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This study was designed to explore the effect and mechanism of Gegen Qinlian Decoction(GQD) on cardiac function of diabetic mice with damp-heat syndrome. The db/db diabetic mice were exposed to the damp-heat environment test chamber for inducing the damp-heat syndrome. Forty-eight six-week-old db/db mice were randomly divided into six groups, namely the db/db diabetic model group, db/db diabetic mouse with damp-heat syndrome(db/db-dh) group, db/db diabetic mouse with damp-heat syndrome treated with low-dose GQD(db/db-dh+GQD-L) group, db/db-dh+GQD-M(medium-dose) group, db/db-dh+GQD-H(high-dose) group, and db/db-dh+lipro(liprostatin-1, the inhibitor of ferroptosis) group, with eight six-week-old db/m mice classified into the control group. The results showed that mice presented with the damp-heat syndrome after exposure to thequot;high-fat dietquot; andquot;damp-heat environmentquot;, manifested as the elevated fasting blood glucose, reduced food intake, low urine output, diarrhea, listlessness, loose and coarse hair, and dark yellow and lusterless fur. However, the intragastric administration of the high-dose GQD for 10 weeks ameliorated the above-mentioned symptoms, inhibited myocardial hypertrophy and fibrosis, and improved the cardiac diastolic function of db/db-dh mice. qPCR suggested that GQD regulated the expression of ferroptosis-related genes, weakened the lipid peroxidation in the myocardium, and up-regulated glutathione peroxidase 4(GPX4) expression in comparison with those in the db/db-dh group. At the same time, the ferroptosis inhibitor liprostatin-1 significantly improved the cardiac function and reversed the cardiac remodeling of db/db-dh mice. It can be concluded that the damp-heat syndrome may aggravate myocardial ferroptosis and accelerate cardiac remodeling of db/db mice, thus leading to diastolic dysfunction. GQD is able to improve cardiac remodeling and diastolic function in diabetic mice with damp-heat syndrome, which may be related to its inhibition of myocardial ferroptosis.

Inflammation and apoptosis of vascular endothelial cells play a key role in the occurrence and development of atherosclerosis (AS), and the AMPK/mTOR/Nrf2 signaling pathway plays an important role in alleviating the symptoms of AS. Geniposide combined with notoginsenoside R1 (GN combination) is a patented supplement for the prevention and treatment of AS. It has been proven to improve blood lipid levels and inhibit the formation of AS plaques; however, it is still unclear whether GN combination can inhibit inflammation and apoptosis in AS by regulating the AMPK/mTOR/Nrf2 signaling pathway and its downstream signals. Our results confirmed that the GN combination could improve blood lipid levels and plaque formation in ApoE−/− mice fed with a high-fat diet (HFD), inhibit the secretion of serum inflammatory factors and oxidative stress factors. It also decreased the expression of pyrin domain containing protein 3 (NLRP3) inflammasome-related protein and Bax/Bcl2/caspase-3 pathway-related proteins. At the same time, the GN combination could also inhibit the H2O2-induced inflammatory response and apoptosis of human umbilical vein endothelial cells (HUVECs), which is mainly related to the activation of the AMPK/mTOR pathway by GN combination, which in turn induces the activation of Nrf2/HO-1 signal. In addition, the above phenomenon could be significantly reversed by dorsomorphin. Therefore, our experiments proved for the first time that the GN combination can effectively inhibit AS inflammation and apoptosis by activating the AMPK/mTOR/Nrf2 signaling pathway to inhibit the NLRP3 inflammasome and Bax/Bcl2/caspase-3 pathway.

Macrophage autophagy defect is closely related to the progression of atherosclerosis (AS) and is regulated by the triggering receptor expressed on myeloid cell 2 (TREM2). TREM2 is a key factor in the development of Alzheimer’s disease (AD), the deficiency of which leads to anomalous autophagy in microglia. However, the role of TREM2 in the autophagy of plaque macrophages is still unclear. Geniposide (GP) can inhibit AS progression and enhance macrophage autophagy, although the underlying mechanisms remain unknown. We found that high-fat diet (HFD) feeding significantly increased TREM2 levels and inhibited autophagy in the macrophages of ApoE[Formula: see text] mice. TREM2 overexpression in RAW264.7 macrophages decreased autophagy via activation of mTOR signaling. GP inhibited the progression of AS in ApoE[Formula: see text] mice, reinforced macrophage autophagy, and downregulated TREM2 by inhibiting mTOR signaling. Taken together, augmenting the autophagy levels in plaque macrophages by inhibiting the TREM2/mTOR axis can potentially impede atherosclerotic progression. The promising therapeutic effects of GP seen in this study should be validated in future trials, and the underlying mechanisms have to be elucidated in greater detail.

Objective To evaluate the efficacy and safety of Ding Xin Recipe (DXR) combined with amiodarone in patients with PVCs.Methods A total of 360 patients with PVCs across 7 centers in China were randomly assigned in a 1:1:1 ratio to receive up to 8 weeks of amiodarone combined with DXR placebo (amiodarone group), DXR combined with amiodarone placebo (DXR group), or DXR combined with amiodarone (DCA group) from July 2012 to December 2013. Randomization was conducted according to a centralized randomization schedule prepared by an independent steering committee. Staff and patients at all sites were masked to treatment allocation. All patients received best-evidence advice. The primary outcome was the efficacy for treating PVCs, with efficacy assessed by the reduction of premature ventricular contractions. Other outcome measures included PVCs-related symptom scores. All data were analyzed by intention to treat.Results The efficacy for treating PVCs in the DCA group (90.7%) significantly increased compared with that in the amiodarone group (72.3%) and the DXR group (73.9%). The frequency, the degree, and the duration per week of heart palpitations, chest tightness, shortness of breath and fatigue improved significantly in the DCA group in comparison with the amiodarone group and the DXR group (P < 0.05), while no significant difference was observed in the improvement of insomnia among the three groups (P > 0.05). With regard to laboratory parameters for safety, there were no clinically relevant changes in the three groups.Conclusion The present study demonstrates that DXR combined with amiodarone is significantly more effective than DXR or amiodarone alone for treating PVCs. Keywords: Remae ventricular complexes, Amiodarone, Ding Xin Recipe, Safety, Clinical trial

The purpose of this study was to investigate the anti-injury effect and protective mechanism of hydrogen-enriched water in a rat model of acute liver injury induced by aflatoxin B

Interferon-inducible protein (IFI204) (p204, the murine homolog of human IFI16) is known as a cytosolic DNA sensor to recognize DNA viruses and intracellular bacteria. However, little is known about its role during extracellular bacterial infection. Here we show that IFI204 is required for host defense against the infection of Staphylococcus aureus, an extracellular bacterial pathogen. IFI204 deficiency results in decreased survival, increased bacterial loads, severe organs damage, and decreased recruitment of neutrophils and macrophages. Production of several inflammatory cytokines/chemokines including IFN-β and KC is markedly decreased, as well as the related STING-IRF3 and NF-κB pathways are impaired. However, exogenous administration of recombinant KC or IFN-β is unable to rescue the susceptibility of IFI204-deficient mice, suggesting that other mechanisms rather than KC and IFN-β account for IFI204-mediated host defense. IFI204 deficiency leads to a defect in extracellular bacterial killing in macrophages and neutrophils, although bacterial engulf, and intracellular killing activity are normal. Moreover, the defect of bactericidal activity is mediated by decreased extracellular trap formation in the absence of IFI204. Adoptively transferred WT bone marrow cells significantly protect WT and IFI204-deficient recipients against Staphylococcus infection compared with transferred IFI204-deficient bone marrow cells. Hence, this study suggests that IFI204 is essential for the host defense against Staphylococcus infection.

Interferon-inducible protein (IFI204) (p204, the murine homolog of human IFI16) is known as a cytosolic DNA sensor to recognize DNA viruses and intracellular bacteria. However, little is known about its role during extracellular bacterial infection. Here we show that IFI204 is required for host defense against the infection of Staphylococcus aureus, an extracellular bacterial pathogen. IFI204 deficiency results in decreased survival, increased bacterial loads, severe organs damage, and decreased recruitment of neutrophils and macrophages. Production of several inflammatory cytokines/chemokines including IFN-β and KC is markedly decreased, as well as the related STING-IRF3 and NF-κB pathways are impaired. However, exogenous administration of recombinant KC or IFN-β is unable to rescue the susceptibility of IFI204-deficient mice, suggesting that other mechanisms rather than KC and IFN-β account for IFI204-mediated host defense. IFI204 deficiency leads to a defect in extracellular bacterial killing in macrophages and neutrophils, although bacterial engulf, and intracellular killing activity are normal. Moreover, the defect of bactericidal activity is mediated by decreased extracellular trap formation in the absence of IFI204. Adoptively transferred WT bone marrow cells significantly protect WT and IFI204-deficient recipients against Staphylococcus infection compared with transferred IFI204-deficient bone marrow cells. Hence, this study suggests that IFI204 is essential for the host defense against Staphylococcus infection.

The intestinal mucosal barrier is critical for host defense against pathogens infection. Here, we demonstrate that the mixed lineage kinase-like protein (MLKL), a necroptosis effector, promotes intestinal epithelial barrier function by enhancing inflammasome activation. MLKL−/− mice were more susceptible to Salmonella infection compared with wild-type counterparts, with higher mortality rates, increased body weight loss, exacerbated intestinal inflammation, more bacterial colonization, and severe epithelial barrier disruption. MLKL deficiency promoted early epithelial colonization of Salmonella prior to developing apparent intestinal pathology. Active MLKL was predominantly expressed in crypt epithelial cells, and experiments using bone marrow chimeras found that the protective effects of MLKL were dependent on its expression in non-hematopoietic cells. Intestinal mucosa of MLKL−/− mice had impaired caspase-1 and gasdermin D cleavages and decreased interleukin (IL)-18 release. Moreover, administration of exogenous recombinant IL-18 rescued the phenotype of increased bacterial colonization in MLKL−/− mice. Thus, our results uncover the role of MLKL in enhancing inflammasome activation in intestinal epithelial cells to inhibit early bacterial colonization.

To investigate the anti-oxidative effect of celastrol on H

Infectious agents can reach the placenta either via the maternal blood or by ascending the genito-urinary tract, and then initially colonizing the maternal decidua. Decidual stromal cells (DSCs) are the major cellular component of the decidua. Although DSCs at the maternal–fetal interface contribute to the regulation of immunity in pregnancy in the face of immunological and physiological challenges, the roles of these DSCs during viral infection remain ill defined. Here, we characterized the response of DSCs to a synthetic double-stranded RNA molecule, polyinosinic-polycytidylic acid [poly(I:C)], which is a mimic of viral infection. We demonstrated that both transfection of cells with poly(I:C) and addition of extracellular (non-transfected) poly(I:C) trigger the necroptosis of DSCs and that this response is dependent on RIG-I-like receptor/IPS-1 signaling and the toll-like receptor 3/TIR-domain-containing adapter-inducing interferon-β pathway, respectively. Furthermore, following poly(I:C) challenge, pregnant mixed lineage kinase domain-like protein-deficient mice had fewer necrotic cells in the mesometrial decidual layer, as well as milder pathological changes in the uterine unit, than did wild-type mice. Collectively, our results establish that necroptosis is a contributing factor in poly(I:C)-triggered abnormal pregnancy and thereby indicate a novel therapeutic strategy for reducing the severity of the adverse effects of viral infections in pregnancy.

The adiabatic shear bands (ASB) of the thick-walled cylinder have been studied by many researchers in the recent years. The onset and evolutions of the multiple shear failure of metal cylinder under explosive loadings are affected by many factors such as the characteristics of the impulsive loadings, the dynamic behavior of the materials, etc. In this work, a tube compression driven by electro-magnetic forces is introduced, which enables to carry out the experiments of the spontaneous evolution of multiple adiabatic shear bands in metal tube. The FEM simulation was conducted to investigate the evolution process of strain localization with coupled thermo-mechanical analysis. The FEM results show that ASB initiates when the stress drops rapidly and strain growth and not when it reaches the maximum shear stress. Once the shear band is formed, elastic unloading occurs beside the shear band. The different behaviors of the damage introduced in the strain softening model affect the initial nucleation strain and the distribution of ASBs. With the increase of material damage softening, the initial strain of shear band decreases and the number of shear bands increases.

A new experimental technology based on the Split Hopkinson Pressure Bar (SHPB) is developed for conducting expanding ring tests. The technique is useful for the studies of the dynamic tensile deformation and the fracture (fragmentation) properties of ductile metallic materials. The loading fixture includes a hydraulic cylinder filled with the incompressible fluid, which is pushed by a piston connected to the input bar. As the liquid is driven, it transfers the pressure to the specimen, compressing and expanding the metallic ring specimen in the radial direction. The approximately incompressible property of the liquid makes it possible to transfer a relatively low piston-driving velocity to a very high radial-expansion velocity of the specimen, as the sectional area of the cylinder narrows significantly. Using this experimental technology the ring specimens made of LY12 aluminum alloy were dynamically expanded and fragmentized. Results show apparent increases of the fragment numbers and fracture strain of the specimen with the increase of the impact velocity. The recovered ring fragments were examined and measured to obtain the average fragment sizes (lengths) during each test. These fragment sizes were compared with the estimates from the classical fragmentation theory that was initiated by N.F. Mott and later developed by D.E. Grady. It was found that the Mott-Grady theory provides reasonably good predictions of the fragment sizes for ductile materials. This conclusion agrees with the recent findings of ours based on the numerical simulations and physical arguments.

To study the propagating behavior of a dynamic crack in brittle materials, an experimental technique was developed that measures the propagation speed of a fast crack in a preloaded brittle strip. The specimen is a rectangular PMMA plate clamped by two heavy steel fixtures that are attached to a MTS test machine. After the specimen was tensile loaded to a prescribed load level, a sharp crack was initiated at the middle point on one side of the specimen. Due to the brittleness of the material, the crack propagates quickly across the specimen. The propagation velocity of the crack was measured by using the equally spaced conductive lines that were painted on the specimen surface before the tests. High speed video camera was also used for monitoring the propagation behavior of the cracks. The experimental results show that for each preloaded plate, the crack arrives at a steady velocity v0 after a short acceleration stage. In the steady stage crack propagation is in self-similar state. The steady velocity of the crack was found to be an increasing function of the energy Gc stored in the preloaded strip, which means that the material has a "velocity-toughening" property. When the crack speed exceeds a threshold, the crack exhibits apparent speed oscillations. This speed oscillation corresponds to the occurrence of the periodic grooves on the fractured surface. Further increase of the preload results in the bending, micro branching, and full bifurcations of the crack paths.

Inflammasomes are multiprotein complexes that control the production of IL-1β and IL-18. NLRP3 inflammasome, the most characterized inflammasome, plays prominent roles in defense against infection, however aberrant activation is deleterious and leads to diseases. Therefore, its tight control offers therapeutic promise. Liver X receptors (LXRs) have significant anti-inflammatory properties. Whether LXRs regulate inflammasome remains unresolved. We thus tested the hypothesis that LXR's anti-inflammatory properties may result from its ability to suppress inflammasome activation. In this study, LXRs agonists inhibited the induction of IL-1β production, caspase-1 cleavage and ASC oligomerization by NLRP3 inflammasome. The agonists also inhibited inflammasome-associated mtROS production. Importantly, the agonists inhibited the priming of inflammasome activation. In vivo data also showed that LXRs agonist prevented NLRP3-dependent peritonitis. In conclusion, LXRs agonists are identified to potently suppress NLRP3 inflammasome and the regulation of LXRs signaling is a potential therapeutic for inflammasome-driven diseases.

To study the effect of polydatin on the expression level of miR-214 and liver function in atherosclerotic mice.Forty male ApoE(-/-) mice were randomly allocated into 4 groups (n=10), namely the model group, low- and high-dose polydatin groups, and simvastin group, with 10 male C57BL/6J mice serving as the normal control group. Mouse models of atherosclerosis were established by feeding the ApoE(-/-) mice with a high-fat diet. After 12 weeks of treatment, blood levels of glucose, lipids, AST, and ALT and the contents of T-SOD and MDA in the liver tissue were detected. The pathologies of the liver were examined with HE staining, and miR-214 expression in the liver was detected using quantitative real-time PCR.Compared with the normal control mice, the mice in the model group showed significantly increased blood glucose, serum TC, TG, LDL-C, ALT, and AST levels, and MDA contents in the liver (P0.01), with significantly decreased serum HDL-C level and SOD and miR-214 levels in liver (P0.01). Polydatin treatment significantly ameliorated such changes in blood glucose, serum ALT, AST, TC, TG, LDL-C, and HDL-C levels, and MDA, SOD, and miR-214 contents in liver tissue (P0.05).s Polydatin can reduce blood glucose and lipid levels and protect the liver function in atherosclerotic mice possibly by up-regulating the expression of miR-214 and T-SOD and down-regulating MDA in the liver.

BACKGROUND Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon. Our previous results showed increased semaphorin 3A (SEMA3A) expression may be the risk factor for HSCR pathology in a subset of patients. Therefore, the association between polymorphisms in SEMA3A and the risk of HSCR was examined. METHODS The genotypes of two SNPs (rs7804122 and rs797821) in the SEMA3A gene in 119 patients with HSCR and 93 controls were examined using PCR-sequencing to determine the contribution of SEMA3A to the HSCR phenotype. PCR reaction with cDNA template was also used to find out whether a novel mutation (Chr7:83634610AT) influences the SEMA3A pre-mRNA splicing. RESULTS Genotypes comprising allele G of rs7804122 (GG or AG) were over-represented in patients (48.74 vs. 24.8%; p = 0.0013) which indicated that the risk of HSCR was significantly higher among subjects with the GG or AG genotype than among the subjects with the AA genotype. No statistically significant associations were found for SNP rs797821 at the allele or genotype levels. The differences in genotypes and allele distributions of rs7804122 and rs797821 between various clinical classifications were not statistically significant. The novel heterozygous mutation (Chr7:83634610AT) 30bp away from an intron/exon boundary, had no detectable effect on splicing efficiency. CONCLUSION Our results for rs7804122 provided preliminary evidence that the SEMA3A gene is involved in the susceptibility to HSCR in the Northeastern Chinese population. Birth Defects Research (Part A) 2012. © 2011 Wiley Periodicals, Inc.

The gut microbiota and microRNAs play important roles in the defense against infection. However, the role of miR-146a in L. monocytogenes infection and gut microbiota remains unclear. We tried to determine whether miR-146a controlled L. monocytogenes infection by regulating the gut microbiota. Wild-type and miR-146a-deficient mice or macrophages were used to characterize the impact of miR-146a on animal survival, cell death, bacterial clearance, and gut microbiota following L. monocytogenes challenge. We found that L. monocytogenes infection induced miR-146a expression both in vitro and in vivo. When compared to wild-type mice, miR-146a-deficient mice were more resistant to L. monocytogenes infection. MiR-146a deficiency in macrophages resulted in reduced invasion and intracellular survival of L. monocytogenes. High-throughput sequencing of 16S rRNA revealed that the gut microbiota composition differed between miR-146a-deficient and wild-type mice. Relative to wild-type mice, miR-146a-deficient mice had decreased levels of the Proteobacteria phylum, Prevotellaceae family, and Parasutterella genus, and significantly increased short-chain fatty acid producing bacteria, including the genera Alistipes, Blautia, Coprococcus_1, and Ruminococcus_1. Wild-type mice co-housed with miR-146a-deficient mice had increased resistance to L. monocytogenes, indicating that miR-146a deficiency guides the gut microbiota to alleviate infection. Together, these results suggest that miR-146a deficiency protects against L. monocytogenes infection by regulating the gut microbiota.

Dynamic damage evolution and its influence on the constitutive relation for materials in high strain rate are experimentally and theoretically studied. It is revealed that damage evolution is a rate-dependent process depending on both strain and strain rate, and can be modeled by the thermo-activation mechanism. For polymer PMMA, PP/PA blend and concrete, the coupled damage evolution law and the rate dependent constitutive relation (DM-ZWT model) are obtained and well supported by the experimental data.

Objective To evaluate the feasibility, safety and efficacy of atlas pedicle screws system fixation and fusion for the treatment of upper cervical diseases. Methods Twenty-three consecutive patients with upper cervical disorders requiring stabilization, including 19 cases of atlantoaxial dislocation (4 congenital odontoid disconnections, 6 old odontoid fractures, 4 fresh odontoid fractures of Aderson II C, 3 ruptures of the C1 transverse ligament, and 2 fractures of C1), 2 cases of C2 tumor (instability after the resection of the tumors), and 2 giant neurilemomas of C2-C3(instabilityafter resectionofthetumors), weretreated by posterior fixation and fusion with the atlas pedicle screw system, in which the screws were inserted through the posterior arch of C1. The operative time, bleeding volume and complications were reported. All patients were immobilized without external fixation or with rigid cervical collars for 1-3 months. All patients were followed up and evaluated with radiographs and CT. Results In the 23 patients, 46 C1 pedicle screws, 42 C2 pedicle screws and 6 lower cervical lateral mass screws and 2 lower cervical pedicle screws were placed. The mean operative time and bleeding volume was 2.7 hours and 490 ml respectively. No intraoperative complications were directly related to surgical technique. No neurological, vascular or infective complications were encountered. All patients were followed up for 3-36 months (average 15 months). Firm bony fusion was documented in all patients after 3-6 months. One patient with atlas fracture showed anterior occipitocervical fusion. There was no implant failure. Conclusions Posterior fixation and fusion of the atlas pedicle screw system is feasible and safe for the treatment of upper cervical diseases, and may be applicable to a larger number of patients.

To study the effect of Huangzhi oral liquid (HZOL) on I/R after 2 h and 4 h and determine its regulatory function on caspase-3 and protein networks. 70 SD male rats were randomly divided into seven groups and established myocardial I/R injury model by ligating the left anterior descending coronary artery. Myocardial infarction model was defined by TTC staining and color of the heart. The levels of CK-MB, CTnI, C-RPL, SOD, and MDA were tested at 2 h and 4 h after reperfusion. HE staining and ultramicrostructural were used to observe the pathological changes. The apoptotic index (AI) of cardiomyocyte was marked by TUNEL. The expression levels of caspase-3, p53, fas, Bcl-2, and Bax were tested by immunohistochemistry and western blot. HZOL corrected arrhythmia, improved the pathologic abnormalities, decreased CK-MB, CTnI, C-RPL, MDA, AI, caspase-3, p53, fas, and Bax, and increased SOD ans Bcl-2 with different times of myocardial reperfusion; this result was similar to the ISMOC (P>0.05). HZOL could inhibit arrhythmia at 2 and 4 h after I/R and ameliorate cardiac function, which was more significant at 4 h after reperfusion. This result may be related to decreased expression of caspase-3, p53, and fas and increased Bcl-2/Bax ratio.

To optimize the method for preparing samples for amniotic fluid proteomics study.Pregnant rats were sacrificed with an overdose of Chloral hydrate at E17. The fetuses and amniotic fluid were harvested. The samples were processed by three different methods including trichloroacetic acid (TCA)-acetone precipitation (protocol 1), TCA-acetone precipitation combined with an Albumin and IgG Removal Kit (protocol 2), and a Centrifugal Filter concentrating combined with an Albumin and IgG Removal Kit (protocol 3). The samples were run through a two-dimensional electrophoresis gel, stained and analyzed with a Image Master 6.0 software. Protein spots were identified with a LCQ Deca XP mass spectrometer.The total numbers of protein spots for samples processed by protocol 1, 2 and 3 were 253 ± 28, 749 ± 32 and 782 ± 27, respectively. And there was a significant difference between protocol 1 has and other two methods. Those with MW50 kDa were 57± 14, 45 ± 13 and 41 ± 14, respectively. Protocol 2 differed significantly from protocol 3. Protein number of samples with MW50 kDa was 196± 29, 702± 35 and 735 ± 29, respectively. Again, protocol 1 has differed significantly from other two methods.By removing albumin and IgG from the serum, low abundance proteins can be enriched with little loss of high abundance proteins. Centrifugal Filter concentrating combined with Albumin and IgG Removal Kit can be effectively applied for amniotic fluid proteomics study.

To evaluate the effect of ossicular reconstruction with partial ossicular replacement prosthesis (PORP) in patients with tympanosclerosis.The data of 31 cases of tympanosclerosis treated between 1992 and 2009 were reviewed. Of the 31 patients, 17 (17 ears) underwent ossicular reconstruction with porous macromolecular polyethylene PORP, and 14 (14 ears) with bioceramic PORP. All the patients were followed up for 3-24 months.Significant improvement was found in postoperative speech frequency (500, 1000, 2000 Hz) pure tone average (PTA) and air-bone gap (ABG) (P0.05) after the treatments without statistically significant differences between the two groups (P0.05).Porous macromolecular polyethylene and bioceramic are valuable ossicular prosthesis for tympanosclerosis.