infecciones por Clostridium/epidemiología , Fallo Hepático/cirugía , Trasplante de Hígado , Adulto , Clostridioides difficile , Comorbilidad , Diarrea/microbiología , Enfermedad Hepática en Estado Terminal/epidemiología , Enfermedad Hepática en Estado Terminal/microbiología , Femenino , Humanos , Enfermedades Intestinales/microbiología , Tiempo de Internación , Fallo Hepático/microbiología , Masculino , Michigan , Persona de Mediana Edad , Prevalencia , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Osteogenesis imperfecta (OI) is a rare phenotypically and genetically heterogeneous group of inherited skeletal dysplasias. The hallmark features of OI include bone fragility and susceptibility to fractures, bone deformity, and diminished growth, along with a plethora of associated secondary features (both skeletal and extraskeletal). The diagnosis of OI is currently made on clinical grounds and may be confirmed by genetic testing. However, imaging remains pivotal in the evaluation of this disease. The aim of this article is to review the current role played by the various radiologic techniques in the diagnosis and monitoring of OI in the postnatal setting as well as to discuss recent advances and future perspectives in OI imaging. Conventional Radiography and Dual-energy X-ray Absorptiometry (DXA) are currently the two most used imaging modalities in OI. The cardinal radiographic features of OI include generalized osteopenia/osteoporosis, bone deformities, and fractures. DXA is currently the most available technique to assess Bone Mineral Density (BMD), specifically areal BMD (aBMD). However, DXA has important limitations and cannot fully characterize bone fragility in OI based on aBMD. Novel DXA-derived parameters, such as Trabecular Bone Score (TBS), may provide further insight into skeletal changes induced by OI, but evidence is still limited. Techniques like Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) can be useful as problem-solvers or in specific settings, including the evaluation of cranio-cervical abnormalities. Recent evidence supports the use of High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) as a promising tool to improve the characterization of bone fragility in OI. However, HR-pQCT remains a primarily research technique at present. Quantitative Computed Tomography (QCT) is an alternative to DXA for the determination of BMD at central sites, with distinct advantages but considerably higher radiation exposure. Quantitative Ultrasound (QUS) is a portable, inexpensive, and radiation-free modality that may complement DXA evaluation, providing information on bone quality. However, evidence of usefulness of QUS in OI is poor. Radiofrequency Echographic Multi Spectrometry (REMS) is an emerging non-ionizing imaging method that holds promise for the diagnosis of low BMD and for the prediction of fracture risk, but so far only one published study has investigated its role in OI. To conclude, several different radiologic techniques have proven to be effective in the diagnosis and monitoring of OI, each with their own specificities and peculiarities. Clinicians should be aware of the strategic role of the various modalities in the different phases of the patient care process. In this scenario, the development of international guidelines including recommendations on the role of imaging in the diagnosis and monitoring of OI, accompanied by continuous active research in the field, could significantly improve the standardization of patient care.
Asunto(s)
Fracturas Óseas , Osteogénesis Imperfecta , Osteoporosis , Humanos , Osteogénesis Imperfecta/diagnóstico por imagen , Osteogénesis Imperfecta/genética , Osteogénesis Imperfecta/patología , Densidad Ósea , Absorciometría de Fotón/métodos , Fracturas Óseas/diagnóstico por imagenRESUMEN
OBJECTIVE: To investigate the association between circulating cardiac biomarkers and minor abnormalities in cardiac phenotype [left ventricular (LV) mass and midwall fractional shortening (MFS)] in elderly individuals in a general population sample. DESIGN AND SETTING: We examined the relationship between plasma concentrations of high-sensitivity cardiac troponin T (hs-cTnT) or N-terminal probrain natriuretic peptide (NT-proBNP) and elevated LV mass (LV mass/body surface area >95 g m(-2) for women and 115 g m(-2) for men), reduced MFS (<15%) or isolated LV diastolic dysfunction in 1973 elderly subjects (mean age 73 ± 5 years, range 65-84) resident in the Lazio region of Italy and enrolled in the PREDICTOR study. RESULTS: Overall, 24.8% of subjects had elevated LV mass, and 30.4% had reduced MFS. Median [quartile 1-3] plasma concentrations of hs-cTnT and NT-proBNP were higher in individuals with elevated than those with normal LV mass: 6.6 [3.5-11.6] and 147 [64-296] ng L(-1) vs. 4.6 [3.0-8.1] and 79 [41-151] ng L(-1) respectively (P < 0.001). There was a graded increase in median hs-cTnT concentrations across clinical categories of LV hypertrophy: 4.6 [3.0-8.1], 5.8 [3.1-10.2], 7.6 [3.8-13.7] and 8.4 [3.8-17.6] ng L(-1) for subjects with normal LV mass and mild, moderate or severe LV hypertrophy respectively (P < 0.0001); hs-cTnT also increased with increasing quartiles of MFS or grades of isolated LV diastolic dysfunction. CONCLUSIONS: Within an extremely low range of concentrations, increased hs-cTnT amongst community-dwelling elderly subjects is associated with subtle alterations in cardiac phenotype, suggesting that minor injury to cardiac myocytes and subsequent release of troponin reflect subclinical pathophysiological LV deterioration in this population.
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Troponina T/sangre , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/fisiopatología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Estudios Transversales , Cistatina C/sangre , Ecocardiografía Doppler en Color , Femenino , Humanos , Masculino , Miocitos Cardíacos/patología , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Fenotipo , Troponina T/metabolismoRESUMEN
TCR engagement triggers the polarized recruitment of membrane, actin, and transducer assemblies within the T cell-APC contact that amplify and specify signaling cascades and T effector activity. We report that caveolin-1, a scaffold that regulates polarity and signaling in nonlymphoid cells, is required for optimal TCR-induced actin polymerization, synaptic membrane raft polarity, and function in CD8, but not CD4, T cells. In CD8(+) T cells, caveolin-1 ablation selectively impaired TCR-induced NFAT-dependent NFATc1 and cytokine gene expression, whereas caveolin-1 re-expression promoted NFATc1 gene expression. Alternatively, caveolin-1 ablation did not affect TCR-induced NF-κB-dependent Iκbα expression. Cav-1(-/-) mice did not efficiently promote CD8 immunity to lymphocytic choriomeningitis virus, nor did cav-1(-/-) OT-1(+) CD8(+) T cells efficiently respond to Listeria monocytogenes-OVA after transfer into wild-type hosts. Therefore, caveolin-1 is a T cell-intrinsic orchestrator of TCR-mediated membrane polarity and signal specificity selectively employed by CD8 T cells to customize TCR responsiveness.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Caveolina 1/inmunología , Sinapsis Inmunológicas/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Actinas/metabolismo , Animales , Linfocitos T CD8-positivos/metabolismo , Caveolina 1/metabolismo , Polaridad Celular , Separación Celular , Citometría de Flujo , Expresión Génica , Regulación de la Expresión Génica/inmunología , Immunoblotting , Sinapsis Inmunológicas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Fluorescente , Receptores de Antígenos de Linfocitos T/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Muscle damage and fibro-fatty replacement of skeletal muscles is a main pathologic feature of Duchenne muscular dystrophy (DMD) with more proximal muscles affected earlier and more distal affected later in the disease course, suggesting that different skeletal muscle groups possess distinctive characteristics that influence their susceptibility to disease. To explore transcriptomic factors driving differential gene expression and modulating DMD skeletal muscle severity, we characterized the transcriptome of vastus lateralis (VL), a more proximal and susceptible muscle, relative to tibialis anterior (TA), a more distal and protected muscle, in 15 healthy individuals using bulk RNA sequencing to identify gene expression differences that may mediate their relative susceptibility to damage with loss of dystrophin. Matching single nuclei RNA sequencing data was generated for 3 of the healthy individuals, to infer cell composition in the bulk RNA sequencing dataset and to improve mapping of differentially expressed genes to their cell source of expression. A total of 3,410 differentially expressed genes were identified and mapped to cell type using single nuclei RNA sequencing of muscle, including long non-coding RNAs and protein coding genes. There was an enrichment of genes involved in calcium release from the sarcoplasmic reticulum, particularly in the myofibers and these myofiber genes were higher in the VL. There was an enrichment of genes in "Collagen-Containing Extracellular Matrix" expressed by fibroblasts, endothelial, smooth muscle and pericytes, with most genes higher in the TA, as well as genes in "Regulation Of Apoptotic Process" expressed across all cell types. Previously reported genetic modifiers were also enriched within the differentially expressed genes. We also identify 6 genes with differential isoform usage between the VL and TA. Lastly, we integrate our findings with DMD RNA sequencing data from the TA, and identify "Collagen-Containing Extracellular Matrix" and "Negative Regulation Of Apoptotic Process" as differentially expressed between DMD compared to healthy. Collectively, these findings propose novel candidate mechanisms that may mediate differential muscle susceptibility in muscular dystrophies and provide new insight into potential therapeutic targets.
RESUMEN
In vitro models of patient-derived muscle allow for more efficient development of genetic medicines for the muscular dystrophies, which often present mutation-specific pathologies. One popular strategy to generate patient-specific myotubes involves reprogramming dermal fibroblasts to a muscle lineage through MyoD induction. However, creating physiologically relevant, reproducible tissues exhibiting multinucleated, aligned myotubes with organized striations is dependent on the introduction of physicochemical cues that mimic the native muscle microenvironment. Here, we engineered patient-specific control and dystrophic muscle tissues in vitro by culturing and differentiating MyoD-directly reprogrammed fibroblasts isolated from one healthy control subject, three patients with Duchenne muscular dystrophy (DMD), and two Limb Girdle 2A/R1 (LGMD2A/R1) patients on micromolded gelatin hydrogels. Engineered DMD and LGMD2A/R1 tissues demonstrated varying levels of defects in α-actinin expression and organization relative to control, depending on the mutation. In genetically relevant DMD tissues amenable to mRNA reframing by targeting exon 44 or 45 exclusion, exposure to exon skipping antisense oligonucleotides modestly increased myotube coverage and alignment and rescued dystrophin protein expression. These findings highlight the value of engineered culture substrates in guiding the organization of reprogrammed patient fibroblasts into aligned muscle tissues, thereby extending their value as tools for exploration and dissection of the cellular and molecular basis of genetic muscle defects, rescue, and repair.