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Diabetic nephropathy (DN) is a multifactorial disease characterized by hyperglycemia and close interaction of hemodynamic, metabolic and inflammatory factors. Nuclear factor-κB (NF-κB) is a principal matchmaker linking hyperglycemia and inflammation. The present work investigates the cell-permeable peptide containing the inhibitor of kappa B kinase γ (IKKγ)/NF-κB essential modulator (NEMO)-binding domain (NBD) as therapeutic option to modulate inflammation in a preclinical model of type 2 diabetes (T2D) with DN. Black and tan, brachyuric obese/obese mice were randomized into 4 interventions groups: Active NBD peptide (10 and 6 µg/g body weight); Inactive mutant peptide (10 µg/g); and vehicle control. In vivo/ex vivo fluorescence imaging revealed efficient delivery of NBD peptide, systemic biodistribution and selective renal metabolization. In vivo administration of active NBD peptide improved albuminuria (>40% reduction on average) and kidney damage, decreased podocyte loss and basement membrane thickness, and modulated the expression of proinflammatory and oxidative stress markers. In vitro, NBD blocked IKK-mediated NF-κB induction and target gene expression in mesangial cells exposed to diabetic-like milieu. These results constitute the first nephroprotective effect of NBD peptide in a T2D mouse model that recapitulates the kidney lesions observed in DN patients. Targeting IKK-dependent NF-κB activation could be a therapeutic strategy to combat kidney inflammation in DN.
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Péptidos de Penetración Celular/administración & dosificación , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/química , Albúmina Sérica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Sitios de Unión , Línea Celular , Péptidos de Penetración Celular/farmacología , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/diagnóstico por imagen , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Ratones , FN-kappa B/metabolismo , Células RAW 264.7 , Distribución Aleatoria , Distribución Tisular , Resultado del TratamientoRESUMEN
BACKGROUND: Tamoxifen (TAM), a selective modulator of estrogen receptors (SERMs) has been recently explored as a therapeutic option for the oral treatment of airway inflammation in the horse. The objective of this work was to establish pharmacokinetic parameters of TAM and its main metabolites in equines, as well as to determine its clinical safety in short-term treatments. RESULTS: We determined TAM and its three main metabolites (4-OH tamoxifen, endoxifen, and N-desmethyl tamoxifen) in plasma after single administration of 0.25 mg/kg in healthy adult horses (n = 12). A maximum concentration of TAM was achieved 3 h after the oral administration (4.65 pg/mL ± 1.69); 4-OH tamoxifen was the metabolite that reached the highest concentration (78 pg/mL ± 70), followed by N-desmethyl tamoxifen (0.43 pg / mL ± 0.48), and finally endoxifen (0.17 pg/mL ± 0.17). All metabolites showed peak concentration 2 h after oral administration of the drug. Oral TAM bioavailability was 13,15% ± 4,18, with a steady state volume of distribution of 7831 ± 2922 (L/kg). Elimination half-life was 15.40 ± 5.80 h, and clearance was 5876 ± 699 (mL/kg/min). Clinical safety of TAM was determined over a 7-day course of treatment (0.25 mg/kg, orally q 24 h, n = 20). No adverse effects were observed through clinical examination, blood hematology, serum biochemistry, ophthalmological and reproductive examinations. Endometrial edema observed in some mares was attributed to normal cyclic activity. CONCLUSIONS: Tamoxifen has moderate oral bioavailability and a large volume of distribution, with three main metabolites in horses. Additionally, oral TAM administration over a 7-day treatment period demonstrated to be clinically safe, without adverse effects on clinical, hematological or serum biochemical parameters. These data could contribute to the continued research into this drug's potential for the treatment of different inflammatory conditions in equine species.
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[This corrects the article DOI: 10.3389/fneph.2024.1379061.].
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Background: Congenital nephrotic syndrome (CNS) is a severe kidney disorder characterized by edema, massive proteinuria, and hypoalbuminemia that manifests in utero or within three months after birth. CNS affects 1-3 per 100,000 children, primarily associated with genetic variants and occasionally with infections. Genetic analysis is the first-line method for diagnosis. The most common founder variants have been identified in European populations, often resulting in end-stage kidney disease by 1-2 years of age. Case-diagnosis/treatment: A female full-term neonate, without prenatal signs of kidney disease, was admitted to Rapa Nui (Eastern Island) Hospital at the age of 2 months due to bronchial obstruction. She presented fever, oliguria, edema, urine protein-to-creatinine ratio (UPCR) 433.33, and hypoalbuminemia (0.9 g/dL). She was transferred to a mainland Chilean hospital following CNS diagnosis. Viral screening detected cytomegalovirus (CMV) positivity in both blood and urine. A kidney biopsy revealed interstitial nephritis and diffuse podocyte damage and the tissue PCR resulted negative for CMV. Interviews with the parents revealed consanguinity, suggestive of hereditary CNS. Genetic analysis identified the Maori founder variant, NPHS1 c.2131C>A (p.R711S), in homozygosis. The patient received albumin infusions and antiviral therapy, being discharged when she was 5 months old, with improved laboratory parameters evidenced by UPCR 28.55, albumin 2.5 g/dL, and cholesterol 190 mg/dL. Subsequent clinical monitoring was conducted through virtual and in-person consultations. At her last follow-up at 4 years 2 months old, she presented UPCR 16.1, albumin 3.3 g/dl and cholesterol 220 mg/dL, maintaining normal kidney function and adequate growth. Conclusions: To our knowledge, this represents the first case of CNS in Chile carrying a NPHS1 variant associated with prolonged kidney survival. As described in the Maori population, the patient exhibited a less severe clinical course compared to classical NPHS1 patients. Genetic testing for the Maori founder variant in CNS patients related to the New Zealand population, could impact management decisions and potentially prevent the need for nephrectomies.
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In the oral cavity, we can find a complex mixture of microorganisms, commensals, and pathogens. The studies of normal oral microbiota, as well as the studies of much oral pathology (e.g., caries, periodontitis), involve the isolation and cultivation of these microorganisms and their molecular analysis. The aim of this study was to validate a quick, easy, efficient, and inexpensive DNA extraction method for the recovery of genomic DNA from gram-positive and gram-negative oral bacteria to be used in polymerase chain reaction amplification. This method worked great with all samples analyzed, providing an approach to extract DNA for different microorganisms.
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ADN Bacteriano , Bacterias Grampositivas , Boca/microbiología , Papel , Reacción en Cadena de la Polimerasa/métodos , Hidróxido de Sodio/química , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Bacteriano/aislamiento & purificación , Bacterias Grampositivas/química , Bacterias Grampositivas/genética , Humanos , Masculino , Metagenoma/genéticaRESUMEN
BACKGROUND: Exercise programmes are essential for burn rehabilitation, however patients often have barriers accessing these services. Home-based telerehabilitation (HBT) may be an alternative. This study aimed to determine if exercise programs delivered via HBT were as effective as in-person (IP) programs with respect to clinical outcomes and participant and therapist satisfaction. METHODS: A single center, randomized, controlled, non-inferiority pilot trial with blinded assessment was undertaken. Forty-five adults with ≤ 25% total body surface area (TBSA) burns were randomized to receive a 6-week exercise program delivered either by HBT or IP. The primary outcome was burn-specific quality of life (Burn Specific Health Scale - Brief). Secondary outcomes included health-related quality of life, burn scar-specific outcomes, exercise self-efficacy, pain severity, muscle strength and range of motion (ROM). Participant and therapist satisfaction, technical disruptions and adverse events were also recorded. RESULTS: We found no significant within- or between-group differences for any outcome measures except ROM. Achievement of full ROM was significantly different between groups at Week 12 (IP=100% vs HBT=70%, p = 0.005). Non-inferiority was inconclusive. Participant satisfaction was high (median ≥ 9.8/10), with no significant between-group differences. Therapist satisfaction was high (median ≥ 8.9/10), major technical disruptions low (8%) and no adverse events reported. CONCLUSION: HBT is a safe, effective option to deliver exercise programs for patients with burn injuries ≤ 25% TBSA with comparable clinical outcomes to in-person programmes. Ongoing research is required to further analyze ROM and investigate the effectiveness of HBT for patients with larger burns.
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Quemaduras , Telerrehabilitación , Adulto , Humanos , Telerrehabilitación/métodos , Resultado del Tratamiento , Calidad de Vida , Proyectos Piloto , Quemaduras/rehabilitación , Terapia por Ejercicio/métodosRESUMEN
The main objective of this study was to estimate the performance, under local epidemiological conditions, of two in-house ELISA assays for the combined detection of anti-SARS-CoV-2 IgA, IgM, and IgG immunoglobulins. A total of 94 serum samples were used for the assessment, where 44 corresponded to sera collected before the pandemic (free of SARS-CoV-2 antibodies), and 50 sera were collected from confirmed COVID-19 patients admitted to the main public hospital in the city of Valdivia, southern Chile. The Nucleocapsid (Np) and the receptor-binding domain (RBD) proteins were separately used as antigens (Np and RBD ELISA, respectively) to assess their diagnostic performance. A receiver operating characteristic (ROC) analysis was performed to estimate the optical density (OD) cut-off that maximized the sensitivity (Se) and specificity (Sp) of the ELISA assays. Np ELISA had a mean Se of 94% (95% CI = 83.5-98.8%) and a mean Sp of 100% (95% CI = 92.0-100%), with an OD 450 nm positive cut-off value of 0.88. On the other hand, RBD ELISA presented a mean Se of 96% (95% CI = 86.3-99.5%) and a mean Sp of 90% (95% CI = 78.3-97.5%), with an OD 450 nm positive cut off value of 0.996. Non-significant differences were observed between the Se distributions of Np and RBD ELISAs, but the latter presented a significant lower Sp than Np ELISA. In parallel, collected sera were also analyzed using a commercial lateral flow chromatographic immunoassay (LFCI), to compare the performance of the in-house ELISA assays against a commercial test. The LFCI had a mean sensitivity of 94% (95% CI = 87.4-100%) and a mean specificity of 100% (95% CI = 100-100%). When compared to Np ELISA, non-significant differences were observed on the performance distributions. Conversely, RBD ELISA had a significant lower Sp than the LFCI. Although, Np ELISA presented a similar performance to the commercial test, this was 2.5 times cheaper than the LFCI assay (labor cost not considered). Thus, the in-house Np ELISA could be a suitable alternative tool, in resource limited environments, for the surveillance of SARS-CoV-2 infection, supporting further epidemiological studies.
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COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , SARS-CoV-2 , Inmunoglobulina A , Ensayo de Inmunoadsorción Enzimática/métodos , Inmunoglobulina G , Sensibilidad y Especificidad , Inmunoglobulina M , Anticuerpos AntiviralesRESUMEN
OBJECTIVE: To evaluate the efficacy of two new mouthrinses in the reduction of xerostomía-associated symptomatology. BACKGROUND: Xerostomia is a common chronic health condition that affects a great number of adults and significantly deteriorates quality of life, such that treatment is necessary. MATERIALS AND METHODS: Sixty-seven adult subjects of both sexes presenting xerostomia of diverse origin were selected. Mouthrinses were tested using a double-blind, randomized, cross-over clinical trial with an intervining wash out period. RESULTS: The 100% of subjects presented sensation of dry mouth, and 86% stated sensation of thick saliva. Burning tongue sensation, need to drink liquids to swallow and the sensation of swallowing difficulty were recorded in more than 50% of the patients. The most frequent pathologies in the sample were depression, arthritis, and arterial hypertension. Results of the clinical tests showed that mouthrinse 1 relieves sensation of dry mouth, need to drink liquids, and swallowing difficulty. In contrast, mouthrinse 2 relieves only latter two symptoms. Both rinses were more effective in relieving xerostomía-associated symptomatology in patients taking 3 or more medicines simultaneously. CONCLUSION: Both mouthrinses were effective in relieving various xerostomia symptoms, could be distributed at a low cost, thereby improving the quality of life of population affected.
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Antisépticos Bucales/uso terapéutico , Xerostomía/prevención & control , Adulto , Aloe , Artritis/tratamiento farmacológico , Síndrome de Boca Ardiente/prevención & control , Cetilpiridinio/análisis , Ácido Cítrico/análisis , Estudios Cruzados , Deglución/efectos de los fármacos , Trastornos de Deglución/prevención & control , Depresión/tratamiento farmacológico , Método Doble Ciego , Femenino , Aromatizantes/análisis , Glicerol/análisis , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Mentha spicata , Persona de Mediana Edad , Antisépticos Bucales/análisis , Propilenglicol/análisis , Saliva/efectos de los fármacos , Saliva/metabolismo , Tasa de Secreción/efectos de los fármacos , Cloruro de Sodio/análisis , Fluoruro de Sodio/análisis , Lengua/efectos de los fármacos , Resultado del Tratamiento , Xilitol/análisisRESUMEN
Physical activity behavior has not been previously described in hospitalized adults with burn injuries. This prospective, cross-sectional study used a standardized behavioral mapping protocol to observe patient behavior related to physical activity over a 12-hour period on one weekday in a quaternary referral specialist burn center. Structured observations were recorded for each of four domains: 1) patient location, 2) position, 3) activity performed, and 4) the presence of others. Observations were summarized across all participants as median (interquartile range [IQR]) proportion of time. Participants (n = 17) were predominantly male (82%) with a mean age of 44.3 (SD 15.2) years, a mean burn size of 34.9% (SD 26.7) TBSA, and a median hospital length of stay of 18 (IQR 6-49) days at time of observation. Participants spent a median of 83% (IQR 73-93) of time in their bedroom, 92% (IQR 68-97) of time in or on their bed and a median of 5% (IQR 3-13) of time mobilizing. Exercise accounted for 10% (IQR 8-17) of activity-related observations. A median of 68% (IQR 39-83) of time was spent alone. Results suggest time spent engaging in physical activity is low. Further studies are required to investigate motivators and barriers to performing physical activity in this population. This will consequently inform the development and implementation of appropriate strategies to improve physical activity behavior in this cohort.
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Quemaduras , Adulto , Quemaduras/terapia , Estudios Transversales , Ejercicio Físico , Femenino , Humanos , Tiempo de Internación , Masculino , Estudios ProspectivosRESUMEN
Mesenchymal stem/stromal cells (MSCs) therapy has been a cornerstone of regenerative medicine in humans and animals since their identification in 1968. MSCs can interact and modulate the activity of practically all cellular components of the immune response, either through cell-cell contact or paracrine secretion of soluble mediators, which makes them an attractive alternative to conventional therapies for the treatment of chronic inflammatory and immune-mediated diseases. Many of the mechanisms described as necessary for MSCs to modulate the immune/inflammatory response appear to be dependent on the animal species and source. Although there is evidence demonstrating an in vitro immunomodulatory effect of MSCs, there are disparate results between the beneficial effect of MSCs in preclinical models and their actual use in clinical diseases. This discordance might be due to cells' limited survival or impaired function in the inflammatory environment after transplantation. This limited efficacy may be due to several factors, including the small amount of MSCs inoculated, MSC administration late in the course of the disease, low MSC survival rates in vivo, cryopreservation and thawing effects, and impaired MSC potency/biological activity. Multiple physical and chemical pre-conditioning strategies can enhance the survival rate and potency of MSCs; this paper focuses on hypoxic conditions, with inflammatory cytokines, or with different pattern recognition receptor ligands. These different pre-conditioning strategies can modify MSCs metabolism, gene expression, proliferation, and survivability after transplantation.
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Cyclosporine (CsA) and tacrolimus (TAC) are immunosuppressant drugs characterized by a narrow therapeutic range and high pharmacokinetic variability. The effect of polymorphisms in genes related to the metabolism and transport of these drugs, namely CYP3A4, CYP3A5, MDR1 and POR genes, has been evaluated in diverse populations. However, the impact of these polymorphisms on drug disposition is not well established in Latin American populations. Using TaqMan® probes, we determined the allelic frequency of seven variants in CYP3A4, CYP3A5, MDR1 and POR in 139 Chilean renal transplant recipients, of which 89 were treated with CsA and 50 with TAC. We tested associations between variants and trough and/or 2-hour concentrations, normalized by dose (C0/D and C2/D) at specific time points post-transplant. We found that CYP3A5*3/*3 carriers required lower doses of TAC. In TAC treated patients, most CYP3A5*3/*3 carriers presented higher C0/D and a high proportion of patients with C0 levels outside the therapeutic range relative to other genotypes. These results reinforce the value of considering CYP3A5 genotypes alongside therapeutic drug monitoring for TAC treated Chilean kidney recipients.
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Mesenchymal stem/stromal cells (MSCs) are increasingly explored for the treatment of degenerative and inflammatory diseases in human and veterinary medicine. One of the key characteristics of MSCs is that they modulate inflammation mainly through the secretion of soluble mediators. However, despite widespread clinical use, knowledge regarding the effector mechanisms of equine MSCs, and consequently their effectiveness in the treatment of diseases, is still unknown. The objectives of this study were to determine the mechanisms underlying inhibition of lymphocyte proliferation by equine bone marrow-derived MSCs, and to evaluate the effect of pre-conditioning of equine MSCs with different pro-inflammatory cytokines on inhibition of lymphocyte proliferation. We determined that inhibition of lymphocyte proliferation by equine MSCs depends on activity of prostaglandin-endoperoxide synthase 2 and indoleamine 2,3-dioxygenase. Additionally, pre-conditioning of MSCs with TNF-α, IFN-γ or their combination significantly increased the expression of prostaglandin-endoperoxide synthase 2, indoleamine 2,3-dioxygenase, iNOS and IL-6. This upregulation correlated with an increased inhibitory effect of MSCs on lymphocyte proliferation. In conclusion, pre-conditioning of bone marrow-derived MSC increases their inhibitory effect on lymphocyte proliferation in horses.
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BACKGROUND: Polymorphonuclear neutrophils (PMN) are the largest leukocyte population in the blood of most mammals including horses, and play an important defensive role in many infectious diseases. However, the mechanisms that increase PMN as one of the main cellular subsets in the defense against pathogens could also be involved in the pathophysiology of dysregulated inflammatory conditions. Mesenchymal stem/stromal cells (MSCs) are a heterogeneous population with a modulatory potential on the inflammatory response and are known to interact with nearly all cells of the immune system, including PMN. In this study, the in vitro modulation of equine bone marrow-derived MSCs on equine PMN phagocytosis, ROS production, and NETs generation was assessed. RESULTS: In co-culture with MSCs, unstimulated PMN produce less ROS (2.88 %⯱â¯1.43) than PMN in single culture (5.89 %⯱â¯2.63) (pâ¯=â¯0.016). Moreover, PMN co-cultured with MSCs remain conditioned to produce fewer ROS after PMA stimulation in comparison to PMN in single culture (pâ¯<â¯0.05). Additionally, it was found that incubation with MSC supernatant strongly inhibited ROS production (83 %⯱â¯6.35 less than control) without affecting phagocytosis or capacity for NETosis (pâ¯<â¯0.01). CONCLUSIONS: These results suggest a modulatory effect of equine BM-derived MSCs on PMN respiratory burst, without impairing other important microbicidal functions. This supports the potential use of equine MSCs in excessive or persistent inflammatory conditions in which neutrophils are the main effector cells.
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Células de la Médula Ósea/citología , Células Madre Mesenquimatosas/citología , Neutrófilos/inmunología , Especies Reactivas de Oxígeno/metabolismo , Animales , Células Cultivadas , Técnicas de Cocultivo , Femenino , Caballos , Masculino , Neutrófilos/metabolismo , Fagocitosis , Estallido Respiratorio/inmunología , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
The absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the effects of its blockade in experimental models of DN is still controversial. Here, we test the effects of a therapeutic anti-VEGFR2 treatment, using a VEGFR2 kinase inhibitor, on the progression of renal damage in the BTBR ob/ob (leptin deficiency mutation) mice. This experimental diabetic model develops histological characteristics mimicking the key features of advanced human DN. A VEGFR2 pathway-activation blockade using the VEGFR2 kinase inhibitor SU5416, starting after kidney disease development, improves renal function, glomerular damage (mesangial matrix expansion and basement membrane thickening), tubulointerstitial inflammation and tubular atrophy, compared to untreated diabetic mice. The downstream mechanisms involved in these beneficial effects of VEGFR2 blockade include gene expression restoration of podocyte markers and downregulation of renal injury biomarkers and pro-inflammatory mediators. Several ligands can activate VEGFR2, including the canonical ligands VEGFs and GREMLIN. Activation of a GREMLIN/VEGFR2 pathway, but not other ligands, is correlated with renal damage progression in BTBR ob/ob diabetic mice. RNA sequencing analysis of GREMLIN-regulated genes confirm the modulation of proinflammatory genes and related-molecular pathways. Overall, these data show that a GREMLIN/VEGFR2 pathway activation is involved in diabetic kidney disease and could potentially be a novel therapeutic target in this clinical condition.
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BACKGROUND: Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal cells currently tested for multiple therapeutic purposes. Their potential to home into tumors, to secrete trophic/vasculogenic factors, and to suppress immune response raises questions regarding their biosafety. Our aim was to evaluate whether systemically administered allogeneic MSCs modify the natural progression of precancerous lesions and whether their putative effect depends on cancer stage and/or cell dose. METHODS: Oral squamous cell carcinoma (OSCC) was induced in Syrian golden hamsters by topical application of 7,12-dimethylbenz[a]anthracene in one buccal pouch. At hyperplasia, dysplasia, or papilloma stage, animals received intracardially the vehicle or 0.7 × 106, 7 × 106, or 21 × 106 allogeneic bone marrow-derived MSCs/kg. OSCC progression was assessed according to the presence of erythroplakia and leukoplakia, extent of inflammation and vascularization, and appearance, volume, and staging of tumors. Also, the homing of donor cells was studied. RESULTS: Precancerous lesions progressed from hyperplasia to dysplasia in 2 weeks, from dysplasia to papilloma in 3 weeks, and from papilloma to carcinoma in 4 weeks. This time course was unmodified by the systemic administration of MSCs at hyperplasia or dysplasia stages. When MSCs were administered at papilloma stage, lesions did not progress to carcinoma stage. Tumors developed in hamsters receiving 0.7 × 106 or 7 × 106 MSCs/kg at hyperplasia stage were significantly smaller than those found in control animals (25 ± 4 or 23 ± 4 mm3 versus 72 ± 19 mm3, p < 0.05). Similar results were obtained when 0.7 × 106, 7 × 106, or 21 × 106 MSCs/kg were administered at papilloma stage (44 ± 15, 28 ± 7, or 28 ± 5 mm3 versus 104 ± 26 mm3, p < 0.05). For dysplasia stage, only the lower concentration of MSCs reached statistical significance (21 ± 9 mm3 versus 94 ± 39 mm3, p < 0.05). Animals receiving 21 × 106 MSCs/kg at hyperplasia stage developed tumors larger than those found in animals that received the vehicle (147 ± 47 mm3 versus 72 ± 19 mm3, p < 0.05). Donor cells were rarely found in precancerous lesions. CONCLUSIONS: Systemically administered allogeneic MSCs do not aggravate the progression of precancerous lesions. Moreover, they preclude cancer progression and tumor growth.
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Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Trasplante Homólogo/métodos , Administración Cutánea , Animales , Diferenciación Celular , Cricetinae , Progresión de la EnfermedadRESUMEN
Multipotent stromal cells (MSCs) are envisioned as a powerful therapeutic tool. As they home into tumors, secrete trophic and vasculogenic factors, and suppress immune response their role in carcinogenesis is a matter of controversy. Worldwide oral squamous cell carcinoma (OSCC) is the fifth most common epithelial cancer. Our aim was to determine whether MSC administration at precancerous stage modifies the natural progression of OSCC. OSCC was induced in Syrian hamsters by topical application of DMBA in the buccal pouch. At papilloma stage, the vehicle or 3×106 allogenic bone marrow-derived MSCs were locally administered. Four weeks later, the lesions were studied according to: volume, stratification (histology), proliferation (Ki-67), apoptosis (Caspase 3 cleaved), vasculature (ASMA), inflammation (Leukocyte infiltrate), differentiation (CK1 and CK4) and gene expression profile (mRNA). Tumors found in individuals that received MSCs were smaller than those presented in the vehicle group (87±80 versus 54±62mm3, p<0.05). The rate of proliferation was two times lower and the apoptosis was 2.5 times higher in lesions treated with MSCs than in untreated ones. While the laters presented dedifferentiated cells, the former maintained differentiated cells (cytokeratin and gene expression profile similar to normal tissue). Thus, MSC administration at papilloma stage precludes tumor growth and epithelial dedifferentiation of OSCC.
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Carcinoma de Células Escamosas/patología , Células Epiteliales/citología , Hiperplasia/patología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Neoplasias de la Boca/patología , Animales , Apoptosis , Células de la Médula Ósea/citología , Carcinoma de Células Escamosas/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Desdiferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Cricetinae , Progresión de la Enfermedad , Regulación hacia Abajo , Células Epiteliales/metabolismo , Femenino , Hiperplasia/metabolismo , Inmunofenotipificación , Queratinas/genética , Queratinas/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Masculino , Células Madre Mesenquimatosas/metabolismo , Mesocricetus , Neoplasias de la Boca/metabolismo , Papiloma/metabolismo , Papiloma/patología , Fenotipo , Transcriptoma , Trasplante HomólogoRESUMEN
OBJECTIVE: The aim of the study was to determine the longitudinal validity, reproducibility, responsiveness and interpretability of the adult version of the Brisbane Burn Scar Impact Profile, a patient-report measure of health-related quality of life. METHODS: A prospective longitudinal cohort study of patients with or at risk of burn scarring was conducted at three assessment points (at baseline around the time of wound healing, one to two weeks post-baseline and 1-month post-baseline). Participants attending a major metropolitan adult burn centre at baseline were recruited. Participants completed the Brisbane Burn Scar Impact Profile and the 36-item Short Form Health Survey and Patient Observer Scar Assessment Scale. Intraclass Correlation Coefficients (ICCs), smallest detectable change, percentage of those who improved, stayed the same or worsened and Area under the Receiver Operating Characteristic Curve (AUC) were used to test the aim. RESULTS: Data were included for 118 participants at baseline, 68 participants at one to two weeks and 57 participants at 1-month post-baseline. All groups of items had acceptable reproducibility, except for the overall impact of burn scars (ICC = 0.69), the impact of sensations which was not expected to be stable (ICC = 0.63), mobility and daily activities (ICC = 0.63, 0.67 respectively). The responsiveness of six out of seven groups of items able to be tested against external criterion was supported (AUC = 0.72-0.75). Hypothesised correlations of changes in the Brisbane Burn Scar Impact Profile items with changes in criterion measures generally supported longitudinal validity (e.g., nine out of thirteen hypotheses using the SF-36 as an external criterion were supported). Internal consistency estimates, item-total and inter-item correlations indicated there was likely redundancy of some groups of items, particularly in the relationships and social interaction, appearance and emotional reactions items (Chronbach's alpha range = 0.94-0.95). CONCLUSION: Support was found for the reproducibility, longitudinal validity, responsiveness and interpretability of most groups of Brisbane Burn Scar Impact Profile items and some individual items in the test population. Potential redundancy of items should be investigated further.
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Quemaduras/psicología , Cicatriz/psicología , Psicometría/métodos , Perfil de Impacto de Enfermedad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quemaduras/patología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Calidad de Vida , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Adulto JovenRESUMEN
INTRODUCTION: No burn-scar specific, health-related quality of life (HRQOL) measure exists. This study aimed to develop a patient-reported, evaluative HRQOL measure to assess the impact of burn scarring in children and adults. METHOD: Semi-structured interviews, content validation surveys, and cognitive interviews were used to develop and test content validity of a new measure - the Brisbane Burn Scar Impact Profile (BBSIP). RESULTS: Participants comprised Australian adults (n=23) and children (n=19) with burn scarring; caregivers of children with burn scarring (n=28); and international scar management experts (n=14). Items distinct from other burn scar measures emerged. Four versions of the BBSIP were developed; one for children aged 8-18 years, one for adults, one for caregivers (as proxies for children aged less than 8-years), and one for caregivers of children aged 8-18 years. Preliminary content validity of the BBSIP was supported. Final items covered physical and sensory symptoms; emotional reactions; impact on social functioning and daily activities; impact of treatment; and environmental factors. CONCLUSION: The BBSIP was developed to assess burn-scar specific HRQOL and will be available at http://www.coolburns.com.au under a creative commons license. Further testing is underway.
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Quemaduras/complicaciones , Cicatriz/psicología , Calidad de Vida , Perfil de Impacto de Enfermedad , Adolescente , Adulto , Anciano , Quemaduras/psicología , Cuidadores/psicología , Niño , Estudios Transversales , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVE: Amelogenesis imperfecta (AI) is a group of clinically and genetically heterogeneous inherited conditions, causing alterations in the structure of enamel and chemical composition of enamel matrix during development. The objective of this study was to compare the clinical, radiographic, histological and immunohistochemical phenotypes of subjects affected with hypocalcified AI from three Chilean families and identify causal mutations in the FAM83H gene. DESIGN: The diagnosis was made using clinical, radiographic, histological and genealogical data from the patients, who were evaluated according to the classification criteria by Witkop. PCR and Sanger sequencing of the complete coding sequence and surrounding intron regions of the FAM83H gene were conducted. The structural study of the affected teeth was performed with light microscopy, scanning electron microscopy and immunohistochemistry. RESULTS: The probands of the three families were diagnosed with hypocalcified AI, but in only one of them the missense variant p.Gly557Cys was identified. This variant was not present in the SNP database or in 100 healthy controls and segregated with the disease in the affected family. Using light microscopy, a normal prismatic structure was observed in all three cases. However, the ultrastructure was found to be affected in two of the cases, showing persistence of organic matter including amelogenins. CONCLUSIONS: These results suggest that FAM83H missense mutation reported in one of the families analyzed in this study might cause a phenotype of hypocalcified enamel more attenuated with retention of amelogenin.
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Amelogénesis Imperfecta/genética , Amelogenina/genética , Mutación Missense/genética , Proteínas/genética , Chile , Exones , Femenino , Humanos , Inmunohistoquímica , Masculino , Microscopía Electrónica de Rastreo , Linaje , FenotipoRESUMEN
UNLABELLED: Burns for contact with irons are an important preventable cause of burns in children. The objective of this study, was to document and describe these burns. The report describes 50 children with iron burns who were treated at our Burns Unit between 1997 and 2001. METHODS: Prospective data collection demographics, nature of contact with iron, site, body surface area (BSA), medical and surgical interventions and complications and hand preference were examined. RESULTS: The median of age patients was 17 months. The majority of burns were caused by touching the iron (44%) or by pulling the cord (38%). Most of the children were supervised (74%) and the iron was switched off in 34% of the injuries. Seventy-six percent of children sustained hand burns. Although, burn areas were relatively small, 36% required grafting. Residual scarring occurred in 42% and contractures in 10%. Surgical release of contractures was required in 4%. CONCLUSION: There is clearly a wide scope for prevention of hot iron burns. A public education campaign is now planned including: leaflets distributed at the point of purchase of the iron, public education via media outlets and lobbying of iron manufacturers to improve safety features.