Repression of caspase-3 and RNA-binding protein HuR cleavage by cyclooxygenase-2 promotes drug resistance in oral squamous cell carcinoma.

A well-studied RNA-binding protein Hu Antigen-R (HuR), controls post-transcriptional gene regulation and undergoes stress-activated caspase-3 dependent cleavage in cancer cells. The cleavage products of HuR are known to promote cell death; however, the underlying molecular mechanisms facilitating caspase-3 activation and HuR cleavage remains unknown. Here, we show that HuR cleavage associated with active caspase-3 in oral cancer cells treated with ionizing radiation and chemotherapeutic drug, paclitaxel. We determined that oral cancer cells overexpressing cyclooxygenase-2 (COX-2) limited the cleavage of caspase-3 and HuR, which reduced the rate of cell death in paclitaxel resistant oral cancer cells. Specific inhibition of COX-2 by celecoxib, promoted apoptosis through activation of caspase-3 and cleavage of HuR in paclitaxel-resistant oral cancer cells, both in vitro and in vivo. In addition, oral cancer cells overexpressing cellular HuR increased the half-life of COX-2 mRNA, promoted COX-2 protein expression and exhibited enhanced tumor growth in vivo in comparison with cells expressing a cleavable form of HuR. Finally, our ribonucleoprotein immunoprecipitation and sequencing (RIP-seq) analyses of HuR in oral cancer cells treated with ionizing radiation (IR), determined that HuR cleavage product-1 (HuR-CP1) bound and promoted the expression of mRNAs encoding proteins involved in apoptosis. Our results indicated that, cellular non-cleavable HuR controls COX-2 mRNA expression and enzymatic activity. In addition, overexpressed COX-2 protein repressed the cleavage of caspase-3 and HuR to promote drug resistance and tumor growth. Altogether, our observations support the use of the COX-2 inhibitor celecoxib, in combination with paclitaxel, for the management of paclitaxel resistant oral cancer cells.

Impact of proctoring on success rates for percutaneous revascularisation of coronary chronic total occlusions.

OBJECTIVE: To assess the impact of proctoring for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in six UK centres. METHODS: We retrospectively analysed 587 CTO procedures from six UK centres and compared success rates of operators who had received proctorship with success rates of the same operators before proctorship (pre-proctored) and operators in the same institutions who had not been proctored (non-proctored). There were 232 patients in the pre-proctored/non-proctored group and 355 patients in the post-proctored group. Complexity was assessed by calculating the Japanese CTO (JCTO) score for each case. RESULTS: CTO PCI success was greater in the post-proctored compared with the pre-proctored/non-proctored group (77.5% vs 62.1%, p<0.0001). In more complex cases where JCTO≥2, the difference in success was greater (70.7% vs 49.5%, p=0.0003). After proctoring, there was an increase in CTO PCI activity in centres from 2.5% to 3.5%, p<0.0001 (as a proportion of total PCI), and the proportion of very difficult cases with JCTO score ≥3 increased from 15.3% (35/229) to 29.7% (105/354), p<0.0001. CONCLUSIONS: Proctoring resulted in an increase in procedural success for CTO PCI, an increase in complex CTO PCI and an increase in total CTO PCI activity. Proctoring may be a valuable way to improve access to CTO PCI and the likelihood of procedural success.

Successful autotransplantation of a mature mesiodens to replace a traumatized maxillary central incisor.

AIM: This case describes the successful transplantation of a mature mesiodens tooth to replace a traumatized maxillary central incisor. SUMMARY: A 17-year-old male attended 1 week after a traumatic injury to his left maxillary central incisor (tooth 21). Radiographs revealed a horizontal root fracture and a poor prognosis. The tooth was atraumatically removed and replaced with a mesiodens lying in the same region. After stabilization, root canal treatment was performed and aesthetics were restored with a tooth coloured restoration. A 2-year follow-up revealed the tooth had good aesthetics and function. KEY LEARNING POINTS: A supernumerary nonfunctional tooth such as a mesiodens can be successfully used to replace a missing permanent tooth by autotransplantation. Autotransplantation has a high success rate if case selection is good, appropriate surgery is carried out and excellent hygiene is maintained. Autotransplantation should be considered as one of the most biologic techniques for replacing a missing tooth with minimal cost. Autotransplantation can be carried out even after complete root formation in the donor tooth.

Near room temperature reduction of graphene oxide Langmuir-Blodgett monolayers by hydrogen plasma.

Langmuir-Blodgett monolayer sheets of graphene oxide (GO) were transferred onto Si and SiO2/Si, and subjected to hydrogen plasma treatment near room temperature. GO monolayers were morphologically stable at low power (15 W) plasma treatment, for durations up to 2 min and temperatures up to 120 °C. GO monolayers reduced under optimized plasma treatment conditions (30 s duration at 50 °C) exhibit a sheet thickness of (0.5-0.6) nm, high sp(2)-C content (75%), a low O/C ratio (0.16) and a significant red-shift of Raman G-mode to 1588 cm(-1), indicating efficient de-oxygenation and a substantial decrease of defects. A study of the valence band electronic structure of hydrogen plasma reduced GO monolayers shows an increase of DOS in the vicinity of the Fermi level, due to the increase of C 2p-π states, and a substantial decrease of work function. These results, along with conductivity measurements and transfer characteristics, reveal the p-type nature of hydrogen plasma reduced GO monolayers, displaying a conductivity of (0.2-31) S cm(-1) and a field effect mobility of (0.1-6) cm(2) V(-1) s(-1). Plasma treatment at higher temperatures results in a substantial increase in sp(3)-C/damaged alternant hydrocarbon content and incorporation of defects related to the hydrogenation of the graphitic network, as evidenced by multiple Raman features, including a large red-shift of D-mode to 1331 cm(-1) and a high I(D)/I(G) ratio, and supported by the appearance of mid-gap states in the vicinity of the Fermi level.

Study of simultaneous reduction and nitrogen doping of graphene oxide Langmuir-Blodgett monolayer sheets by ammonia plasma treatment.

Graphene oxide (GO) monolayer sheets, transferred onto Si by the Langmuir-Blodgett technique, were subjected to ammonia plasma treatment at room temperature with the objective of simultaneous reduction and doping. Scanning electron microscopy and atomic force microscopy studies show that plasma treatment at a relatively low power (∼10 W) for up to 15 min does not affect the morphological stability and monolayer character of GO sheets. X-ray photoelectron spectroscopy has been used to study de-oxygenation of GO monolayers and the incorporation of nitrogen in graphitic-N, pyrrolic-N and pyridinic-N forms due to the plasma treatment. The corresponding changes in the valence band electronic structure, density of states at the Fermi level and work function have been investigated by ultraviolet photoelectron spectroscopy. These studies, supported by Raman spectroscopy and electrical conductivity measurements, have shown that a short duration plasma treatment of up to 5 min results in an increase of sp²-C content along with a substantial incorporation of the graphitic-N form, leading to the formation of n-type reduced GO. Prolonged plasma treatment for longer durations results in a decrease of electrical conductivity, which is accompanied by a substantial decrease of sp²-C and an increase in defects and disorder, primarily attributed to the increase in pyridinic-N content.

Growth of CdS nanocrystallites on graphene oxide Langmuir-Blodgett monolayers.

Large area GO-Cd composite Langmuir-Blodgett monolayers were transferred onto Si substrate by introducing Cd(2+) ions into the subphase. The changes in the behaviour of the Langmuir monolayer isotherm in the presence of Cd(2+) ions are attributed to changes in the microstructure and density of the GO sheets on the subphase surface. The uptake of Cd onto the GO monolayers and the effect of subsequent sulphidation were investigated by AFM, FTIR, Raman, XPS and HRTEM techniques. The incorporation of Cd into the GO monolayers causes some overlapping of sheets and extensive formation of wrinkles. Sulphidation of the GO-Cd sheets results in the formation of uniformly distributed CdS nanocrystallites on the entire basal plane of the GO monolayers. The de-bonding of Cd with oxygen functional groups results in a reduction of the wrinkles. The GO sheets function primarily as a platform for the interaction of metal ions with oxygen functionalities and their structure and characteristic features are not affected by either uptake of Cd or formation of CdS.

A laboratory comparison of apical leakage between immediate versus delayed post space preparation in root canals filled with Resilon.

AIM: To analyse ex vivo the integrity of the apical seal of Resilon root fillings following immediate post space preparation or after 1 week when leaving either 5 mm or 3 mm of remaining filling material. METHODOLOGY: One hundred and fifty freshly extracted mandibular premolar teeth with single, straight root canals were used. Teeth were autoclaved and cleaned of debris and soft tissue. After decoronation at 16 mm length, the root canals were instrumented using the K3 rotary system to apical file size 45, 0.04 taper with intermittent irrigation using 1% sodium hypochlorite. The teeth were randomly divided into five groups with 30 teeth in each group. Group 1: control group in which the root canals were not filled. Group 2: the canals were filled with Resilon and a post space prepared immediately leaving 5 mm of apical filling. Group 3: the canals were filled and post space preparation delayed for 1 week leaving 5 mm of material apically. Group 4: post space preparation in the canals was initiated immediately after filling leaving 3 mm of material apically. Group 5: the root canals were filled and post space preparation was delayed for 1 week leaving 3 mm of material apically. Microleakage was evaluated using a fluid transport device. The results were analysed statistically using one-way anova followed by Bonferroni's post hoc test. P < 0.05 was considered as statistically significant. RESULTS: There was a highly significant difference amongst the groups (P < 0.001). The maximum mean leakage was observed in group 5 (141.63 x 10(-6) microL min(-1) cm(-1)) and the least microleakage in group 2 (99.87 x 10(-6) microL min(-1) cm(-1)). CONCLUSION: Immediate post space preparation was associated with less microleakage than delayed preparation when both 5 mm and 3 mm of apical filling remained. Leaving 5 mm of Resilon provided a significantly better seal compared to leaving 3 mm of material.

The development and validation of a Nocturnal Gastro-oesophageal Reflux Disease Symptom Severity and Impact Questionnaire for adults.

BACKGROUND: Current questionnaires for assessing gastro-oesophageal reflux disease (GERD) symptoms are limited in their ability to capture nocturnal symptoms. AIM: To develop and validate an instrument, the Nocturnal Gastro-oesophageal Reflux Disease Symptom Severity and Impact Questionnaire (N-GSSIQ), to assess severity and impact of nocturnal GERD symptoms. METHODS: Two focus groups and 16 cognitive debriefing interviews were conducted among GERD patients to identify key issues about nocturnal symptoms. A draft instrument was tested in 196 patients at 11 clinics in the US to evaluate psychometric properties. Exploratory factor and item response theory analyses were conducted to finalize items and subscales. Internal consistency reliability, reproducibility and construct validity were examined. RESULTS: Mean age was 45 (s.d. = 13.8) years; 76% were female and 68% were Caucasian. Patient-rated severity was mild-moderate for 69% of participants; 48% reported symptoms on two to three nights the past week. The final questionnaire includes 20 items and three subscales: Nocturnal GERD Symptoms, Morning Impact of Nocturnal GERD and Concern about Nocturnal GERD. The subscales demonstrated internal consistency reliability (Cronbach's alpha 0.84-0.94) and were significantly correlated with similar measures and disease severity (0.41-0.81; P < 0.0001). CONCLUSION: The results support the reliability and validity of the N-GSSIQ as a measure of severity, morning impact and concern about nocturnal GERD.

Influence of activating and inhibitory killer immunoglobulin-like receptors on predisposition to recurrent miscarriages.

BACKGROUND: Understanding of the immune events and mechanisms occurring at the feto-maternal interface is likely to help in understanding the ability of the fetus to survive within the maternal body. Evidence supporting extensive roles of natural killer cells during pregnancy gives rise to a possibility that these NK cells can be mis-regulated and involved in fetal allograft rejection. Killer immunoglobulin-like receptors (KIR) play an important role in regulating the NK cell activity through their activating and inhibiting isoforms. Since there exists a considerable, genetically determined variation in the repertoire of KIR receptors between different individuals, a particular maternal KIR repertoire may predispose to recurrent miscarriages (RMs). METHODS: Gene-specific PCR amplification (PCR-SSP) was used to determine the individual KIR genotypes in women experiencing RM and controls. RESULTS: A higher prevalence of activating KIR genes was seen in patients than in controls. Among women experiencing RM, the BB genotypes were more prevalent (P < 0.0001, OR = 4.4, 95% CI = 2.89-6.69) compared with controls. CONCLUSIONS: Our results indicate that the balance between inhibitory and activating receptor-mediated signals present in natural killer cells is inclined toward a more activating state that may contribute to pregnancy loss.

Diabetic therapeutic effects of ethyl acetate fraction from the roots of Musa paradisiaca and seeds of Eugenia jambolana in streptozotocin-induced male diabetic rats.

The folklore medicine of primitive people has been greatly appreciated for centuries. Many researchers study the curative efficiency and mode of action of various medicinal plants. Serum glucose level, lipid profile, glucose tolerance, hepatic and muscle glycogen contents as well as the activities of hepatic hexokinase and glucose-6-phosphatase recovered significantly after oral administration of ethyl acetate fractions of Eugenia jambolana (E. jambolana) or Musa paradisiaca (M. paradisiaca) in separate (E. jambolana L.: 200 mg/kg of body weight and M. paradisiaca: 100 mg/kg of body weight) or combined form for 90 days (twice a day through gavage) to streptozotocin-induced diabetic rats. The loss in body weight of diabetic animals was reversed and serum levels of insulin as well as C-peptide, which were found to be reduced in diabetic rats, increased significantly after oral administration of the fractions. A histological study of the rats' pancreas revealed that after 90 days of oral treatment with the plant fractions in separate or combined form, the size and volume of pancreatic islets in diabetic treated rats increased significantly compared with the diabetic control group. Treatment of diabetic rats with the combined dose (300 mg/kg of body weight) of plant fractions (200 mg E. jambolana and 100 mg M. paradisiaca) was found to be more effective than treatment with the individual fraction. The doses of E. jambolana and M. paradisiaca selected for this study are the optimum antihyperglycemic doses of the plant fractions, which were determined after conducting a dose-dependent study at various dose levels (50-500 mg/kg) in our pilot experiments. The plant fractions were found to be free from metabolic toxicity. Through HPTLC finger printing, three different compounds were noted in the ethyl acetate fraction of E. jambolana L. and eight different compounds in the ethyl acetate fraction of M. paradisiaca L.

Orange-red luminescence from Cu doped CdS nanophosphor prepared using mixed Langmuir-Blodgett multilayers.

Cu doped CdS nanophosphors were fabricated through Langmuir-Blodgett route for the first time. Precursors mixed Langmuir-Blodgett multilayers of cadmium arachidate-copper arachidate were used to grow doped sulfide nanoparticles within the organic matrix through postdeposition treatment with H(2)S gas. Changes in composition and layered structure of precursor multilayers were studied using Fourier transform infrared and x-ray reflection. Uptake of Cu in the multilayers was analyzed by inductively coupled plasma atomic emission spectroscopy measurements. Unannealed H(2)S exposed multilayers containing CdS nanoparticles show strong surface state emission centered at approximately 570 nm, whereas Cu doped CdS nanoparticles show orange-red luminescence. Photoluminescence (PL) spectra of annealed-Cu doped CdS nanoparticles show distinct Cu-related emission compared to annealed-undoped CdS nanoparticles. Power dependent PL measurements of annealed samples show that an efficient carrier recombination takes place at T(2) level of Cu(++). The carrier relaxation from the excitonic states to T(2) level results in the strong orange-red luminescence.

Interventional cardiology and cardiac surgery in India.

In India, as is happening world wide, the use of coronary interventions is likely to maintain the pace of growth seen in the past decade. This will be facilitated by better access to experienced cardiologists and catheterisation laboratories across the country. Similar growth has occurred in cardiovascular surgery despite constraints of infrastructure and affordability. Cardiovascular research established four decades ago is being carried forward with provision of indigenous technology equal to the best in the world, but tailored to local need and affordability.

The remodeling transient and the calcium economy.

UNLABELLED: The remodeling transient describes a change in bone mass that lasts one remodeling cycle following an intervention that disturbs the calcium economy. We demonstrated the transient in a study of the response of bone density to calcium/vitamin D3 supplementation and show the hazards of misinterpretation if the transient is not considered. INTRODUCTION: The remodeling transient describes a change in bone mass that lasts for one remodeling cycle following an intervention that disturbs the calcium economy. METHODS: We report an intervention with calcium and vitamin D supplementation in 208 postmenopausal African-American women where the remodeling transient was considered a priori in the study design. Both groups (calcium alone vs. calcium + 20 microg (800 IU) vitamin D3) were ensured a calcium intake in excess of 1200 mg/day. RESULTS: There were no differences between the two groups in changes in BMD over time. These BMD changes were therefore interpreted to reflect increased calcium intake in both groups but not any influence of vitamin D. A transient increase in bone mineral density was observed during the first year of study, followed by a decline. The remodeling period was estimated at about 9 months, which is similar to histomorphometric estimates. CONCLUSION: It is problematic to draw conclusions concerning interventions that influence the calcium economy without considering the remodeling transient in study design. Studies of agents that effect bone remodeling must be carried out for at least two remodeling cycles and appropriate techniques must be used in data analysis.

Chimerism monitoring following allogeneic hematopoietic stem cell transplantation.

Information regarding the chimeric status of hematopoietic stem cell transplantation (HSCT) recipients is of great significance when comparing different conditioning and prophylactic therapies. In recent years, short tandem repeats/variable number tandem repeats (STRs/VNTRs) have emerged as the best tool for chimerism monitoring. However, the polymorphisms of STR/VNTR markers vary within and between ethnic groups. The issue is further complicated in a heterogeneous population such as occurs in the Indian subcontinent. In the present study, we attempted to devise a robust scheme to identify a set of polymorphic STRs/VNTRs most suitable for chimerism evaluation in north Indian HCST recipients. At first, we did genotyping of 11 STR and one VNTR in 1000 randomly chosen north Indian individuals to quantify different diversity parameters. Resulting data indicated that ApoB3'HVR, FES, VWA, D3S1358 and D16S310 were most polymorphic loci with the average heterozygosity being 0.756+/-0.17. Furthermore, all markers were genotyped in 77 HLA-matched donor-recipient pairs to evaluate the informativeness in differentiating donor's and recipient's cells. A panel of seven markers (ApoB3HVR-D3S1358-HUM-THO1-VWF-1-D16S310-FES-VWA) differentiated 98.70% of donor-recipient pairs. This set of markers also successfully monitored the graft status in 14 HSCT cases during multiple time points following HSCT. The results were compared to the commercially available AmpF/STR SGM Plus multiplex PCR kit (Applied Biosystems, Foster City, CA, USA). Our findings established that the panel of seven markers we identified was more cost-effective and informative.

Disease progression and adverse events in patients listed for elective percutaneous coronary intervention.

OBJECTIVE: To record disease progression and the timing of adverse events in patients on a waiting list for elective percutaneous coronary intervention (PCI). DESIGN: Observational prospective study. SETTINGS: A UK tertiary cardiothoracic centre, at a time when waiting lists for PCI were up to 18 months. PATIENTS: 145 patients (116 men, median age 59.5 years) placed on an elective waiting list for PCI between October 1998 and September 1999. MAIN OUTCOME MEASURES: Adverse events recorded were death, myocardial infarction, need for urgent hospital admission because of unstable angina, and need for emergency revascularisation while waiting for PCI. RESULTS: During a median follow up of 10 months (range 1-18 months), nine (6.2%) patients experienced an adverse event. Eight (5.52%) patients were admitted with unstable angina as emergencies. One was admitted with a myocardial infarction. Twenty nine (20.0%) patients had significant disease progression at the time of the repeat angiogram before PCI. In 10 (7%), disease had progressed so that PCI was no longer feasible and patients were referred for coronary artery bypass graft. Sixteen (11%) were removed from the PCI waiting list because of almost complete resolution of their anginal symptoms. CONCLUSION: Adverse coronary events and clinically significant disease progression occur commonly in patients waiting for PCI. Despite the presence of severe coronary lesions, myocardial infarction was rare and no patients died while on the waiting list. Resolution of anginal symptoms was also comparatively common. The pathophysiology of disease progression frequently necessitates a change in the treatment of patients waiting for PCI.

Recordings, behaviour and models related to corticothalamic feedback.

In this paper, we review recent work on aspects of corticothalamic interactions in the auditory and in the visual systems. There are gross similarities in the arrangements of these systems, but considerable contrasts in the processing computations and in the effects of corticothalamic feedback.

Tubercular pseudoaneurysms of aorta.

BACKGROUND: Tubercular pseudoaneurysm of aorta is a rare but important complication of tuberculosis. With worldwide resurgence of tuberculosis due to increasing incidence of drug-resistant tuberculosis and its association with acquired immunodeficiency syndrome, the tubercular pseudoaneurysm has become a real clinical entity. METHODS: In the past 3 years, 5 young patients (22 to 40 years) presented with tubercular pseudoaneurysm. Site of involvement included ascending aorta, distal aortic arch, proximal descending thoracic aorta, distal descending thoracic aorta, and infrarenal abdominal aorta. Two patients had macroscopic focus of tuberculosis in the nearby vicinity, and all 5 patients had evidence of active/treated pulmonary pericardial tuberculosis. All patients either had received antitubercular therapy previously or were receiving it at the time of presentation. Rapid deterioration in the clinical status was the most marked clinical feature. All patients underwent operation. Graft interposition was performed in 2, patch repair in 2, and direct closure of the rent was performed in 1 patient. All 5 patients received antitubercular therapy in the postoperative period. RESULTS: All patients survived the operation and were discharged from the hospital. One patient developed recurrence at the original site after 8 months and died at reoperation. The remaining patients are symptom free at 18 to 36 months postoperatively. CONCLUSIONS: A combination of chemotherapy and operation yields gratifying results for the treatment of tubercular pseudoaneurysm.

Reorganization in awake rat auditory cortex by local microstimulation and its effect on frequency-discrimination behavior.

In common with other sensory cortices, the mammalian primary auditory cortex (AI) demonstrates the capacity for large-scale reorganization following many experimental situations. For example, training animals in frequency-discrimination tasks has been shown to result in an increase in cortical frequency representation. Such central changes-most commonly, an increase in central representation of specific stimulus parameters-have been hypothesized to underlie the improvements in perceptual acuity (perceptual learning) seen in many learning situations. The actual behavioral relevance of central reorganizations, however, remains speculative. Here, we directly examine this issue. We first show that stimulating the AI cortex of the awake rat with a weak electric current (intracortical microstimulation or ICMS) has the effect of inducing central reorganizations similar to those accompanying the traditional plasticity experiments (a result previously noted only in anesthetized preparations). Depending on the site of AI stimulation, ICMS enlarged the cortical representation of certain frequencies. Next we examined the direct perceptual consequences of ICMS-induced AI reorganization for the rat's ability to discriminate frequencies. Over the course of the experiment, we also detailed, and made comparisons between, the frequency-response characteristics of rat AI cortex in the awake and ketamine-anesthetized animal. AI cells that responded to pure tones were divided into two categories--strongly and weakly responsive--based on the strength of their evoked discharge. Individual cells maintained their respective response strengths in both awake and anesthetized conditions. Strongly responsive cells showed at least four different temporal responses and tended to be narrowly tuned. Their responses were stable over the long term. In general frequency-response characteristics were qualitatively similar in the anesthetized and awake animal; bandwidths tended to be broader in awake animals. Although both strong and weak cell populations respond to tones, only the strongly responsive cells fit into a tonotopically organized scheme. By contrast, weakly responsive cells did not exhibit a frequency mapping and may represent a more diffuse input to AI than that underlying strongly responsive cells. In general, the overall frequency organization of AI was found to be equally well expressed in both the awake and anesthetized rat. ICMS reorganization of AI did not alter frequency-discrimination behavior in the rat--either signal detectability or response bias--suggesting that an increase in central representation, by itself, is insufficient to account for perceptual learning. It is likely that cortical reorganizations that accompany perceptual learning are strongly keyed to specific behavioral contexts.

Fate of mild aortic valve disease after mitral valve intervention.

OBJECTIVE: This study was performed to assess the long-term outcome of untreated mild aortic valve disease present at the time of initial mitral valve intervention. METHODS: A total of 284 patients with rheumatic heart disease aged 7 to 62 years (mean, 23.5 +/- 12.2 years) who underwent mitral valve intervention and had mild aortic valve disease initially were followed up for 2 to 18 years (mean, 10.8 +/- 3.7 years). At initial intervention, 232 patients had pure mild aortic regurgitation, and 52 patients had mild aortic stenosis with or without aortic regurgitation. RESULTS: Among patients with mild aortic regurgitation initially, 11 (5%) patients progressed to moderate (n = 6) or severe (n = 5) regurgitation over an interval of 9 to 17 years (mean, 12.1 +/- 2.8 years), and 1 patient had moderate aortic stenosis and severe aortic regurgitation after 10 years. Freedom from development of moderate-severe aortic valve disease in patients who initially had mild aortic regurgitation was 100%, 97.0% +/- 1.7%, and 87.4% +/- 4.6% at 5, 10, and 15 years, respectively. Seventeen (35%) patients with initial mild aortic stenosis (with or without regurgitation) had moderate or severe stenosis (with or without moderate-severe regurgitation) after an interval of 4.9 +/- 3.8 years. Freedom from development of moderate-severe aortic valve disease in patients who initially had mild aortic stenosis was 75.6% +/- 6.2%, 61.5% +/- 8.5%, and 46.1% +/- 11.2% at 5, 10, and 15 years, respectively. Ten patients required aortic valve replacement for aortic valve dysfunction. CONCLUSIONS: Mild aortic regurgitation present at the time of mitral valve intervention progresses very slowly and less frequently requires reintervention. However, mild aortic stenosis diagnosed initially progresses more often and more rapidly and thus needs closer follow-up.