RESUMEN
This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Humanos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/terapia , Fibrosis Quística/genética , Fibrosis Quística/diagnóstico , Nivel de Atención , Conducto Deferente/anomalías , Bronquiectasia/terapia , Bronquiectasia/diagnóstico , Bronquiectasia/etiología , Pancreatitis/terapia , Pancreatitis/diagnóstico , Pancreatitis/etiología , Aspergilosis Broncopulmonar Alérgica/diagnóstico , Aspergilosis Broncopulmonar Alérgica/terapia , Masculino , Enfermedades Urogenitales MasculinasRESUMEN
After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Nivel de Atención , Humanos , Fibrosis Quística/terapia , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Asesoramiento Genético , Pruebas Genéticas/métodos , Recién NacidoRESUMEN
Cerebral palsy (CP) is one of the most common conditions leading to lifelong childhood physical disability. Literature reported previously altered muscle properties such as lower number of satellite cells (SCs), with altered fusion capacity. However, these observations highly vary among studies, possibly due to heterogeneity in patient population, lack of appropriate control data, methodology and different assessed muscle. In this study we aimed to strengthen previous observations and to understand the heterogeneity of CP muscle pathology. Myogenic differentiation of SCs from the Medial Gastrocnemius (MG) muscle of patients with CP (n = 16, 3-9 years old) showed higher fusion capacity compared to age-matched typically developing children (TD, n = 13). Furthermore, we uniquely assessed cells of two different lower limb muscles and showed a decreased myogenic potency in cells from the Semitendinosus (ST) compared to the MG (TD: n = 3, CP: n = 6). Longitudinal assessments, one year after the first botulinum toxin treatment, showed slightly reduced SC representations and lower fusion capacity (n = 4). Finally, we proved the robustness of our data, by assessing in parallel the myogenic capacity of two samples from the same TD muscle. In conclusion, these data confirmed previous findings of increased SC fusion capacity from MG muscle of young patients with CP compared to age-matched TD. Further elaboration is reported on potential factors contributing to heterogeneity, such as assessed muscle, CP progression and reliability of primary outcome parameters.
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Células Madre Adultas , Parálisis Cerebral , Contractura , Humanos , Niño , Preescolar , Parálisis Cerebral/patología , Reproducibilidad de los Resultados , Músculo Esquelético/patología , Contractura/patologíaRESUMEN
This paper is the first in a series providing updated guidance on the definition, evaluation and management of people with a Cystic Fibrosis Transmembrane conductance Regulator (CFTR)-Related Disorder (CFTR-RD). The need for this update relates to more precise characterisation of CFTR gene variants and improved assessment of CFTR protein dysfunction. The exercise is co-ordinated by the European CF Society Standards of Care Committee and Diagnostic Network Working Group and involves stakeholder engagement. This first paper was produced by a core group using an extensive literature review and papers graded for their quality. Subsequent wider stakeholder agreement was achieved. The definition of a CFTR-RD remains "a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF". Clearer guidance on CFTR dysfunction and relevant CFTR variants will be provided. Thresholds for clinical presentations are presented and the paradigm that pathobiological processes may be evident in more than one organ is agreed. In this paper we reflect on the early patient journey, highlighting that CF specialists as well as other relevant specialists should be involved in the care of people with a CFTR-RD.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Humanos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Fibrosis Quística/terapia , Nivel de Atención , Mutación , Transporte IónicoRESUMEN
SUMMARY: Vitamin D intoxication in children is rare but its incidence is increasing as vitamin D is supplemented more often and in higher doses. Children with cystic fibrosis (CF) are at risk for vitamin D intoxication due to incorrect compounded preparations of liposoluble vitamins. Here, we report a severe vitamin D intoxication in a 4-year-old girl with CF, due to an error in the compounded vitamin A, D, E, and K preparation, presenting clinically with weight loss, constipation, polydipsia, polyuria, and nycturia. The administered compounded preparation contained 10 000-fold the prescribed vitamin D dose. The patient was treated with hyperhydration, loop diuretics, and bisphosphonates. Serum calcium levels normalized after 4 days but serum 25-hydroxyvitamin D levels remained elevated even up to 2 months after treatment. LEARNING POINTS: Vitamin D intoxication should be ruled out when patients with cystic fibrosis (CF) present with acute polyuria, constipation, and weight loss. Prompt treatment is necessary to avert life-threatening complications. Regularly measuring serum calcium and 25-hydroxyvitamin D concentrations in children with CF receiving vitamin A, D, E, and K supplements is important during their follow-up.
RESUMEN
More than five decades after the introduction of the quantitative pilocarpine iontophoresis technique, surveys still highlight inconsistencies in the performance and reporting of sweat tests in Europe. The sweat test remains key for the Cystic Fibrosis (CF) diagnostic pathway for all age groups, as it reflects the basic pathophysiological defect in the sweat gland. It is also critical following newborn screening as a confirmatory diagnostic step. Despite its importance, sweat test quality is variable whether performed in the laboratory or as a point of care test. The ECFS DNWG aims to improve sweat test performance, taking into account the barriers and issues identified in the European survey; the previous step in the ECFS sweat test project. This manuscript proposes a grading of sweat test guidance from "acceptable" to "optimal", aiming to pragmatically improve quality while taking into account local situations, especially in resource-limited settings.
Asunto(s)
Fibrosis Quística , Sudor , Cloruros/metabolismo , Fibrosis Quística/diagnóstico , Humanos , Recién Nacido , Mejoramiento de la Calidad , Nivel de Atención , Sudor/metabolismoRESUMEN
BACKGROUND: Enteral tube feeding (ETF) is often used in an attempt to optimize the nutritional status. The aim of this study was to observe the long term effect of ETF and to compare the start of ETF with the current European guidelines on nutrition care in CF. METHOD: From all patients who received ETF (ETFp) between February 2000 and September 2016 in the Ghent University Hospital (GUH) or Brussels University Hospital (BUH), z-scores for body weight (W), height (H), growth velocity (GV) and BMI, FEV1%, and FVC% were retrospectively collected from the patients' medical record, 3 years before and 5 years after the year of ETF initiation. Gender, age, and pancreatic status matched controls were selected from the GUH database. RESULTS: All baseline (T0) measurements in ETFp were worse compared to controls. Only 11% of the controls had a Hz < -1.6 compared 58% of the ETFp. After the initiation of ETF a rapid weight gain was noted until the second year (T + 2:-1.9 (-2.8; -1.0) vs. T0:-2.7 (-3.2; -2.1) (p = 0.01) with a stabilization afterwards. A rapid GVz increase was noted at T + 1:1.0 (-0.8; 1.9) vs. T0:-1.5 (-2.0;-0.3). After the start of ETF until T + 3, a stabilization of FEV1% was noted. However, compared to controls, it remained significantly lower (p < 0.05). CONCLUSION: ETF as a nutritional intervention has its effect on weight, height, GV, and BMI. To our knowledge this is the first study that describes the evolution of growth in ETFp. The effect on GV argues for a faster introduction of ETF in malnourished children with CF.
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Fibrosis Quística , Nutrición Enteral , Bélgica , Niño , Fibrosis Quística/terapia , Humanos , Estado Nutricional , Estudios RetrospectivosRESUMEN
We tested the in vitro susceptibility of ceftazidime-avibactam and ceftolozane-tazobactam and 13 other antibiotics against 91 Burkholderia cepacia complex (BCC) strains isolated from cystic fibrosis patients since 2012. The highest susceptibility (82%) was found for trimethoprim-sulfamethoxazole. Eighty-one and 63% of all BCC strains were susceptible to ceftazidime-avibactam and ceftolozane-tazobactam, respectively. For temocillin, ceftazidime, piperacillin-tazobactam, and meropenem, at least 50% of the strains were susceptible. B. stabilis seems to be more resistant than other BCC species.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Complejo Burkholderia cepacia/efectos de los fármacos , Ceftazidima/farmacología , Cefalosporinas/farmacología , Fibrosis Quística/microbiología , Tazobactam/farmacocinética , Antibacterianos/farmacología , Complejo Burkholderia cepacia/aislamiento & purificación , Combinación de Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , Sulfametoxazol/farmacología , Tazobactam/farmacología , Trimetoprim/farmacologíaRESUMEN
BACKGROUND: CFTR2 provides clinical and functional information of the most common CFTR-mutations. Rare mutations (RMs) occur in only a few patients with limited reported clinical data. Their role in CF-disease liability is hardly documented. METHODS: Belgian CF-Registry 2013 data were analyzed to identify CF with at least 1 RM (CF+RM). Clinical data and sweat chloride of CF+RM were compared to CF-controls, carrying 2 class 1 to 3 mutations (CFclassic). Disease severity was compared between both groups. To avoid bias in the comparison, transplanted patients were excluded from each group. RESULTS: Seventy-seven CF+RM were identified (77/1183 = 6.5%). Sixty-four different RM were detected, of which 21 had not been previously reported. All RMs, corresponding to HGVS (Human Genome Variation Society) nomenclature, were listed in supplementary data. Seven transplanted CF+RM were excluded for further analysis. CF+RM had higher age at diagnosis [median (IQR)] [3.7 y (0.3-18.3) vs. 0.3y (0.1-2,0) (p < 0.0001)], lower sweat chloride [96 mmol/L (64-107) vs. 104 mmol/L (97-115) (p < 0.0001)], higher FEV1%pred [77%pred (58-96) vs. 68%pred (48-86) (p = 0.017)], were less frequently pancreatic insufficient [56% vs. 98% (p < 0.0001)], Pseudomonas aeruginosa colonized [24% vs. 44% (p = 0.0093)] and needed fewer IV antibiotics [36% vs. 51% (p = 0.041)] than CFclassic. However, a wide spectrum of disease severity was seen amongst CF+RM. CONCLUSIONS: CF-patients with a RM cover 6.5% of the Belgian CF-population. Rare mutations can be found in severely ill patients, but more often in late diagnosed, pancreatic sufficient patients.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Mutación/genética , Antibacterianos/uso terapéutico , Bélgica , Femenino , Genotipo , Humanos , Masculino , Páncreas/patología , Fenotipo , Pseudomonas aeruginosa/patogenicidadRESUMEN
BACKGROUND: According to European and US protocols, two nasal potential difference (NPD) measurement methods are considered acceptable, although they have not been formally compared: subcutaneous agar-filled needle with calomel (Ndl) and dermal abrasion with conducting cream and Ag/AgCl electrodes (Abr). We compared both in CF and healthy volunteers (HV), assessing their discriminative value and subject's preference. METHODS: Twelve classic CF and 17 HV underwent both NPD methods, performed by one operator in random order. A written questionnaire, assessing preference, was completed after each test. Tracings were coded, scored in a semi-blinded fashion and categorised as CF/non-CF. RESULTS: 110 tracings (56 Ndl/54 Abr) were collected: 42/110 scored CF and 68/110 non-CF, showing a good correlation. No significant preference for either method was reported. CONCLUSION: Both NPD methods are similar in terms of discriminative value and subject's preference, comparing classical CF and HV. For diagnosing CF, the operator's preferred NPD-method may be used.
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Cloruros , Fibrosis Quística , Mucosa Nasal/fisiopatología , Sudor/metabolismo , Adulto , Cloruros/análisis , Cloruros/metabolismo , Fibrosis Quística/diagnóstico , Fibrosis Quística/metabolismo , Fibrosis Quística/fisiopatología , Electrodiagnóstico/instrumentación , Electrodiagnóstico/métodos , Femenino , Humanos , Masculino , Potenciales de la Membrana , Prioridad del Paciente , Reproducibilidad de los ResultadosRESUMEN
Effective microbiogical eradication of methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) can be obtained, but its effect is not always clear-cut in terms of spirometric indices. The aim of this observational prospective cohort study was to study the potential effect of eradication of chronic MRSA infection on lung function including ventilation distribution. Six CF patients, chronically colonized with MRSA (median age: 21 years (range 14-46); median FEV1: 76 (95%CI 58-98)%pred) were successfully eradicated using oral rifampicin and fusidic acid in combination with topical decolonization measures. Lung function and multiple breath washout test were performed at the start and at the end of the eradication protocol and after an average follow-up period of 7·5±1·5(SD) months. One patient cultured MRSA again 4 months after successful eradication. All patients reported reduced sputum production and viscosity. By the end of the follow-up period, there was an increase in ventilated FRCMBW and no change in plethysmographic FRCPL. This resulted in a significant decrease of trapped air by half a litre (from 579 to 40 ml; Pâ=â0·013). Lung clearance index (LCI) also showed a small but significant decrease (from 7·2 to 6·7; Pâ=â0·014) after eradication of MRSA. We conclude that MRSA eradication can be successful, also in terms of recruitment of previously unventilated air spaces, potentially due to reduced sputum production and/or viscosity.
Asunto(s)
Antibacterianos/uso terapéutico , Fibrosis Quística/complicaciones , Pulmón/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas/tratamiento farmacológico , Adolescente , Adulto , Antibacterianos/farmacología , Ácido Fusídico/farmacología , Ácido Fusídico/uso terapéutico , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Pruebas de Función Respiratoria , Rifampin/farmacología , Rifampin/uso terapéutico , Adulto JovenRESUMEN
In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis. Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts. The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/análisis , Fibrosis Quística/diagnóstico , Biomarcadores/análisis , Fibrosis Quística/tratamiento farmacológico , Humanos , Reproducibilidad de los ResultadosRESUMEN
In children with persistent respiratory symptoms despite regular anti-asthma inhalation treatment, diagnostic investigations to exclude underlying disease are warranted. 124 children were prospectively enrolled, and 24-h oesophageal pH measurement and fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) were performed. BAL fluid (BALF) was processed for neutrophil counting and bacterial culture. Inflammation of the respiratory mucosa was assessed. A structural abnormality of the central airways was found in 47% of subjects (40% females). In 19% of subjects, neither anatomical anomalies nor inflamed respiratory mucosa were observed, whereas in 64%, definite macroscopic mucosal inflammation was observed. Inflammation of the respiratory mucosa was associated with a significantly higher percentage of neutrophils in the BALF: median (interquartile range) 48 (14-82)% compared with 7 (0-16)% (p<0.025). A positive BALF culture was found in 62% of the infants with mucosal inflammation compared with 25% in the group without inflammation (p<0.016). 56% of the BALF samples were positive for bacterial culture. In children with persistent respiratory symptoms, nearly half have anatomical anomalies of the central airways. In 62% of the children with mucosal inflammation, a positive BAL culture and a significantly higher percentage of BALF neutrophils were detected.
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Laringomalacia/inmunología , Neumonía Bacteriana/inmunología , Neumonía/inmunología , Traqueomalacia/inmunología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Broncoscopía , Tos/epidemiología , Tos/inmunología , Tos/patología , Femenino , Humanos , Lactante , Laringomalacia/epidemiología , Laringomalacia/patología , Masculino , Neutrófilos/citología , Neumonía/epidemiología , Neumonía/patología , Neumonía Bacteriana/epidemiología , Neumonía Bacteriana/patología , Prevalencia , Estudios Prospectivos , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Ruidos Respiratorios/inmunología , Traqueomalacia/epidemiología , Traqueomalacia/patologíaRESUMEN
INTRODUCTION: Assessment of the reflux-cough association in children is challenging. Esophageal (impedance) pH recording is sensitive to recognize reflux. However, cough recorded by an event marker, possibly lacks accuracy. We aimed to study the exact time relationship between reflux and cough in children with chronic cough. METHODS: Twenty-six children (12 boys; 1-10.5 years) with chronic unexplained cough underwent ambulatory impedance-pH-manometry recordings. Manometry was used for precise cough recognition. Reflux was assessed with impedance-pH monitoring and defined as acid (pH <4), weakly acidic (WA) (pH 4-7), weakly alkaline (WALK) (pH ≥7), or acid only (pH <4 for ≥4 sec without impedance pattern). Cough was considered "induced by" reflux, if it started ≤2 min after reflux. The Symptom Association Probability (SAP) was calculated and considered positive if >95%. Cough-induced reflux if it occurred 30 sec before the reflux event. RESULTS: Impedance-pH detected 30 (21-52) reflux episodes/patient (55.2% acid, 41.5% WA, and 3.3% WALK). Additionally 59 acid only events were identified [1 (0-21)/patient]. Manometry detected 47 (5-203) cough bursts/patient. Reflux-cough was found in 22/26 patients. Ten patients had a +SAP for reflux-cough (one acid, six WA, and three acid + WA gastroesophageal reflux [GER]), of which nine had a normal acid exposure. Six out of 10 patients with +SAP using manometry had a +SAP using the event marker. Cough-reflux was detected in 19 patients [3 (0-7)/patient]. Only a small fraction of the esophageal acid exposure [9.6 (0.4-31.8%)] was secondary to cough. CONCLUSION: Both acid and WA GER may precede cough in children with unexplained cough, but cough does not induce GER. Objective cough recording improves symptom association analysis.
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Tos/etiología , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/fisiopatología , Niño , Preescolar , Enfermedad Crónica , Impedancia Eléctrica , Femenino , Humanos , Concentración de Iones de Hidrógeno , Lactante , Masculino , Manometría , Monitoreo AmbulatorioRESUMEN
OBJECTIVES: Increased gastroesophageal reflux (GER) is common in children with cystic fibrosis (CF). We studied the occurrence of acid, weakly acidic (WA), and weakly alkaline (WALK) reflux in children with CF and evaluated a possible surrogate marker for risk of gastric content aspiration. PATIENTS AND METHODS: Twenty-four children with CF underwent impedance-pH monitoring for detection of acid (pH < 4), WA (pH 4-7), and WALK-GER (pH > or = 7). In 11 children, cough was objectively recorded with esophageal manometry and the symptom association probability was calculated to determine the reflux-cough relation. Presence of bile acids (BA) was measured in the saliva of 65 patients with CF and 23 healthy children, respectively. RESULTS: Sixteen of the 24 children had increased GER (esophageal acid exposure). The majority of reflux events were acidic in nature. WA reflux was less common and WALK reflux was rare. The sequence reflux-cough was found in 8 of the 11 children and 1 of 11 children had a positive symptom association probability for reflux-cough. The sequence cough-reflux was found in only 3 of the 11 children. Only a small fraction of the total esophageal acid and volume exposure was secondary to cough. Twenty-three of the 65 children with CF had BA in saliva compared with none of the healthy controls. CONCLUSIONS: Although WA-GER is uncommon, acid GER is prevalent in children with CF. It is a primary phenomenon and is not secondary to cough. One third of the children with CF have BA in saliva, which may indicate an increased risk for aspiration. However, the impact of salivary BA and potential aspiration on CF pulmonary disease needs further investigation.
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Tos/etiología , Fibrosis Quística/complicaciones , Esófago/fisiopatología , Reflujo Gastroesofágico/complicaciones , Aspiración Respiratoria/etiología , Adolescente , Ácidos y Sales Biliares/análisis , Biomarcadores , Niño , Preescolar , Tos/epidemiología , Fibrosis Quística/fisiopatología , Impedancia Eléctrica , Monitorización del pH Esofágico , Femenino , Ácido Gástrico/química , Reflujo Gastroesofágico/fisiopatología , Humanos , Concentración de Iones de Hidrógeno , Lactante , Masculino , Prevalencia , Factores de Riesgo , Saliva/químicaRESUMEN
UNLABELLED: Our goal was to assess mineral density and geometry of the cortex at the level of the forearm in adolescents and young adults with cystic fibrosis, using peripheral quantitative computed tomography. We found that density was normal, but cortical thickness significantly reduced, as well in males as in females. INTRODUCTION: Our goal was to measure bone mineral density as a volumetric density, as well as total cross-sectional area, cortical area and cortical thickness, using peripheral quantitative computed tomography (pQCT) at the forearm in adolescents and young adults with cystic fibrosis. We evaluated relationships between forearm bone measurements and body composition assessed using dual energy X-ray absorptiometry (DXA). METHODS: An XCT 2000 pQCT (Stratec, Pforzheim, Germany) and a QDR 4500 A-upgraded to Discovery DXA device (Hologic, Waltham, MA, USA) were used. RESULTS: Forty-eight patients (31 males,17 females, mean+/-SD 20+/5 years) were studied. Anthropometric features were: height 169+/- 10 cm, SDS 0.05+/-0.12, body mass index 19.8+/- 2.5 kg/m(2), SDS -0.56+/-0.14. Bone mineral density and total cross-sectional area of the forearm and body composition were normal, whereas cortical thickness was significantly reduced in males (mean Z-score - 1.22, p < 0.05), and in females (mean Z-score - 1.61, p < 0.05). Total body lean mass correlated more strongly with cortical thickness (r = 0.72, p < 0.001) than with total bone mineral density at the proximal radius (r = 0.39, p < 0.05). CONCLUSIONS: Adolescents and young adults with cystic fibrosis, presenting with only a slight degree of underweight, have at the radius a preserved bone mineral density but a reduced cortical thickness.
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Fibrosis Quística/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Radio (Anatomía)/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Absorciometría de Fotón/métodos , Adolescente , Adulto , Composición Corporal , Índice de Masa Corporal , Densidad Ósea , Estudios de Casos y Controles , Fibrosis Quística/fisiopatología , Femenino , Humanos , Modelos Lineales , Masculino , Radio (Anatomía)/fisiopatología , Adulto JovenRESUMEN
Treatment of cutaneous melanoma (M-3 and B16-F10 implanted in mice) with rapidly-scanned, tightly-focused near infrared light elicits selective destruction of tumor tissue. A single laser treatment yielded complete eradication in >90% of B16-F10 tumors with thicknesses of approximately 3 mm; amelanotic M-3 tumors proved less responsive (ca 25% clearance rate). In addition to local tumor destruction, laser treatment of B16-F10 tumors in immunocompetent mice stimulated enhanced cytokine levels (interleukin-2 and interleukin-10) within treated tumor tissues and rejection of tumor cells upon a subsequent challenge dose. Such an antitumor immune response may lead to improved outcomes at both the treatment site and at sites of distant metastasis.
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Rayos Infrarrojos , Melanoma Experimental/radioterapia , Neoplasias Cutáneas/radioterapia , Animales , Femenino , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patologíaRESUMEN
Five toxins (APE 1 to APE 5) of the sea anemone species Anthopleura elegantissima (Brandt) have been isolated from a toxic by-product fraction of its concentrated crude watery-methanolic extract, prepared previously for the isolation of a neuropeptide (the head-activator) by Schaller and Bodenmüller (Proc. Natl. Acad. Sci. USA 78 (1981) 7000) from 200kg sea anemones. Toxin purification was performed by desalting of the starting material by dialysis (MWCO 3500) against distilled water, anion exchange chromatography on QAE-Sephadex A25 at pH 8, twice gel filtration on Sephadex G50 m, repeated chromatography on QAE-Sephadex at pH 10 and chromatography on the cation exchanger Fractogel EMD SO(3)(-)-650 M.Final purification of the toxins was achieved by HPLC on MN SP 250/10 Nucleosil 500-5 C(18) PPN and MN SP 250/21 Nucleosil 300-7 C(18). Each toxin was composed of at least two isotoxins of which APE 1-1, APE 1-2, APE 2-1, APE 2-2 and APE 5-3 were isolated in preparative scale. With exception of APE 5-3 the sequences of the isotoxins have been elucidated. They resemble the 47 residue type-I long polypeptide toxins native to Anemonia sulcata (Pennant). All isotoxins paralyse the shore crab (Carcinus maenas) by tetanic contractions after i.m. application. The toxins modify current passing through the fast Na(+) channel in neuroblastoma cells, leading to delayed and incomplete inactivation. APE 1-1, APE 2-1 and APE 5-3 produce a positive inotropic effect in mammalian heart muscle, although they differ in potency. The order of potency is APE 2-1>APE 1-1>APE 5-3 (i.e. threshold concentrations are 1, 10 and 300nM, respectively). In addition, they enhance the spontaneous beating frequency in isolated right atria (guinea pig). The most potent cardiotoxic isotoxin is APE 2-1, its sequence is identical with that of AP-C, a toxin isolated and characterised previously by Norton et al. (Drugs and Foods from the Sea, 1978, University of Oklahoma Press, p. 37-50).LD50 APE 2-1:1 micro g/kg b.w. C. maenas (i.m.). LD50 APE 1-1:10 microg/kg b.w. C. maenas (i. m.). LD50 APE 5-3:50 microg/kg b.w. C. maenas (i.m.).
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Venenos de Cnidarios/aislamiento & purificación , Venenos de Cnidarios/toxicidad , Neurotoxinas/aislamiento & purificación , Péptidos/aislamiento & purificación , Anémonas de Mar , Animales , Células Cultivadas , Cromatografía Líquida de Alta Presión , Cobayas , Dosificación Letal Mediana , Masculino , Ratones , Contracción Miocárdica/efectos de los fármacos , Técnicas de Placa-Clamp , Péptidos/toxicidad , Canales de Sodio/efectos de los fármacosRESUMEN
The excitation and emission properties of several psoralen derivatives are compared using conventional single-photon excitation and simultaneous two-photon excitation (TPE). Two-photon excitation is effected using the output of a mode-locked titanium: sapphire laser, the near infrared output of which is used to promote nonresonant TPE directly. Specifically, the excitation spectra and excited-state properties of 8-methoxypsoralen and 4'-aminomethyl-4,5,8-trimethylpsoralen are shown to be equivalent using both modes of excitation. Further, in vitro feasibility of two-photon photodynamic therapy (PDT) is demonstrated using Salmonella typhimurium. Two-photon excitation may be beneficial in the practice of PDT because it would allow replacement of visible or UV excitation light with highly penetrating, nondamaging near infrared light and could provide a means for improving localization of therapy. Comparison of possible laser excitation sources for PDT reveals the titanium: sapphire laser to be exceptionally well suited for nonlinear excitation of PDT agents in biological systems due to its extremely short pulse width and high repetition rate that together provide efficient PDT activation and greatly reduced potential for biological damage.