Prevention of sclerosis around cannulated screw after treatment of femoral neck fractures with bioceramic nails: a finite element analysis.

PURPOSE: Conventional cannulated screws (CS) are the main treatment method for femoral neck fractures (FNF). However, the rate of femoral head necrosis remains high after FNF treatment. The study aimed to compare the biomechanical features of different internal fixation materials for the treatment of Pauwel type III FNF to explore new strategies for clinical management. METHODS: A new material was prepared by applying casting, freeze drying and sintering process. The independently developed calcium magnesium silicate ceramic powder and hydrogel solution were evenly mixed to obtain a high-viscosity bio-ink, and a bioceramic nail (BN) with high mechanical strength and high fracture toughness was successfully prepared. Four internal fixations were developed to establish the Pauwel type III FNF and healed fracture finite element models: A, three CSs; B, three BNs; C, two BNs and one CS; D, one BN and two CSs. Von Mises stress and displacement of the implants and femur were observed. RESULTS: The measured Mg content in ceramic powder was 2.08 wt%. The spectral data confirmed that the ceramic powder has high crystallinity, which coincides with the wollastonite-2 M (PDF# 27-0088). The maximum von Mises stresses for the four models were concentrated in the lower part of the fracture surface, at 318.42 Mpa, 103.52 MPa, 121.16 MPa, and 144.06 MPa in models A, B, C, and D, respectively. Moreover, the maximum Von-mises stresses of the implants of the four models were concentrated near the fracture end at 243.65 MPa (A) and 58.02 MPa (B), 102.18 MPa (C), and 144.06 MPa (D). The maximum displacements of the four models were 5.36 mm (A), 3.41 mm (B), 3.60 mm (C), and 3.71 mm (D). The displacements of the three models with BNs were similar and smaller than that of the triple CS fracture model. In the fracture healing models with and without three CSs, the greatest stress concentration was scattered among the lowest screw tail, femoral calcar region, and lateral femur shaft. The displacement and stress distributions in both models are generally consistent. The stress distribution and displacement of the three healed femoral models with BNs were essentially identical to the healing models with three CSs. The maximum von Mises stresses were 65.94 MPa (B), 64.61 MPa (C), and 66.99 MPa (D) while the maximum displacements of the three healed femoral models were 2.49 mm (B), 2.56 mm (C), and 2.49 mm (D), respectively. CONCLUSIONS: Bioceramic nails offer greater advantages than conventional canulated screws after femoral neck fractures. However, the combination of bioceramic nails and CSs is more clinically realistic; replacing all internal fixations with bioceramic nails after the healing of femoral neck fractures can solve the problem of sclerosis formation around CSs and improve bone reconstruction by their bioactivity.

Saúde incorpora o natalizumabe para o tratamento da esclerose

Os pacientes que sofrem de esclerose múltipla ganham mais um aliado no combate à doença. O Ministério da Saúde ampliou o uso do natalizumabe no tratamento da esclerose múltipla remitente-recorrente que representa 85% dos casos da doença.

Neuroprotective effects and improvement of learning and memory elicited by erythravine and 11α-hydroxy-erythravine against the pilocarpine model of epilepsy.

Deficits in cognitive functions are often observed in epileptic patients, particularly in temporal lobe epilepsy (TLE). Evidence suggests that this cognitive decline can be associated with the occurrence of focal brain lesions, especially on hippocampus and cortex regions. We previously demonstrated that the erythrinian alkaloids, (+)-erythravine and (+)-11α-hydroxy-erythravine, inhibit seizures evoked in rats by different chemoconvulsants. AIMS: The current study evaluated if these alkaloids would be acting in a neuroprotective way, reducing hippocampal sclerosis, and consequently, improving learning/memory performance. MAIN METHODS: Here we confirmed the anticonvulsant effect of both alkaloids by means of the pilocarpine seizure-induced model and also showed that they enhanced spatial learning of rats submitted to the Morris Water Maze test reverting the cognition deficit. Additionally, immunohistochemistry assays showed that neuronal death and glial activation were prevented by the alkaloids in the hippocampus CA1, CA3 and dentate gyrus regions at both hemispheres indistinctly 15 days after status epilepticus induction. KEY FINDINGS: Our results show, for the first-time, the improvement on memory/learning elicited by these erythrinian alkaloids. Furthermore, data presented herein explain, at least partially, the cellular mechanism of action of these alkaloids. Together, (+)-erythravine and (+)-11α-hydroxy-erythravine seem to be a promising protective strategy against TLE, comprising three main aspects: neuroprotection, control of epileptic seizures and cognitive improvement. SIGNIFICANCE: Moreover, our findings on neuroprotection corroborate the view that seizure frequency and severity, hippocampal lesions and memory deficits are interconnected events.

Rac1 GTPase Inhibition Blocked Podocyte Injury and Glomerular Sclerosis during Hyperhomocysteinemia via Suppression of Nucleotide-Binding Oligomerization Domain-Like Receptor Containing Pyrin Domain 3 Inflammasome Activation.

Elevated homocysteine (Hcy) levels have been shown to activate nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome leading to podocyte dysfunction and glomerular injury. However, it remains unclear how this inflammasome activation in podocytes is a therapeutic target for reversal of glomerular injury and ultimate sclerosis. The present study tested whether inhibition of Rac1 GTPase activity suppresses NLRP3 inflammation activation and thereby blocks podocyte injury induced by elevated Hcy. In cultured podocytes, we found that L-Hcy (the active Hcy form) stimulated the NLRP3 inflammasome formation, as shown by increased colocalization of NLRP3 with apoptosis-associated speck-like protein (ASC) or caspase-1, which was accompanied by increased interleukin-1ß production and caspase-1 activity, indicating NLRP3 inflammasome activation. Rac1 activator, uridine triphosphate (UTP), mimicked L-Hcy-induced NLRP3 inflammasome activation, while Rac1 inhibitor NSC23766 blocked it. This Rac1 inhibition also prevented L-Hcy-induced podocyte dysfunction. All these effects were shown to be mediated via lipid raft redox signaling platforms with nicotinamide adenine dinucleotide phosphate oxidase subunits and consequent O2- production. In animal studies, hyperhomocysteinemia (hHcy) induced by folate-free diet was shown to induce NLRP3 inflammasome formation and activation in glomeruli, which was also mimicked by UTP and inhibited by NSC23766 to a comparable level seen in Nlrp3 gene knockout mice. These results together suggest that Rac1 inhibition protects the kidney from hHcy-induced podocyte injury and glomerular sclerosis due to its action to suppress NLRP3 inflammasome activation in podocytes.

Porphyrin-Based SOD Mimic MnTnBu OE -2-PyP5+ Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis.

Background Aortic valve sclerosis ( AVS c), the early asymptomatic presentation of calcific aortic valve (AV) disease, affects 25% to 30% of patients aged >65 years. In vitro and ex vivo experiments with antioxidant strategies and antagonists of osteogenic differentiation revealed that AVS c is reversible. In this study, we characterized the underlying changes in the extracellular matrix architecture and valve interstitial cell activation in AVSc and tested in vitro and in vivo the activity of a clinically approved SOD (superoxide dismutase) mimic and redox-active drug MnTnBu OE -2-PyP5+ ( BMX -001). Methods and Results After receiving informed consent, samples from patients with AVS c, AV stenosis, and controls were collected. Uniaxial mechanical stimulation and in vitro studies on human valve interstitial cells were performed. An angiotensin II chronic infusion model was used to impose AV thickening and remodeling. We characterized extracellular matrix structures by small-angle light scattering, scanning electron microscopy, histology, and mass spectrometry. Diseased human valves showed altered collagen fiber alignment and ultrastructural changes in AVS c, accumulation of oxidized cross-linking products in AV stenosis, and reversible expression of extracellular matrix regulators ex vivo. We demonstrated that MnTnBu OE -2-PyP5+ inhibits human valve interstitial cell activation and extracellular matrix remodeling in a murine model (C57 BL /6J) of AVS c by electron microscopy and histology. Conclusions AVS c is associated with architectural remodeling despite marginal effects on the mechanical properties in both human and mice. MnTnBu OE -2-PyP5+ controls AV thickening in a murine model of AVS c. Because this compound has been approved recently for clinical use, this work could shift the focus for the treatment of calcific AV disease, moving from AV stenosis to an earlier presentation ( AVS c) that could be more responsive to medical therapies.

IL-33-Mediated Expansion of Type 2 Innate Lymphoid Cells Protects from Progressive Glomerulosclerosis.

Innate lymphoid cells (ILCs) have an important role in the immune system's response to different forms of infectious and noninfectious pathologies. In particular, IL-5- and IL-13-producing type 2 ILCs (ILC2s) have been implicated in repair mechanisms that restore tissue integrity after injury. However, the presence of renal ILCs in humans has not been reported. In this study, we show that ILC populations are present in the healthy human kidney. A detailed characterization of kidney-residing ILC populations revealed that IL-33 receptor-positive ILC2s are a major ILC subtype in the kidney of humans and mice. Short-term IL-33 treatment in mice led to sustained expansion of IL-33 receptor-positive kidney ILC2s and ameliorated adriamycin-induced glomerulosclerosis. Furthermore, the expansion of ILC2s modulated the inflammatory response in the diseased kidney in favor of an anti-inflammatory milieu with a reduction of pathogenic myeloid cell infiltration and a marked accumulation of eosinophils that was required for tissue protection. In summary, kidney-residing ILC2s can be effectively expanded in the mouse kidney by IL-33 treatment and are central regulators of renal repair mechanisms. The presence of ILC2s in the human kidney tissue identifies these cells as attractive therapeutic targets for CKD in humans.

Hippocampal Sclerosis: Causes and Prevention.

Hippocampal sclerosis is the commonest cause of drug-resistant epilepsy in adults, and is associated with alterations to structures and networks beyond the hippocampus.In addition to being a cause of epilepsy, the hippocampus is vulnerable to damage from seizure activity. In particular, prolonged seizures (status epilepticus) can result in hippocampal sclerosis. The hippocampus is also vulnerable to other insults including traumatic brain injury, and inflammation. Hippocampal sclerosis can occur in association with other brain lesions; the prevailing view is that it is probably a secondary consequence. In such instances, successful surgical treatment usually involves the resection of both the lesion and the involved hippocampus. Experimental data have pointed to numerous neuroprotective strategies to prevent hippocampal sclerosis. Initial neuroprotective strategies aimed at glutamate receptors may be effective, but later, metabolic pathways, apoptosis, reactive oxygen species, and inflammation are involved, perhaps necessitating the use of interventions aimed at multiple targets. Some of the therapies that we use to treat status epilepticus may neuroprotect. However, prevention of neuronal death does not necessarily prevent the later development of epilepsy or cognitive deficits. Perhaps, the most important intervention is the early, aggressive treatment of seizure activity, and the prevention of prolonged seizures.

Osteopetrosis autosómica dominante: a propósito de 3 casos y una mutación / Autosomal dominant osteopetrosis: A presentation of 3 cases and a new gene mutation

La osteopetrosis (OP) es una rara enfermedad ósea congénita producida por una alteración funcional en los osteoclastos con incapacidad para la reabsorción ósea normal, produciéndose un aumento de la densidad mineral ósea y esclerosis ósea. Puede clasificarse en autosómica recesiva (OPTB) o autosómica dominante (OPTA1-2). Existe una gran variabilidad clínica de la enfermedad, desde asintomática a letal en los primeros meses de vida, con expresividad variable en los miembros de una familia. Su diagnóstico es principalmente clínico con confirmación genética, y el tratamiento es sintomático. Se presentan una serie de casos de OP, con el hallazgo de una nueva mutación en el gen LRP5 causante de OPTA1 en uno de ellos

Osteopetrosis (OP) is a congenital bone disease which is caused by a functional disorder in osteoclasts with inability for normal bone resorption, leading to increased bone mineral density and bone sclerosis. It can be classified into different groups according to their clinical and their genetic characteristics: autosomal recessive with several subtypes (OPTB) or autosomal dominant type 1 or 2 (OPTA1-2). There is a wide clinical variability of the disease, from asymptomatic to lethal in the first months of life, with variable expressivity in the family members. Diagnosis is mainly clinical with genetic confirmation of the OP, and treatment is symptomatic. Three cases of OP are presented, with the discovery of a new gene mutation in LRP5 which caused OPTA1 in one of them

R-268712, an orally active transforming growth factor-ß type I receptor inhibitor, prevents glomerular sclerosis in a Thy1 nephritis model.

R-268712 is a novel and specific inhibitor of activin receptor-like kinase 5 (ALK5), a transforming growth factor ß (TGF-ß) type I receptor. Evaluation of in vitro inhibition indicated that R-268712 is a potent and selective inhibitor of ALK5 with an IC50 of 2.5nM, an approximately 5000-fold more selectivity for ALK5 than p38 mitogen-activated protein kinase (MAPK). Oral administration of R-268712 at doses of 1, 3 and 10mg/kg also inhibited the development of renal fibrosis in a dose-dependent manner in a unilateral ureteral obstruction (UUO) model. Additionally, we evaluated the efficacy of R-268712 in a heminephrectomized anti-Thy1 glomerulonephritis model at doses of 0.3 and 1mg/kg. R-268712 reduced proteinuria and glomerulosclerosis significantly with improvement of renal function. Collectively, these results suggested that R-268712 and other ALK5 inhibitors could suppress glomerulonephritis as well as glomerulosclerosis by an inhibitory mechanism that involves suppression of TGF-ß signaling.

[An experimental study of the effectiveness of the drug afalaza in chronic aseptic prostatitis].

A pilot study evaluated the efficacy of the drug afalaza (mixture of affinity purified antibodies to PSA and endothelial NO-synthase) compared with the Serenoa repens extract in a model of chronic abacterial prostatitis in Wistar rats caused by suturing of prostate tissue by silk thread. Except for the animals of intact group, rats (n = 13 in each group) underwent intraperitoneal injection of distilled water (10 ml/kg), afalaza (at a doses of 5, 7.5 and 10 ml/kg) or an Serenoa repens extract (50 mg/kg) 1 month after surgery for 45 days. After infusion, the mass, volume, and prostate weighting factor were evaluated, and prostate tissue was examined histologically. 2.5 months after surgery, development of chronic abacterial prostatitis was observed in the control group. Compared with intact group, significant increase in weight, weighting factor, and volume of prostate were detected in control group. Against the background of administration of Serenoa repens extract and afalaza, these parameters were not significantly different from control values. The use of Serenoa repens extract prevented the development of atrophic processes and slowed the development of sclerotic processes. Administration of afalaza at all studied doses prevented the development of sclerotic changes, and a dose of 7.5 ml/kg prevented the development of atrophic processes with the effectiveness matching to Serenoa repens extract. Taking into account the high safety of afalaza, this drug is a promising treatment for chronic prostatitis.

Radiofrequency ablation as a possible method for preparing pathologically altered myocardium for intramyocardial cell transplantation.

We studied the effects of radiofrequency ablation on the results of intramyocardial transplantation of bone marrow NSC into the myocardium of rats with postinfarction cardiosclerosis. It was shown that exposure of the pathologically changed myocardium to radiofrequency radiation led to destruction of formed connective tissue. Transplantation of MSC into sites exposed to radiofrequency radiation promoted the development of regenerative processes (abundant infiltration with mononuclear cells, presence of granulation tissue, and numerous newly formed blood vessels). We concluded that preliminary radiofrequency irradiation of the myocardial areas promotes realization of the regenerative potential of cell transplantation.

Review of the literature and description of a case of sclerosing encapsulating peritonitis requiring home parenteral nutrition.

We present a case of a 48 year old HIV patient, who had recurrent episodes of ascites since 2007. His history includes ischaemic heart disease, for which he was treated with atenolol from 2005 to 2007, and Type 2 diabetes; he was later started on propranolol 40  mg twice a day from 2007 for Didanosine-induced portal hypertension. Because of negative cultures and neutrophil count < 250 cells/µL, spontaneous bacterial peritonitis was excluded. However, some low grade-peritoneal irritation cannot be ruled out because his CRP varied from 24 to 258, during 2007 - 2009, without any other obvious inflammatory cause. He was finally diagnosed in July 2009 with sclerosing encapsulating peritonitis (SEP) based on clinical features of intestinal obstruction, histology and imaging, including computed tomography and magnetic resonance imaging. Propranolol was stopped in November 2009.  Because of the patient's severe intestinal obstruction, he was started on parenteral nutrition 2  L/day. Since then, his CRP has returned to normal levels and there is a great improvement of his clinical features. This case demonstrates beta-blockers as a potential cause of SEP, while the presence of some low-grade peritoneal inflammation leading to SEP is also very likely.

Neuroprotective effect of levetiracetam on hippocampal sclerosis-like change in spontaneously epileptic rats.

The spontaneously epileptic rat (SER) begins to exhibit both tonic convulsions and absence seizures from 6 weeks of age and SERs have stable seizures after 10 weeks of age. Low-dose administrations of levetiracetam (LEV) for 4- to 5-weeks-old SERs which did not show spontaneous seizures reduced both seizures 5 weeks after termination of administration. The hippocampus of SER exhibited decreased CA3 neurons, sprouting of mossy fibers, and hyperexpression of the brain-derived neurotrophic factor (BDNF). We attempted prophylactic LEV administrations in preseizure-manifesting SERs to evaluate if such a treatment regimen would protect the hippocampal sclerosis-like changes observed in SERs. The osmotic mini-pump administered LEV dissolved in saline to 4-weeks-old SERs for 4 weeks at 2.5 µl/h. LEV was administered at 420 mg/ml for 4 weeks in Group A. In Group B, LEV was given at 420 mg/ml for the first 2 weeks followed by doubling the dosage (840 mg/ml) in the following 2 weeks. LEV administrations in preseizure-manifesting SERs reduced the decrease of CA3 neurons and mossy fibers sprouting at 10-11 weeks of age in both group A and B. LEV attenuated BDNF expression in inner molecular layers of the dentate gyrus, striatum radiatum, and CA3 in 10- to 11- and 14- to 15-weeks-old SERs. In group B, LEV decreased BDNF expression in hilus and CA1 of 10- to 11- weeks-old SER. The present results suggest that prophylactic treatment with LEV in preseizure-manifesting SERs inhibits hippocampal sclerosis-like neuronal degeneration and/or regeneration.

The preventive effect of N-nitro L-arginine methyl ester in experimentally induced myringosclerosis.

OBJECTIVE: The purpose of this study was to investigate the antiinflammatory and antifibrotic effects of N-nitro L-arginine methyl ester (L-name) in experimentally induced myringosclerosis. METHODS: Twenty Wistar albino rats were bilaterally myringotomized and divided randomly into four groups, each including five rats. Group I received no treatment, Group II was treated with topical saline solution, Group III received topical L-NAME and Group IV received intraperitoneally administered L-NAME. After 2 weeks, the tympanic membranes were examined and scored by otomicroscopy regarding the extent of the myringosclerosis. Then the tympanic membranes were harvested and evaluated histopathologically by light microscopy. The intensity of inflammation and degree of myringosclerosis were evaluated, the mean thickness of tympanic membranes were also measured. RESULTS: The tympanic membranes of Groups I and II showed extensive myringosclerosis in contrast to those of Groups III and IV which had significantly less or no changes (p < 0.05). The inflammation and fibroblastic activity of the lamina propria in the tympanic membranes of Groups III and IV were found to be significantly less pronounced (p < 0.05). The tympanic membranes were found to be significantly thicker in Groups I and II when compared with Groups III and IV (p < 0.05). CONCLUSION: Our results showed that both topical and intraperitoneal applications of L-NAME supressed inflammation, reduced fibroblastic proliferation and decreased the formation of myringosclerosis in myringotomized rat tympanic membranes.

Antroquinonol reduces oxidative stress by enhancing the Nrf2 signaling pathway and inhibits inflammation and sclerosis in focal segmental glomerulosclerosis mice.

Oxidative stress, inflammation, and fibrosis are involved in the development and progression of focal segmental glomerulosclerosis (FSGS), a common form of idiopathic nephrotic syndrome that represents a therapeutic challenge because it has a poor response to steroids. Antroquinonol (Antroq), a purified compound, is a major active component of a mushroom, namely Antrodia camphorata, that grows in the camphor tree in Taiwan, and it has inhibitory effects on nitric oxide production and inflammatory reactions. We hypothesized that Antroq might ameliorate FSGS renal lesions by modulating the pathogenic pathways of oxidative stress, inflammation, and glomerular sclerosis in the kidney. We demonstrate that Antroq significantly (1) attenuates proteinuria, renal dysfunction, and glomerulopathy, including epithelial hyperplasia lesions and podocyte injury; (2) reduces oxidative stress, leukocyte infiltration, and expression of fibrosis-related proteins in the kidney; (3) increases renal nuclear factor E2-related factor 2 (Nrf2) and glutathione peroxidase activity; and (4) inhibits renal nuclear factor-κB (NF-κB) activation and decreases levels of transforming growth factor (TGF)-ß1 in serum and kidney tissue in a mouse FSGS model. Our data suggest that Antroq might be a potential therapeutic agent for FSGS, acting by boosting Nrf2 activation and suppressing NF-κB-dependent inflammatory and TGF-ß1-mediated fibrosis pathways in the kidney.

A low-protein diet supplemented with ketoacids plays a more protective role against oxidative stress of rat kidney tissue with 5/6 nephrectomy than a low-protein diet alone.

Dietary protein restriction is one major therapy in chronic kidney disease (CKD), and ketoacids have been evaluated in CKD patients during restricted-protein diets. The objective of the present study was to compare the efficacy of a low-protein diet supplemented with ketoacids (LPD+KA) and a low-protein diet alone (LPD) in halting the development of renal lesions in CKD. 5/6 Nephrectomy Sprague-Dawley rats were randomly divided into three groups, and fed with either 22 % protein (normal-protein diet; NPD), 6 % protein (LPD) or 5 % protein plus 1 % ketoacids (LPD+KA) for 24 weeks. Sham-operated rats were used as controls. Each 5/6 nephrectomy group included fifteen rats and the control group included twelve rats. Proteinuria, decreased renal function, glomerular sclerosis and tubulointerstitial fibrosis were found in the remnant kidneys of the NPD group. Protein restriction ameliorated these changes, and the effect was more obvious in the LPD+KA group after 5/6 nephrectomy. Lower body weight and serum albumin levels were found in the LPD group, indicating protein malnutrition. Lipid and protein oxidative products were significantly increased in the LPD group compared with the LPD+KA group. These findings indicate that a LPD supplemented with ketoacids is more effective than a LPD alone in protecting the function of remnant kidneys from progressive injury, which may be mediated by ketoacids ameliorating protein malnutrition and oxidative stress injury in remnant kidney tissue.

The effect of topical doxycycline in the prevention of experimental tympanosclerosis.

OBJECTIVES: The aim of this study is to determine the effectiveness of topical doxycycline used in the process of experimental myringosclerosis and tympanosclerosis. STUDY DESIGN: A prospective experimental animal study. METHODS: Experimental tympanosclerosis was accomplished in 25 healthy adult guinea pigs by inoculation with 2.5 x 10(7) colony-forming units of type-3 Streptococcus pneumoniae microorganisms followed by bilateral myringotomy. While the animals' right ears received a topical doxycycline treatment daily, their left ears were left untreated and used as controls. Otomicroscopic examination was carried out weekly and healing tympanic membranes were remyringotomized. After a 6-week follow-up, the temporal bones of 24 of 25 animals were removed and light-microscopy examination was done regarding tympanic membrane myringosclerosis and middle ear mucosal sclerosis. RESULTS: Myringosclerosis was noticed to a lesser extent in the doxycycline-treated group when compared to the untreated control group. Light microscopy evaluation revealed a difference in the area and thickness of the sclerotic plaques of myringosclerosis of the tympanic membranes in the doxycycline-treated group and the control group, being significantly smaller and thinner in the treated group (P < .001, P < .04, respectively). Similarly, the area and thickness of the sclerotic plaques in the middle ear mucosa were significantly smaller and thinner in the doxycycline treated group (P < .001, P < .03). CONCLUSION: This study demonstrated that the potent matrix metallo-proteinase inhibitor doxycycline plays a preventive role in the development of experimentally induced tympanosclerosis.

Rapamycin inhibits PAI-1 expression and reduces interstitial fibrosis and glomerulosclerosis in chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) is characterized by deposition of extracellular matrix (ECM) in all renal compartments. PAI-1 seems to play a pivotal role in ECM turnover in CAN. Rapamycin has been shown to improve long-term graft survival in patients with CAN. The aim of the study was to evaluate the molecular mechanisms underlying the beneficial effects of rapamycin on CAN progression at glomerular and tubulointerstitial level. METHODS: After a biopsy-proven CAN diagnosis (T0), 18 patients on calcineurin inhibitors (CNI) were randomly assigned in a 2:1 ratio to continue CNI (6 patients) or to receive rapamycin (RAPA; 12 patients). After 2 years of treatment (T24), all patients underwent a second renal biopsy. Morphometric analysis was conducted at T0 and at T24. PAI-1 expression was evaluated at T0 and T24 by immunohistochemistry. We evaluated the effect of rapamycin on PAI-1 gene expression in cultured proximal tubular cells incubated with CD40L or thrombin, two potential CAN pathogenic mediators. RESULTS: The RAPA group showed a significant regression of glomerulosclerotic lesions and only a 26% increase in interstitial fibrosis after 2 years compared to baseline, whereas the CNI group showed progression of glomerulosclerosis and 112% increase in fibrosis. Glomerular and tubulointerstitial PAI-1 expression was reduced compared to the baseline in the RAPA group, while they were unchanged in the CNI group. In vitro data showed that rapamycin significantly reduced PAI-1 gene expression induced by both CD40L and thrombin in proximal tubular epithelial cells. CONCLUSIONS: These data suggest that rapamycin may modulate ECM deposition in CAN reducing PAI-1 expression.

Effects of topical mitomycin and trimetazidine on myringosclerosis.

INTRODUCTION: Myringosclerosis, one of the most common complications of ventilation tube placement, is a kind of tympanosclerosis and is defined as subepithelial hyalinization of the tympanic membrane. There are two arguments in the development of myringosclerosis: inflammation triggering the development of myringosclerosis and free oxygen radicals released during inflammation causing myringosclerosis. OBJECTIVE: The aim of the present study was to explore the effects on the development of myringosclerosis of mitomycin, which has anti-inflammatory effects, and trimetazidine, which is believed to inhibit free oxygen radicals when given systemically. MATERIALS AND METHOD: The study was carried out on rabbits. Animals were divided into five groups, with six rabbits in each group: three control groups (paracentesis only, paracentesis+tube placement, and no intervention), a trimetazidine group, and a mitomycin group. Mitomycin (0.4 mg/mL) and trimetazidine (20 mg/mL) were applied topically to the tympanic membrane, and the presence and degree of sclerosis were graded histopathologically after Masson's trichrome staining. RESULTS: In the histopathologic examination, sclerosis that developed in the tympanic membranes of rabbits that had undergone paracentesis or paracentesis plus tube application or received trimetazidine was significantly more extensive than sclerosis in the membranes of unoperated animals and those that had been administered mitomycin. CONCLUSIONS: Paracentesis in rabbits, independent of tube placement, causes sclerosis of the tympanic membrane. Results show that topical use of mitomycin, due to its anti-inflammatory effect, had alleviating effects on myringosclerosis, whereas topical trimetazidine did not.

The effect of caffeic acid phenethyl ester on the prevention of experimentally induced myringosclerosis.

OBJECTIVES: Myringosclerosis is a common sequela of ventilation tube insertion for the treatment of the otitis media with effusion. Several antioxidants have been identified to prevent myringosclerosis. The objective of this study was to investigate the effect of caffeic acid phenethyl ester (CAPE) on the prevention of experimentally induced myringosclerosis. METHODS: Thirty-five Sprague-Dawley rats were unilaterally myringotomized. The rats were divided into four groups randomly: group 1 received no treatment, group 2 received intraperitoneally administered saline and group 3 received intraperitoneally administered CAPE. The tympanic membranes were examined by otomicroscopy on the 15th day after treatment. The membranes were then harvested and evaluated histologically by light microscopy. RESULTS: The tympanic membranes from group 1 showed extensive myringosclerosis; those from group 2 showed a similar occurrence of myringosclerosis. However, group 3 had a reduced occurrence of myringosclerosis by otomicroscopic evaluation. Under light microscopic examination, the lamina propria of the pars tensa was found to be thicker and more sclerotic in groups 1 and 2 when compared with group 3. CONCLUSIONS: Systemic treatment with CAPE was found to be effective in the prevention of sclerotic lesions in myringotomized rat tympanic membranes.