Spironolactone effect on circulating procollagen type I carboxy-terminal propeptide: Pooled analysis of three randomized trials.

BACKGROUND: Spironolactone might improve the prognosis of patients with heart failure with preserved left ventricular ejection fraction (HFpEF), but the mechanisms by which it acts are uncertain. Serum concentrations of procollagen type I carboxy-terminal propeptide (PICP) reflect the synthesis of type I collagen and correlate well with histologically proven cardiac fibrosis. AIMS: To investigate the effect of spironolactone on serum PICP concentration in patients with stage B and C HFpEF across three trials (HOMAGE, ALDO-DHF, and TOPCAT) for which measurements of serum PICP were available. METHODS: Random-effects meta-analysis. RESULTS: A total of 1038 patients with PICP measurements available both at baseline and 9-12 months were included in this analysis: 488 (47.0%) from HOMAGE, 386 (37.2%) from ALDO-DHF, and 164 (15.8%) from TOPCAT. The median (percentile25-75) serum PICP was 98 (76-128) ng/mL. Compared to placebo or usual care, administration of spironolactone for 9 to 12 months reduced serum PICP by -7.4 ng/mL, 95%CI -13.9 to -0.9, P-value =0.02. The effect was moderately heterogeneous (I2 = 64%) with the most pronounced effect seen in TOPCAT where PICP was reduced by -27.0 ng/mL, followed by HOMAGE where PICP was reduced by -8.1 ng/mL, and was least marked in ALDO-DHF where PICP changed by -2.9 ng/mL. The association between spironolactone and serum PICP was not mediated substantially by blood pressure. CONCLUSIONS: Spironolactone reduced serum concentrations of PICP in patients with HFpEF with different severity and stages of disease. These findings are consistent with spironolactone having an anti-fibrotic effect.

Extracorporeal Shock Wave Therapy Improves Nontraumatic Knee Contracture in a Rat Model.

BACKGROUND: Joint contractures occur frequently after trauma or immobilization, but few reliable treatments are available. Extracorporeal shock wave therapy (ESWT) is often used for various musculoskeletal conditions, but whether it is effective for treating joint contractures and the mechanisms through which it might work for that condition remain unclear. QUESTIONS/PURPOSES: Using a rat model, we asked, does ESWT (1) inhibit the progression of knee contracture, (2) ameliorate histopathologic joint changes, and (3) improve serum and myofascial fibrosis-related factors? We also asked, (4) what is the possible mechanism by which ESWT inhibits knee contracture? METHODS: Thirty-two male Sprague-Dawley rats (12 weeks old and weighing 300 to 400 g) were randomly separated into two groups: control group (eight rats) and noncontrol group (24) in the first week. Rats in the control group were kept free in cages for 4 weeks, and the right lower limbs of the rats in the noncontrol group were immobilized in plaster for 4 weeks. ROM was then measured for each rat with or without 4 weeks of immobilization. After ROM measurement, rats in the noncontrol group were randomly separated into three groups: immobilization group (eight rats), remobilization group (eight rats), and remobilization with ESWT group (eight rats) at Week 4. Knee contracture was induced in rats by fixing the right knee with a plaster cast as in a previous study. The plaster cast was removed after 4 weeks; knee contracture was established when passive ROM was decreased and dysfunction such as abnormal gait occurred. Subsequently, rats with a remobilized joint contracture were treated with or without ESWT for 15 days (on Days 5, 10, and 15). The therapeutic effect was examined using ROM, joint diameter (as an indication of swelling), histopathologic changes, and the levels of fibrosis-related extracellular matrix component factors (hyaluronic acid, serum procollagen peptide, and laminin). The effect of ESWT on fibrosis protein was also evaluated using immunohistochemistry, quantitative polymerase chain reaction (qPCR), and Western blot. The expressions of factors in the TGF-ß/SMADs pathway were also determined using Western blot and qPCR. RESULTS: ESWT mitigated immobilization-induced knee contracture in rats by improving ROM (immobilization versus remobilization with ESWT: 53° ± 8° versus 32° ± 8° [95% confidence interval 13° to 30°]; p < 0.001) and joint swelling (immobilization versus remobilization with ESWT: 8 ± 0.8 cm versus 6 ± 0.3 cm [95% CI 0.4 to 2.2 cm]; p = 0.01). Histopathologic features of remission were alleviated after ESWT (immobilization versus remobilization with ESWT: thickness of the knee space: 0.2 ± 0.03 mm versus 0.6 ± 0.01 mm [95% CI -0.49 to -0.33 mm]; p < 0.001. On Masson staining, the positive expression area, which indicates collagen fiber deposition, was 24% ± 5% versus 9% ± 2% ([95% CI 10% to 21%]; p < 0.001). ESWT improved the serum fibrosis factors of hyaluronic acid, procollagen peptide, and laminin (immobilization versus remobilization with ESWT: hyaluronic acid: 412 ± 32 versus 326 ±15 ng/mL [95% CI 29 to 144 ng/mL]; p = 0.003; serum procollagen peptide: 19 ± 1 versus 12 ±1 ng/mL [95% CI 3 to 11 ng/mL]; p < 0.001; laminin: 624 ± 78 versus 468 ±9 ng/mL [95% CI 81 to 231 ng/mL]; p = 0.006) and myofascial factors of α-SMA and Type I collagen associated with immobilization-induced contractures. CONCLUSION: The findings suggest that ESWT improved joint contracture by inhibiting the TGF-ß1/SMADs signaling pathway in rats. CLINICAL RELEVANCE: This work suggests ESWT may be worth exploring in preliminary research in humans to determine whether it may be a treatment option for patients with nontraumatic knee contractures. If the mechanism of ESWT can be confirmed in humans, ESWT might be a therapy for diseases involved in the TGF-ß1/SMADs signaling pathway, such as hypertroic scarring and scleroderma.

Quantitative lateral flow immunoassay for rapid detection of procollagen type I N-terminal propeptide in the monitoring of osteoporosis treatment.

Appropriate follow-up after treatment initiation in patients with osteoporosis is challenging. Serum biomarkers may offer more efficient monitoring of bone mineral density (BMD) than the currently used dual X-ray absorptiometry; however, significant changes in BMD often occur over at least 12 months. During teriparatide treatment for osteoporosis, monitoring with markers such as procollagen type I propeptide (PINP), which is derived from osteoblasts, can provide clinically useful information for disease management. However, rapid and cost-effective methods for detecting serum PINP are lacking, necessitating a point-of-care test (POCT) for enhanced follow-up efficiency in osteoporosis management. For the quantitative detection of PINP, we developed a high-sensitivity lateral flow immunoassay with a stacking pad (sLFIA). We established a calibration equation based on the test line/control line ratio obtained from our PINP sLFIA results of various nonspiked serum samples to calculate the PINP concentrations in 40 serum samples and compared the result with those obtained using a fully automated electrochemiluminescence immunoassay. PINP concentrations between these two methods exhibited excellent correlation (R = 0.991). In addition, we assessed the serum PINP concentrations of patients with osteoporosis treated with teriparatide. At the 3-month follow-up, their PINP levels were nearly twice as high as those at baseline, thus implying that our method can be used for osteoporosis treatment monitoring. Our findings thus indicate that the PINP sLFIA can serve as a POCT for monitoring medication response and managing osteoporosis.

Glabridin inhibits liver fibrosis and hepatic stellate cells activation through suppression of inflammation and oxidative stress by activating PPARγ in carbon tetrachloride-treated mice.

Glabridin is an active ingredient extracted from the root of Glycyrrhiza glabra. Previous studies showed that glabridin had potent hepatoprotective effect, however, the effect of glabridin on liver fibrosis and its potential mechanisms remain largely unknown. The present study was aimed to study the effect and potential mechanisms of glabridin on liver fibrosis in carbon tetrachloride (CCl4)-treated mouse livers. Glabridin attenuated the liver injury and improved pathological changes in CCl4-treated mouse livers. Glabridin suppressed the liver fibrosis in CCl4-treated mouse livers, as shown by the decreased collagen deposition, the reduced hydroxyproline level together with the decreased mRNA and protein expression of α-SMA, fibronectin and α1(I)procollagen in mouse livers. Interestingly, glabridin increased the mRNA and protein expression of proliferator-activated receptor gamma (PPARγ) in CCl4-treated mouse livers. In addition, both immunohistochemistry and tissue immunofluorescence showed that glabridin upregulated the expression of PPARγ in CCl4-treated mouse livers. Glabridin evidently reduced the levels of pro-inflammatory factors and increased the level of anti-inflammatory factor in CCl4-treated mouse livers and sera. In addition, Glabridin inhibited the level of MDA and increased the level of GSH as well as the total antioxidant capacity (T-AOC) in CCl4-treated mouse livers. In vitro study showed that glabridin reduced the cell viability of PDGF-BB-stimulated JS-1 cells. Noteworthy, glabridin showed no obvious toxicity on normal JS1 cells. Glabridin inhibited the protein expression of α-SMA, fibronectin and α1(I)procollagen, and increased the expression of PPARγ in stimulated JS-1 cells. Furthermore, disruption of PPARγ attenuated the anti-inflammatory and anti-oxidative stress effects of glabridin in stimulated JS-1 cells. Collectively, glabridin inhibited the liver fibrosis and hepatic stellate cells activation by suppressing inflammation and oxidative stress through activation of PPARγ in carbon tetrachloride-treated mice.

Influence of Renal Function on Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose of Romosozumab.

We evaluated the pharmacokinetics, pharmacodynamics, and safety of a single subcutaneous dose of romosozumab 210 mg, a monoclonal antibody against sclerostin, in an open-label, parallel-group study in participants with severe (stage 4) renal impairment (RI; n = 8) or end-stage renal disease requiring hemodialysis (ESRD-RH; n = 8), or healthy participants with normal renal function (n = 8). Compared with the group with normal renal function, the mean romosozumab exposure was 31% and 43% higher as measured by maximum observed serum concentration and area under the concentration-time curve, respectively, in the severe RI group and similar to those in the ESRD-RH group. For all 3 groups, the maximum mean percent increase in procollagen type 1 N terminal propeptide and decrease in serum C-telopeptide levels from baseline were observed on day 15. Changes in procollagen type 1 N terminal propeptide and serum C-telopeptide were of similar patterns in all 3 groups. The single dose of romosozumab 210 mg was well tolerated. Adverse events (AEs) were reported for 13 patients (7 patients with severe RI and 6 with ESRD-RH), with no deaths, AEs, or serious AEs leading to withdrawal. The incidence of subjects with postbaseline transient decreases in serum calcium (severe RI, n = 1; ESRD-RH, n = 5) and increases in intact parathyroid hormone (severe RI, n = 7; ESRD-RH, n = 7; healthy, n = 3) were greater in severe RI and ESRD-RH groups than in the healthy group. All reported events of hypocalcemia (severe RI, n = 1; ESRD-RH, n = 4) were asymptomatic. These results support the use of romosozumab without dose adjustment in patients with severe RI or ESRD-RH.

Osteogénesis imperfecta. Descripción de 15 casos / Osteogenesis imperfecta. Report of 15 cases

La osteogénesis imperfecta (OI) es un trastorno hereditario del tejido conectivo generalmente relacionado con mutaciones de los genes del colágeno tipoI. El diagnóstico se basa en los hallazgos clínicos y radiológicos. El manejo clínico de la OI en adultos no está del todo establecido y comprende desde la rehabilitación física y los procedimientos quirúrgicos hasta el uso de tratamientos antirresortivos y osteoformadores. El objetivo del presente trabajo ha sido analizar las características clínicas y analíticas de estos pacientes en la edad adulta, así como evaluar los diferentes tratamientos administrados. Se han revisado los casos de OI diagnosticados en nuestro centro en los últimos 12 años (2005-2017). Se describen 15 pacientes adultos con OI

Osteogenesis imperfecta (OI) is an inherited connective tissue disease. The disease has been linked to mutations in one of the type I collagen genes. The diagnosis is based on clinical and radiologic findings. The management of OI in adults is not well-established and includes physical rehabilitation, surgical procedures, the use of antiresorptive therapy and anabolic agents. The aim of the present work was to analyze the clinical and analytical characteristics of these patients in adulthood, as well as to evaluate the different treatments administered. We reviewed the cases of OI diagnosed in our center over the last 12 years (2005-2017). We describe 15 adult patients with OI

Informe de evaluación científica en la evidencia disponible: fibrosis pulmonar idiopática / Relatório de avaliação científica das evidências disponíveis: fibrose pulmonar idiopática

INTRODUCCIÓN: La Fibrosis Pulmonar Idiopática es una enfermedad pulmonar crónica de origen desconocido que afecta al intersticio pulmonar de manera progresiva. Es una enfermedad de difícil diagnóstico que requiere la consulta de neumología, histopatología, y un radiólogo para llegar a consenso en el diagnóstico. La mayoría de la gente con fibrosis pulmonar idiopática experimenta síntomas tales como disnea, y tos, con o sin esputo. Con el tiempo, estos síntomas se asocian con una declinación en la función pulmonar, reducción de la calidad de vida, y últimamente la muerte. La mediana de sobrevida de pacientes con esta enfermedad en el Reino Unido es de aproximadamente 3 años desde el diagnóstico. Sin embargo, alrededor de un 20% de la gente diagnosticada sobrevive más de 5 años. La tasa de progresión de la enfermedad varía bastante. La prognosis de una persona es difícil de estimar al momento del diagnóstico y puede recién volverse aparente después de un período de seguimiento. La FPI es una enfermedad que provoca engrosamiento, rigidez y cicatrización del tejido de sus pulmones a lo largo del tiempo. En consecuencia, la cicatrización reduce la capacidad para transferir oxígeno desde los pulmones al torrente sanguíneo, por lo que resulta difícil respirar profundamente. Los pacientes en una etapa leve de la enfermedad suelen ser asintomáticos, o con suave tos no productiva y disnea en estados de esfuerzo excesivo. Los exámenes de Capacidad Vital Forzada (CVF) pueden dar resultados normales o con leves reducciones en la capacidad. Los pacientes con una etapa moderada se caracterizan por tener disnea en estados de esfuerzo moderado, tos no productiva, y la funcionalidad pulmonar con anormalidades leves a moderadas. En referencia a lo último, la CVF puede presentarse reducida. La etapa avanzada está caracterizada clínicamente por disnea en estados de esfuerzo leve y requerimientos de oxigeno suplementario en estados de descanso y/o esfuerzo. Los exámenes de CVF generalmente muestran reducciones moderadas a severas en la función pulmonar. TECNOLOGÍAS SANITARIA DE INTERÉS: Nintedanib: El tratamiento cuenta con registro en el Instituto de Salud Pública (ISP) e indicación para la condición evaluada. Pirfenidona: El tratamiento cuenta con registro en el ISP e indicación para la condición evaluada. EFICACIA DE LOS TRATAMIENTOS: Se utilizaron 7 revisiones sistemáticas, que muestran el resultado de 7 Ensayos Controlados Aleatorizados (ECAs) para nintedanib, y 13 revisiones sistemáticas, que muestran el resultado de 7 ECAs para pirfenidona. Nintedanib podría reducir la mortalidad en la fibrosis pulmonar idiopática, además de que probablemente disminuya el riesgo de exacerbaciones agudas, y probablemente no se asocia a eventos adversos serios. La pirfenidona disminuye la mortalidad y la progresión de la enfermedad. Además podría reducir el riesgo de exacerbaciones agudas, mientras que tiene efectos adversos gastrointestinales frecuentes, aunque no severos. Por último, el tratamiento con pirfenidona conlleva efectos adversos cutáneos frecuentes, aunque no severos. ALTERNATIVAS DISPONIBLES: Trasplante de pulmón: No existe tratamiento curativo para esta patología. La única alternativa disponible sería el trasplante de pulmón. Sin embargo, esta opción es para un número limitado de pacientes, ya que no todos presentan las condiciones clínicas para esta intervención, por lo que es fundamental que el paciente sea tratado por un broncopulmonar, para el manejo de las exacerbaciones e indicación de kinesioterapia respiratoria y oxígeno en caso de ser necesario. Rehabilitación respiratoria: Por otro lado, la rehabilitación respiratoria reduce la intensidad de la disnea, mejora la capacidad de actividad física y reduce la ansiedad. Además, ésta disminuye el número de hospitalizaciones. Oxigenoterapia: La oxigenoterapia puede disminuir las complicaciones derivadas de niveles bajos de oxígeno en la sangre, facilita la respiración y la actividad física y mejora la sensación de bienestar. RESULTADOS DE LA BÚSQUEDA DE EVIDENCIA: Los resultados de la recopilación de la evidencia son presentados para cada una de las tecnologías evaluadas. La información presentada fue extraída de 21 revisiones sistemáticas publicadas entre los años 2010 a 2016, que evaluaron el tratamiento de pirfenidona y nintedanib para pacientes con fibrosis pulmonar idiopática, en comparación a placebo o tratamiento estándar. CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable, de acuerdo a lo establecido en el Título III. De las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

Efficacy of lanolin and bovine type I collagen in the treatment of childhood anal fissures: a prospective, randomized, controlled clinical trial.

PURPOSE: We designed an open-labeled, prospective, randomized, controlled clinical trial to test the efficacy of topical lanolin ointment (PureLan) and bovine type I collagen spray (Gelfix) in the treatment of childhood anal fissures. METHODS: Seventy-one children with acute anal fissure were divided randomly into three groups: group I (control; n = 25), group II (PureLan; n = 28), and group III (Gelfix; n = 18). All children were assigned to have warm sitz baths, topical analgesic creams, and stool softeners. Patients in groups II and III were also treated with topical lanolin ointment and bovine type I collagen, respectively. All children were re-examined 4 weeks later. RESULTS: Complete healing of the anal fissure was observed in 68% of the group I patients, but in 92.9% and 100% of the group II and III patients, respectively. The difference among groups was significant in terms of complete fissure healing (P = 0.003), but the efficacy of topical lanolin ointment and bovine type I collagen spray did not differ significantly (P = 0.078). CONCLUSION: Our data suggest that topical lanolin ointment and bovine type I collagen spray are effective in the treatment of acute anal fissure in children.

Moving one step closer to catching the GH cheats: The GH-2004 experience.

Growth hormone is abused by athletes for its anabolic and lipolytic properties. The detection of GH abuse is challenging because it is an endogenous hormone whose concentration varies widely in any one day. The GH-2000 project proposed a test based on the measurement of IGF-I and type III pro-collagen (P-III-P). When the results of the GH-2000 project were presented to an expert workshop, the method was supported but it was felt that several issues needed to be resolved before the method could be adopted. The first was a potential effect of ethnicity as most subjects in the GH-2000 were white Europeans and the second was a possible effect of injury as P-III-P is a marker of soft tissue turnover. The GH-2004 project was conceived to address these concerns. The GH-2004 project has shown that while there are minor differences in IGF-I and P-III-P between ethnicities, these are small and do not affect the performance of the test. Injury leads to a small rise in P-III-P but again this is not of sufficient magnitude to affect the performance of the test. The GH-2004 project has provided further support for the marker approach as a means of detecting GH abuse in athletes. As WADA have not developed their own immunoassays, however, further work is needed to validate newer commercial assays measuring IGF-I and P-III-P to establish reliable conversion factors to the original GH-2000 units to allow the published formulae to be used.

Activated, type I collagen (CellerateRx) and its effectiveness in healing recalcitrant diabetic wounds: a case presentation.

OBJECTIVE: To review the authors' experience with activated type I collagen in the treatment of recalcitrant wounds in the diabetic population resulting from minor trauma and/or venous stasis disease. With regard to activated collagen, CellerateRx's patented activated collagen fragments are a fraction of the size of the native collagen molecules and particles found in other products, delivering the benefits of collagen to the body immediately. DESIGN: A 2-case presentation wherein patients were treated with CellerateRx (activated, fragmented, and nonintact type I collagen) in a gel and powder form. SUBJECTS: Two middle-aged diabetic male patients with lower extremity wounds refractory to conservative wound care. RESULTS: Complete resolution of recalcitrant wounds in 6 to 7 weeks. CONCLUSIONS: Wound resolution was evident when using the authors' practice protocol, which includes the application of activated collagen. The inherent properties of type I collagen may contribute to a more rapid healing process.

Marcadores bioquímicos de remodelado óseo: aspectos descriptivos / Biochemical markers of bone turnover: descriptives aspects

La osteoporosis posmenopáusica es un problema de salud pública mundial, y su principal causa es la deficiencia estrogénica. El metabolismo óseo presenta dos actividades opuestas: la formación de hueso nuevo por el osteoblasto y la degradación o resorción de hueso viejo por el osteoclasto. Dado que estas actividades cursan con el vertido a la circulación de una serie de productos, los denominados marcadores bioquímicos de remodelado óseo, nosotros podemos estimar la tasa de ambos procesos determinando los valores séricos o urinarios de estos productos en el laboratorio. Estos marcadores son una poderosa herramienta para el ginecólogo, ya que su determinación es fácil de realizar, es barata, puede ser repetida a menudo y refleja el metabolismo óseo en un momento dado. En los últimos años se han desarrollado marcadores más específicos como los telopéptidos del colágeno tipo I (CTx y NTx), y se están introduciendo métodos automatizados para su determinación que disminuyen la variabilidad intra e interensayo, aunque existen diversas fuentes de variabilidad que deben tenerse en cuenta a la hora de evaluar su uso (AU)