ACC/AHA and ESC/EACTS Guidelines for the Management of Valvular Heart Diseases: JACC Guideline Comparison.

Valvular heart disease (VHD) is common and poses important challenges from the standpoints of diagnosis and therapeutic management. Clinical practice guidelines have been developed to help health care professionals to overcome these challenges and provide optimal management to patients with VHD. The American College of Cardiology, in collaboration with the American Heart Association, and the European Society of Cardiology, in collaboration with the European Association for Cardio-Thoracic Surgery, recently updated their guidelines on the management of VHD. Although these 2 sets of guidelines are generally concordant, there are some substantial differences between these guidelines, which may have significant implications for clinical practice. This review prepared on behalf of the EuroValve Consortium describes the consistencies and discrepancies between the guidelines and highlights the gaps in these guidelines and the future research perspectives to fill these gaps.

Effectiveness of Stepped-Care Intervention in Overweight and Obese Patients With Medial Tibiofemoral Osteoarthritis: A Randomized Controlled Trial.

OBJECTIVE: To test the effectiveness of a 32-week, stepped-care intervention on disease remission rates in overweight and obese patients with medial tibiofemoral osteoarthritis (OA) compared to controls. METHODS: In this randomized controlled trial, eligible participants were ≥50 years of age with a body mass index of ≥28 kg/m2 and radiographic evidence of medial tibiofemoral OA. Participants were randomized to stepped-care (n = 87) or control group (n = 84). The stepped-care group received a 2-step intervention. The first step consisted of an 18-week diet and exercise program. The second step consisted of 4 treatment subgroups: 1) diet and exercise maintenance; 2) cognitive-behavioral therapy; 3) unloader knee brace; and 4) muscle strengthening exercises. Allocation into subgroups was based on disease remission state and clinical characteristics. The primary end point was the disease remission rate (yes/no) at 32 weeks, which was reached when participants achieved the Patient Acceptable Symptom State cutoff value for pain and for the patient global assessment of disease activity and/or functional impairment. RESULTS: Disease remission at 32 weeks was achieved by 18 of 68 (26%) in the control group and 32 of 82 (39%) in the stepped-care group (difference 12.6% [95% confidence interval -2.3, 27.4], P = 0.10). The stepped-care group showed an improvement in pain and function between baseline and 20 weeks. While functional improvement was maintained at 32 weeks, pain levels tended to get worse between weeks 20 and 32. CONCLUSION: The proposed intervention did not promote a significant difference in the rate of disease remission in comparison to the control group for overweight or obese patients with medial tibiofemoral OA.

Association between radiographic anterior cruciate ligament tear and joint symptoms: Data from the osteoarthritis initiative.

INTRODUCTION: Symptomatic osteoarthritis (OA) in the knee is defined as the presence of OA radiographic features in combination with knee symptoms. Pain has not been shown to correlate meaningfully to radiographic severity. We aimed to determine the relationship between a tear of the anterior cruciate ligament (ACL) with knee symptoms and radiographic OA. METHODS: A within-person, between-knee cross-sectional study of 37 participants from the Osteoarthritis Initiative (OAI) with a complete or partial ACL tear detected on magnetic resonance imaging in 1 knee (index knee) were included. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS) and radiographs of both knees, 1 with an ACL tear and one without (control knee) were scored for OA severity (Kellgren-Lawrence Grading) and symptoms. A generalized estimating equation with linear regression was used to compare symptom scores within individuals as well as to radiographic severity. RESULTS: Thirty-seven individuals (40% female, average age = 60.7years, body mass index = 31.0 kg/m2 ) reported no difference in knee symptoms (WOMAC pain odds ratio [OR] =1.92, 95%CI 0.699-5.248, P = .21; KOOS symptoms OR = 2.12, 95%CI 0.740-6.065, P = .09), stiffness (OR = 1.67, 95%CI 0.653-5.583, P = .35) or functional disability (OR = 1 0.97, 95%CI 0.515-7.508, P = .32) in the knee that exhibited an ACL tear compared to the control knee. Only knee function and disability (WOMAC Disability OR = 1.12, 95%CI 1.003-1.249, P = .04) were associated with radiographic severity between index and control knees. CONCLUSION: Individuals did not report an increase in knee pain, stiffness or disability in their ACL-deficient knee. Only disability was associated with worsening severity of radiographic OA in ACL-deficient knees.

Stepped care approach for medial tibiofemoral osteoarthritis (STrEAMline): protocol for a randomised controlled trial.

INTRODUCTION: Current guidelines recommend tailored interventions to optimise knee osteoarthritis (OA) management. However, models of care still have a 'one size fits all' approach, which is suboptimal as it ignores patient heterogeneity. This study aims to compare a stepped care strategy with standard care for overweight and obese persons with medial tibiofemoral OA. METHODS AND ANALYSIS: Participants will be randomised into two groups (85 each). The intervention will receive a diet and exercise programme for 18 weeks in the first step of the study. Disease remission will then be assessed using the Patient Acceptable Symptom State (PASS). PASS is defined as the highest level of symptom beyond which patients consider themselves well and takes into account pain intensity, patient's global assessment of disease activity and degree of functional impairment. In the second step, participants in remission will continue with diet and exercise. If remission is not achieved, participants will be assigned in a hierarchical order to cognitive behavioural therapy, knee brace or muscle strengthening for 12 weeks. The intervention will be decided based on their clinical presentation for symptoms of depression and varus malalignment. Participants without depression or varus malalignment will undertake a muscle strengthening programme. The control group will receive educational material related to OA management. Main inclusion criteria are age ≥50 years, radiographic medial tibiofemoral OA, body mass index (BMI) ≥28 kg/m2, knee pain ≥40 (Visual Analogue Scale, 0-100), PASS (0-100) >32 for pain and global assessment, and 31 for functional impairment. Outcomes will be measured at 20-week and 32-week visits. The primary outcome is disease remission at 32 weeks. Other outcomes include functional mobility; patient-reported outcomes; BMI; waist-hip ratio; quadriceps strength; symptoms of depression, anxiety and stress; and knee range of motion. The analysis will be performed according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The local ethics committee approved this protocol (HREC/14/HAWKE/381). Dissemination will occur through presentations at international conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12615000227594.

Psychosis as a sequelae of paraneoplastic syndrome in Small- Cell Lung Carcinoma: A psycho-neuroendocrine interface.

In 2013 more than 150,000 Americans died from all types of lung cancer. Small cell lung cancer (SCLC) represents about 13% of all lung cancers and is notoriously associated with paraneoplastic syndromes (PNS). Here we present an interesting case of psychosis associated with one such PNS-- ectopic Cushing syndrome of SCLC. A 56 year old African-American male with no prior psychiatric history who was diagnosed with SCLC two months prior, presented to the ER for treatment of a right arm laceration he sustained while fighting off attackers, with high concern these individuals may have been part of hallucinatory experiences and well-systematized persecutory delusions regarding his wife. Physical assessment was notable for Cushingoid symptoms. Initial results of serum ACTH and cortisol were 221pg/ml (10-50pg/ml) and 37.1 mcg/dl (10-20mcg/dl) respectively. For psychosis, patient was started on Olanzapine which was titrated from 5 to final dose of 10mg nightly. Since patient was not a surgical candidate, he was treated with metyrapone 250 mg BID and radiation therapy was continued throughout hospitalization. Serum Cortisol level decreased steadily after initiation of metyrapone and psychotic symptoms dramatically reduced on olanzapine, metyrapone, and radiation therapy with apparently resolved persecutory delusions at discharge. This case broadens the available literature and provides data on successful symptomatic treatment with olanzapine while biological treatments of the underlying condition were beginning to take effect. As SCLC remains an important cause of morbidity and mortality in the US, it is imperative that physicians be aware of paraneoplastic syndromes and their psychiatric sequelae.

Comparison in knee osteoarthritis joint damage patterns among individuals with an intact, complete and partial anterior cruciate ligament rupture.

AIM: The aim of this study was to examine the difference in the pattern of articular damage in persons with either a partial anterior cruciate ligament (ACL) tear; a complete ACL tear or no ACL tear. METHODS: Our study included 600 individuals (of the 600 individuals, 25 with a partial, 12 with a complete ACL tear and 563 with no ACL tear) from the progression sub-cohort of the Osteoarthritis Initiative. Individuals had a mean age of 61.8 years (range 45-79 years). Chi-square tests were used to compare the location of meniscal pathology, bone marrow lesions (BMLs) and regional cartilage morphology between individuals with a partial or complete ACL tear, as seen on magnetic resonance imaging, as well as to a control group of 563 knees. RESULTS: Individuals with either a complete or partial ACL tear displayed predominantly medial tibiofemoral damage. Individuals with complete ACL tears were more likely to have cartilage lesions in the lateral posterior tibia (P = 0.03) and the medial anterior femur (P = 0.008) as well as BMLs in the medial posterior tibia (P = 0.007). However, no significant difference in meniscal morphology was found in either compartment. Individuals with no history of knee trauma or ACL injury displayed predominantly medial tibiofemoral compartment damage. CONCLUSION: Individuals with prevalent ACL disruptions exhibited concomitant osteoarthritic changes in the medial tibiofemoral compartment, as seen on MRI. As the changes in joint tissues were predominantly located in the medial compartment, it is thought that these ACL tears may represent a manifestation of the overall disease process rather than the precipitant for osteoarthritis incidence.

Does Age Influence the Risk of Incident Knee Osteoarthritis After a Traumatic Anterior Cruciate Ligament Injury?

BACKGROUND: The development of radiographic knee osteoarthritis (OA) after an anterior cruciate ligament (ACL) rupture has long been studied and proven in the adolescent population. However, similar exhaustive investigations have not been conducted in mature-aged athletes or in older populations. PURPOSE: To identify whether an older adult population had an increased risk of incident radiographic knee OA after a traumatic knee injury compared with a young adult population. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients with ACL ruptures who underwent primary reconstruction were enrolled in a prospective, longitudinal single-center study over 15 years. The adult cohort was defined as participants aged ≥35 years who had a knee injury resulting in an ACL tear, the adolescent-young cohort suffered similar knee injuries and were aged ≤25 years, and a third cohort of participants aged 26 to 34 years who suffered a knee injury was included to identify the existence of any age-related dose-response relationship for the onset of radiographic knee OA. A Kaplan-Meier survival analysis was employed to determine the occurrence of incident radiographic OA across the study populations at 2, 5, 10, and 15 years after reconstruction. Significance at each time point was analyzed using chi-square tests. RESULTS: A total of 215 patients, including 112 adolescents (mean age, 20.4 years; 50.9% female), 71 patients aged 26 to 34 years (mean age, 29.2 years; 42.3% female), and 32 adults (mean age, 40.2 years; 59.4% female), were assessed for International Knee Documentation Committee (IKDC) grading on knee radiographs. It was found that 53.0% and 77.8% of adults at a respective 10 and 15 years after reconstruction had an IKDC grade of B or greater compared with 17.7% and 61.6% of the adolescent-young cohort. Chi-square testing found that adults developed OA earlier than adolescents at 5 and 10 years after reconstruction (P = .017 and P < .0001, respectively). However, survival analysis did not demonstrate that adults were more likely to develop radiographic knee OA at 15 years after reconstruction compared with the adolescent-young cohort (P = .4). CONCLUSION: The age at which an ACL injury is sustained does not appear to influence the rate of incident radiographic knee OA, although mature-aged athletes are likely to arrive at the OA endpoint sooner.

The epidemiology of osteoarthritis.

Osteoarthritis (OA) is a leading cause of disability and its incidence is rising due to increasing obesity and an ageing population. Risk factors can be divided into person-level factors, such as age, sex, obesity, genetics, race/ethnicity and diet, and joint-level factors including injury, malalignment and abnormal loading of the joints. The interaction of these risk factors is complex and provides a challenge to the managing physician. The purpose of this review is to illustrate how each of these factors interact together to instigate incident OA as well as to outline the need for ongoing epidemiologic studies for the future prevention of both incident and progressive OA. It is only by understanding the impact of this disease and the modifiable risk factors that we will be able to truly target public health prevention interventions appropriately.

Osteoarthritis: what does imaging tell us about its etiology?

Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. Due to an aging population and increasing obesity, the incidence of OA is rising. The etiology of OA is multifactorial and complex; thus prevention of OA remains challenging. Risk factors can be divided into person-level factors such as age, sex, obesity, genetics, race/ethnicity, and diet, and joint-level factors including injury, malalignment, and abnormal loading of the joints. This review provides a brief overview of the person-level risk factors and a more in-depth analysis of those at the joint level. It is only through an improved understanding of risk factors for the disease that we may be able to intervene meaningfully and prevent its occurrence.

The use of surface electrodes to record infraspinatus activity is not valid at low infraspinatus activation levels.

Limited information is available to support the validity of using surface electrodes to record activity from infraspinatus. The aims of this study were to compare infraspinatus activity recorded using surface and intramuscular electrodes during several shoulder isometric and dynamic tasks and to establish if infraspinatus activity recorded using intramuscular electrodes is representative of whole muscle activity. Surface and intramuscular electrodes were placed over infraspinatus in nine subjects without shoulder pain. Isometric shoulder external rotation, at 0° and 90° abduction, and extension were performed at six loads. Dynamic shoulder flexion and abduction were performed at 70% maximum load. Results indicated that while surface and intramuscular electrodes record similar activation patterns when infraspinatus is moderately to highly activated (r and slope ∼ 1), only intramuscular electrodes accurately reflected low (<10%MVC) infraspinatus activity (r=0.95 ± 0.04, slope=15.6 ± 16.3). The linear relationship between the activity recorded with surface and intramuscular electrodes when infraspinatus is moderately to highly active also indicated that intramuscular recordings from infraspinatus are representative of activity in the whole muscle. To ensure validity in reporting infraspinatus activation patterns when studying functional shoulder tasks in which infraspinatus may be relatively active and inactive at different phases of these tasks, intramuscular electrodes should be used to record infraspinatus activity.

Bub1 and aurora B cooperate to maintain BubR1-mediated inhibition of APC/CCdc20.

The spindle checkpoint maintains genome stability by inhibiting Cdc20-mediated activation of the anaphase promoting complex/cyclosome (APC/C) until all the chromosomes correctly align on the microtubule spindle apparatus via their kinetochores. BubR1, an essential component of this checkpoint, localises to kinetochores and its kinase activity is regulated by the kinesin-related motor protein Cenp-E. BubR1 also inhibits APC/C(Cdc20) in vitro, thus providing a molecular link between kinetochore-microtubule interactions and the proteolytic machinery that regulates mitotic progression. Several other protein kinases, including Bub1 and members of the Ipl1/aurora family, also regulate anaphase onset. However, in human somatic cells Bub1 and aurora B kinase activity do not appear to be essential for spindle checkpoint function. Specifically, when Bub1 is inhibited by RNA interference, or aurora kinase activity is inhibited with the small molecule ZM447439, cells arrest transiently in mitosis following exposure to spindle toxins that prevent microtubule polymerisation. Here, we show that mitotic arrest of Bub1-deficient cells is dependent on aurora kinase activity, and vice versa. We suggest therefore that the checkpoint is composed of two arms, one dependent on Bub1, the other on aurora B. Analysis of BubR1 complexes suggests that both of these arms converge on the mitotic checkpoint complex (MCC), which includes BubR1, Bub3, Mad2 and Cdc20. Although it is known that MCC components can bind and inhibit the APC/C, we show here for the first time that the binding of the MCC to the APC/C is dependent on an active checkpoint signal. Furthermore, we show that both Bub1 and aurora kinase activity are required to promote binding of the MCC to the APC/C. These observations provide a simple explanation of why BubR1 and Mad2 are essential for checkpoint function following spindle destruction, yet Bub1 and aurora B kinase activity are not. Taken together with other observations, we suggest that these two arms respond to different spindle cues: whereas the Bub1 arm monitors kinetochore-microtubule attachment, the aurora B arm monitors biorientation. This bifurcation in the signalling mechanism may help explain why many tumour cells mount a robust checkpoint response following spindle damage, despite exhibiting chromosome instability.

Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer.

Whereas a recent study reported an increased risk of colorectal cancer associated with any HFE germ line mutation (C282Y or H63D), other investigators have concluded there is no increased risk, or that any increase is dependent on polymorphisms in HFE-interacting genes such as the transferrin receptor (TFR). We have established the frequency of HFE mutations in colorectal cancer patients (n = 327) with a family history of the disease and randomly selected controls (n = 322); this design increases greatly the study's power. Genotyping for the TRF S142G polymorphism was also conducted on a large proportion of the study group. Using PCR, restriction enzyme mapping, sequencing followed by data analysis with Fisher's exact test and logistic regression, we show that the presence of any HFE mutation (Y282 or D63) was not associated with colorectal cancer risk (P = 0.57). In contrast, individuals compound heterozygous for both mutations (15 cases versus 5 controls) had thrice the odds of developing colorectal cancer (odds ratio, 3.03; 95% confidence interval, 1.06-8.61) compared with those with a single mutation. This finding did not quite reach statistical significance after allowing for multiple post hoc testing (P(observed) = 0.038 versus P = 0.025, with Bonferonni correction). Overall, our data indicate that individuals with a single HFE mutation, C282Y or H63D, are unlikely predisposed to develop colorectal cancer. However, risk of colorectal cancer might be increased by compound heterozygosity for the HFE mutations in the small number of subjects studied. TFR gene polymorphism was not an independent risk factor and did not modify the disease risk associated with HFE mutation.

Truncating APC mutations have dominant effects on proliferation, spindle checkpoint control, survival and chromosome stability.

The majority of human tumour cells are aneuploid owing to an underlying chromosome instability phenotype. While the genetic lesions that cause chromosome instability remain undefined, mouse ES cells harbouring homozygous adenomatous polyposis coli (APC) mutations are frequently tetraploid. In addition, colon cancer cells with APC mutations have weakened kinetochore-microtubule interactions. Furthermore, mitotic spindles assembled in APC-depleted Xenopus egg extracts are aberrant. Therefore, to determine whether APC mutations can initiate chromosome instability in human cells, we expressed N-terminal APC fragments in HCT-116 cells, a near diploid colon cancer cell line with two wild-type APC alleles. We show that cells expressing N-APC mutants exit mitosis prematurely in the presence of spindle toxins, consistent with a spindle checkpoint defect. In addition, N-APC cells show enhanced survival following prolonged spindle damage. In contrast to controls, the N-APC survivors frequently contain dicentric chromosomes and then go on to become highly aneuploid. These observations suggest that truncating APC mutations can exert dominant effects which in turn can initiate chromosome instability. As such, APC mutation not only compromises tumour suppressor function but may also have oncogenic properties. We suggest therefore that the initial APC mutation acts as a 'double whammy', destabilising the genome and setting the stage for deregulated proliferation upon loss of the second APC allele.

Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression.

During mitosis, the recruitment of spindle-checkpoint-associated proteins to the kinetochore occurs in a defined order. The protein kinase Bub1 localizes to the kinetochore very early during mitosis, followed by Cenp-F, BubR1, Cenp-E and finally Mad2. Using RNA interference, we have investigated whether this order of binding reflects a level of dependency in human somatic cells. Specifically, we show that Bub1 plays a key role in the assembly of checkpoint proteins at the kinetochore, being required for the subsequent localization of Cenp-F, BubR1, Cenp-E and Mad2. In contrast to studies in Xenopus, we also show that BubR1 is not required for kinetochore localization of Bub1. Repression of Bub1 increases the number of cells with lagging chromosomes at metaphase, suggesting that Bub1 plays a role in chromosome congression. However, repression of Bub1 does not appear to compromise spindle checkpoint function either during normal mitosis or in response to spindle damage. This raises the possibility that, in the absence of Bub1, other mechanisms contribute to spindle checkpoint function.

Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome c, Bax, Bid, and caspases.

The role of apoptosis in acetaminophen (AAP)-induced hepatic injury was investigated. Six hours after AAP administration to BALB/c mice, a significant loss of hepatic mitochondrial cytochrome c was observed that was similar in extent to the loss observed after in vivo activation of CD95 by antibody treatment. AAP-induced loss of mitochondrial cytochrome c coincided with the appearance in the cytosol of a fragment corresponding to truncated Bid (tBid). At the same time, tBid became detectable in the mitochondrial fraction, and concomitantly, Bax was found translocated to mitochondria. However, AAP failed to activate the execution caspases 3 and 7 as evidenced by a lack of procaspase processing and the absence of an increase in caspase-3-like activity. In contrast, the administration of the pan-inhibitor of caspases, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (but not its analogue benzyloxycarbonyl-Phe-Ala-fluoromethylketone) prevented the development of liver injury by AAP and the appearance of apoptotic parenchymal cells. This correlated with the inhibition of the processing of Bid to tBid. The caspase inhibitor failed to prevent both the redistribution of Bax to the mitochondria and the loss of cytochrome c. In conclusion, apoptosis is an important causal event in the initiation of the hepatic injury inflicted by AAP. However, as suggested by the lack of activation of the main execution caspases, apoptosis is not properly executed and degenerates into necrosis.

Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores.

The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, enter mitosis normally, and assemble bipolar spindles. However, chromosome alignment, segregation, and cytokinesis all fail. Despite the presence of maloriented chromosomes, ZM447439-treated cells exit mitosis with normal kinetics, indicating that the spindle checkpoint is compromised. Indeed, ZM447439 prevents mitotic arrest after exposure to paclitaxel. RNA interference experiments suggest that these phenotypes are due to inhibition of Aurora B, not Aurora A or some other kinase. In the absence of Aurora B function, kinetochore localization of the spindle checkpoint components BubR1, Mad2, and Cenp-E is diminished. Furthermore, inhibition of Aurora B kinase activity prevents the rebinding of BubR1 to metaphase kinetochores after a reduction in centromeric tension. Aurora B kinase activity is also required for phosphorylation of BubR1 on entry into mitosis. Finally, we show that BubR1 is not only required for spindle checkpoint function, but is also required for chromosome alignment. Together, these results suggest that by targeting checkpoint proteins to kinetochores, Aurora B couples chromosome alignment with anaphase onset.