The complex role of Rcor2: Regulates mesenchymal stromal cell differentiation in vitro but is dispensable in vivo.

Recent research has revealed several important pathways of epigenetic regulation leading to transcriptional changes in bone cells. Rest Corepressor 2 (Rcor2) is a coregulator of Lysine-specific histone demethylase 1 (Lsd1), a demethylase linked to osteoblast activity, hematopoietic stem cell differentiation and malignancy of different neoplasms. However, the role of Rcor2 in osteoblast differentiation has not yet been examined in detail. We have previously shown that Rcor2 is highly expressed in mesenchymal stromal cells (MSC) and particularly in the osteoblastic lineage. The role of Rcor2 in osteoblastic differentiation in vitro was further characterized and we demonstrate here that lentiviral silencing of Rcor2 in MC3T3-E1 cells led to a decrease in osteoblast differentiation. This was indicated by decreased alkaline phosphatase and von Kossa stainings as well as by decreased expression of several osteoblast-related marker genes. RNA-sequencing of the Rcor2-downregulated MC3T3-E1 cells showed decreased repression of Rcor2 target genes, as well as significant upregulation of majority of the differentially expressed genes. While the heterozygous, global loss of Rcor2 in vivo did not lead to a detectable bone phenotype, conditional deletion of Rcor2 in limb-bud mesenchymal cells led to a moderate decrease in cortical bone volume. These findings were not accentuated by challenging bone formation by ovariectomy or tibial fracture. Furthermore, a global deletion of Rcor2 led to decreased white adipose tissue in vivo and decreased the capacity of primary cells to differentiate into adipocytes in vitro. The conditional deletion of Rcor2 led to decreased adiposity in fracture callus. Taken together, these results suggest that epigenetic regulation of mesenchymal stromal cell differentiation is mediated by Rcor2, which could thus play an important role in defining the MSC fate.

Hepcidin predicts response to IV iron therapy in patients admitted to the intensive care unit: a nested cohort study.

BACKGROUND: Both anaemia and red blood cell (RBC) transfusion are common and associated with adverse outcomes in patients admitted to the intensive care unit (ICU). The aim of this study was to determine whether serum hepcidin concentration, measured early after ICU admission in patients with anaemia, could identify a group in whom intravenous (IV) iron therapy decreased the subsequent RBC transfusion requirement. METHODS: We conducted a prospective observational study nested within a multicenter randomized controlled trial (RCT) of IV iron versus placebo. The study was conducted in the ICUs of four tertiary hospitals in Perth, Western Australia. Critically ill patients with haemoglobin (Hb) of < 100 g/L and within 48 h of admission to the ICU were eligible for participation after enrolment in the IRONMAN RCT. The response to IV iron therapy compared with placebo was assessed according to tertile of hepcidin concentration. RESULTS: Hepcidin concentration was measured within 48 h of ICU admission in 133 patients. For patients in the lower two tertiles of hepcidin concentration (< 53.0 µg), IV iron therapy compared with placebo was associated with a significant decrease in RBC transfusion requirement [risk ratio 0.48 (95% CI 0.26-0.85), p = 0.013]. CONCLUSIONS: In critically ill patients with anaemia admitted to an ICU, baseline hepcidin concentration predicts RBC transfusion requirement and is able to identify a group of patients in whom IV iron compared with placebo is associated with a significant decrease in RBC transfusion requirement. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ANZCTRN12612001249 Registered 26/11/2012.

Effect of immediate initiation of antiretroviral treatment on the risk of acquired HIV drug resistance.

OBJECTIVE: We estimated and compared the risk of clinically identified acquired drug resistance under immediate initiation [the currently recommended antiretroviral therapy (ART) initiation strategy], initiation with CD4 cell count less than 500 cells/µl and initiation with CD4 cell count less than 350 cells/µl. DESIGN: Cohort study based on routinely collected data from the HIV-CAUSAL collaboration. METHODS: For each individual, baseline was the earliest time when all eligibility criteria (ART-naive, AIDS free, and others) were met after 1999. Acquired drug resistance was defined using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. We used the parametric g-formula to adjust for time-varying (CD4 cell count, HIV RNA, AIDS, ART regimen, and drug resistance testing) and baseline (calendar period, mode of acquisition, sex, age, geographical origin, ethnicity and cohort) characteristics. RESULTS: In 50 981 eligible individuals, 10% had CD4 cell count more than 500 cells/µl at baseline, and 63% initiated ART during follow-up. Of 2672 tests for acquired drug resistance, 794 found resistance. The estimated 7-year risk (95% confidence interval) of acquired drug resistance was 3.2% (2.8,3.5) for immediate initiation, 3.1% (2.7,3.3) for initiation with CD4 cell count less than 500 cells/µl, and 2.8% (2.5,3.0) for initiation with CD4 cell count less than 350 cells/µl. In analyses restricted to individuals with baseline in 2005-2015, the corresponding estimates were 1.9% (1.8, 2.5), 1.9% (1.7, 2.4), and 1.8% (1.7, 2.2). CONCLUSION: Our findings suggest that the risk of acquired drug resistance is very low, especially in recent calendar periods, and that immediate ART initiation only slightly increases the risk. It is unlikely that drug resistance will jeopardize the proven benefits of immediate ART initiation.

Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial : A randomized trial of IV iron in critical illness.

PURPOSE: Both anaemia and allogenic red blood cell transfusion are common and potentially harmful in patients admitted to the intensive care unit. Whilst intravenous iron may decrease anaemia and RBC transfusion requirement, the safety and efficacy of administering iron intravenously to critically ill patients is uncertain. METHODS: The multicentre, randomized, placebo-controlled, blinded Intravenous Iron or Placebo for Anaemia in Intensive Care (IRONMAN) study was designed to test the hypothesis that, in anaemic critically ill patients admitted to the intensive care unit, early administration of intravenous iron, compared with placebo, reduces allogeneic red blood cell transfusion during hospital stay and increases the haemoglobin level at the time of hospital discharge. RESULTS: Of 140 patients enrolled, 70 were assigned to intravenous iron and 70 to placebo. The iron group received 97 red blood cell units versus 136 red blood cell units in the placebo group, yielding an incidence rate ratio of 0.71 [95 % confidence interval (0.43-1.18), P = 0.19]. Overall, median haemoglobin at hospital discharge was significantly higher in the intravenous iron group than in the placebo group [107 (interquartile ratio IQR 97-115) vs. 100 g/L (IQR 89-111), P = 0.02]. There was no significant difference between the groups in any safety outcome. CONCLUSIONS: In patients admitted to the intensive care unit who were anaemic, intravenous iron, compared with placebo, did not result in a significant lowering of red blood cell transfusion requirement during hospital stay. Patients who received intravenous iron had a significantly higher haemoglobin concentration at hospital discharge. The trial was registered at http://www.anzctr.org.au as # ACTRN12612001249842.

Anti-N-methyl-D-aspartate receptor encephalitis with an imaging-invisible ovarian teratoma: a case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor encephalitis is a recently discovered disease entity of paraneoplastic limbic encephalitis. It largely affects young women and is often associated with an ovarian teratoma. It is a serious yet treatable condition if diagnosed early. Its remedy involves immunotherapy and surgical removal of the teratoma of the ovaries. This case of anti-N-methyl-D-aspartate receptor encephalitis involves an early surgical intervention with bilateral oophorectomy, despite negative imaging evidence of a teratoma. CASE PRESENTATION: A 25-year-old white woman with anti-N-methyl-D-aspartate receptor encephalitis presented with behavioral changes and seizures that were confirmed to be secondary to anti-N-methyl-D-aspartate receptor encephalitis. She required an admission to our intensive care unit for ventilator support and received a number of immunological therapies. Multiple imaging investigations showed no evidence of an ovarian teratoma; she had a bilateral oophorectomy 29 days after admission. Ovarian histology confirmed the presence of a teratoma with neuronal cells. A few days after the operation she began to show signs of improvement and, apart from mild short-term memory loss, she returned to normal function. CONCLUSIONS: Our patient is an example of teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis, in which the teratoma was identified only microscopically. Her case highlights that even with negative imaging evidence of a teratoma, ovarian pathology should still be considered and explored.

HLA Immunogenotype Determines Persistent Human Papillomavirus Virus Infection in HIV-Infected Patients Receiving Antiretroviral Treatment.

A proportion of human immunodeficiency virus (HIV)-infected patients develop persistent, stigmatizing human papillomavirus (HPV)-related cutaneous and genital warts and anogenital (pre)cancer. This is the first study to investigate immunogenetic variations that might account for HPV susceptibility and the largest to date to categorize the HPV types associated with cutaneous warts in HIV-positive patients. The HLA class I and II allele distribution was analyzed in 49 antiretroviral (ART)-treated HIV-positive patients with persistent warts, 42 noninfected controls, and 46 HIV-positive controls. The allele HLA-B*44 was more frequently identified in HIV-positive patients with warts (P = .004); a susceptible haplotype (HLA-B*44, HLA-C*05; P = .001) and protective genes (HLA-DQB1*06; P = .03) may also contribute. Cutaneous wart biopsy specimens from HIV-positive patients harbored common wart types HPV27/57, the unusual wart type HPV7, and an excess of Betapapillomavirus types (P = .002), compared with wart specimens from noninfected controls. These findings suggest that HLA testing might assist in stratifying those patients in whom vaccination should be recommended.

The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia.

BACKGROUND: Allogeneic red blood cell (RBC) transfusion is associated with significant increases in mortality and major morbidity in patients admitted to the intensive care unit, and the blood supplies it requires are an increasingly scarce and costly resource. Despite high levels of compliance with recommended transfusion thresholds in the ICU, RBC transfusion remains common. Novel interventions to reduce the incidence of RBC transfusion are required. OBJECTIVE: To describe the study protocol for a randomised controlled trial, the Intravenous Iron or Placebo for Anaemia in Intensive Care (IRONMAN) trial, comparing intravenous (IV) iron with placebo in patients who are admitted to an ICU and are anaemic. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A Phase IIb multicentre, randomised, placebo-controlled trial. Patients admitted to the ICU with a haemoglobin (Hb) level < 100 g/L and predicted to require critical care beyond the next calendar day will be randomly assigned in a 1 : 1 ratio to receive IV ferric carboxymaltose (500 mg) or placebo. MAIN OUTCOME MEASURES: The primary end point will be the mean number of RBC units transfused from study enrolment to discharge from hospital. Secondary end points will include change in Hb level and incidence of nosocomial infection. RESULTS AND CONCLUSIONS: The IRONMAN trial is designed to determine whether IV iron administered to patients admitted to an ICU and who are anaemic is associated with a reduction in RBC transfusion, compared with placebo in addition to standard care. The results of this trial may determine whether a Phase III trial of IV iron in ICUs is feasible. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12612001249842).

Role of HIV infection duration and CD4 cell level at initiation of combination anti-retroviral therapy on risk of failure.

BACKGROUND: The development of HIV drug resistance and subsequent virological failure are often cited as potential disadvantages of early cART initiation. However, their long-term probability is not known, and neither is the role of duration of infection at the time of initiation. METHODS: Patients enrolled in the UK Register of HIV seroconverters were followed-up from cART initiation to last HIV-RNA measurement. Through survival analysis we examined predictors of virologic failure (2HIV-RNA ≥400 c/l while on cART) including CD4 count and HIV duration at initiation. We also estimated the cumulative probabilities of failure and drug resistance (from the available HIV nucleotide sequences) for early initiators (cART within 12 months of seroconversion). RESULTS: Of 1075 starting cART at a median (IQR) CD4 count 272 (190,370) cells/mm(3) and HIV duration 3 (1,6) years, virological failure occurred in 163 (15%). Higher CD4 count at initiation, but not HIV infection duration at cART initiation, was independently associated with lower risk of failure (p=0.033 and 0.592 respectively). Among 230 patients initiating cART early, 97 (42%) discontinued it after a median of 7 months; cumulative probabilities of resistance and failure by 8 years were 7% (95% CI 4,11) and 19% (13,25), respectively. CONCLUSION: Although the rate of discontinuation of early cART in our cohort was high, the long-term rate of virological failure was low. Our data do not support early cART initiation being associated with increased risk of failure and drug resistance.

How private is your consultation? Acoustic and audiological measures of speech privacy in the otolaryngology clinic.

The right to confidentiality is a central tenet of the doctor-patient relationship. In the United Kingdom this right to confidentiality is recognised in published GMC guidance. In USA the Healthcare Insurance Portability and Accountability Act of 1996 (HIPAA) strengthened the legal requirement to protect patient information in all forms and failure to do so now constitutes a federal offence. The aims of this study are to assess the acoustic privacy of an otolaryngology outpatient consultation room. Acoustic privacy was measured using the articulation index (AI) and Bamford-Kowal-Bench (BKB) speech discrimination tests. BKB speech tests were calibrated to normal conversational volume (50 dB SPL). Both AI and BKB were calculated in four positions around the ENT clinic: within the consultation room, outside the consulting room door, in the nearest waiting area chair and in the farthest waiting area chair. Tests were undertaken with the clinic room door closed and open to assess the effect on privacy. With the clinic room door closed, mean BKB scores in nearest and farthest waiting area chairs were 51 and 41% respectively. AI scores in the waiting area chairs were 0.03 and 0.02. With the clinic room door open, privacy was lost in both AI and BKB testing, with almost 100% of word discernable at normal talking levels. The results of this study highlight the poor level of speech privacy within a standard ENT outpatient department. AI is a poor predictor or privacy.

Safety of audiology direct access for medicare patients complaining of impaired hearing.

BACKGROUND: Allowing Medicare beneficiaries to self-refer to audiologists for evaluation of hearing loss has been advocated as a cost-effective service delivery model. Resistance to audiology direct access is based, in part, on the concern that audiologists might miss significant otologic conditions. PURPOSE: To evaluate the relative safety of audiology direct access by comparing the treatment plans of audiologists and otolaryngologists in a large group of Medicare-eligible patients seeking hearing evaluation. RESEARCH DESIGN: Retrospective chart review study comparing assessment and treatment plans developed by audiologists and otolaryngologists. STUDY SAMPLE: 1550 records comprising all Medicare eligible patients referred to the Audiology Section of the Mayo Clinic Florida in 2007 with a primary complaint of hearing impairment. DATA COLLECTION AND ANALYSIS: Assessment and treatment plans were compiled from the electronic medical record and placed in a secured database. Records of patients seen jointly by audiology and otolaryngology practitioners (Group 1: 352 cases) were reviewed by four blinded reviewers, two otolaryngologists and two audiologists, who judged whether the audiologist treatment plan, if followed, would have missed conditions identified and addressed in the otolaryngologist's treatment plan. Records of patients seen by audiology but not otolaryngology (Group 2: 1198 cases) were evaluated by a neurotologist who judged whether the patient should have seen an otolaryngologist based on the audiologist's documentation and test results. Additionally, the audiologist and reviewing neurotologist judgments about hearing asymmetry were compared to two mathematical measures of hearing asymmetry (Charing Cross and AAO-HNS [American Academy of Otolaryngology-Head and Neck Surgery] calculations). RESULTS: In the analysis of Group 1 records, the jury of four judges found no audiology discrepant treatment plans in over 95% of cases. In no case where a judge identified a discrepancy in treatment plans did the audiologist plan risk missing conditions associated with significant mortality or morbidity that were subsequently identified by the otolaryngologist. In the analysis of Group 2 records, the neurotologist judged that audiology services alone were all that was required in 78% of cases. An additional 9% of cases were referred for subsequent medical evaluation. The majority of remaining patients had hearing asymmetries. Some were evaluated by otolaryngology for hearing asymmetry in the past with no interval changes, and others were consistent with noise exposure history. In 0.33% of cases, unexplained hearing asymmetry was potentially missed by the audiologist. Audiologists and the neurotologist demonstrated comparable accuracy in identifying Charing Cross and AAO-HNS pure-tone asymmetries. CONCLUSIONS: Of study patients evaluated for hearing problems in the one-year period of this study, the majority (95%) ultimately required audiological services, and in most of these cases, audiological services were the only hearing health-care services that were needed. Audiologist treatment plans did not differ substantially from otolaryngologist plans for the same condition; there was no convincing evidence that audiologists missed significant symptoms of otologic disease; and there was strong evidence that audiologists referred to otolaryngology when appropriate. These findings are consistent with the premise that audiology direct access would not pose a safety risk to Medicare beneficiaries complaining of hearing impairment.

Audiologic management of a patient with a sudden hearing loss and vestibular schwannoma in the contralateral ear.

The case of a 59-year-old male with a sudden-onset sensorineural hearing loss in one ear and an incidental finding of an intracanalicular vestibular schwannoma in the contralateral, normally hearing ear is reported. The patient was successfully fitted with a hearing aid in the ear with the sudden hearing loss, which notably had very poor word recognition. The questionable value of word-recognition scores in determining hearing aid candidacy is discussed. The importance of considering nonaudiologic factors in determining hearing aid candidacy is also highlighted.

Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. Relevance to diabetes and inflammation.

Nuclear factor kappa-B (NF-kappaB)-regulated inflammatory genes, such as TNF-alpha (tumor necrosis factor-alpha), play key roles in the pathogenesis of inflammatory diseases, including diabetes and the metabolic syndrome. However, the nuclear chromatin mechanisms are unclear. We report here that the chromatin histone H3-lysine 4 methyltransferase, SET7/9, is a novel coactivator of NF-kappaB. Gene silencing of SET7/9 with small interfering RNAs in monocytes significantly inhibited TNF-alpha-induced inflammatory genes and histone H3-lysine 4 methylation on these promoters, as well as monocyte adhesion to endothelial or smooth muscle cells. Chromatin immunoprecipitation revealed that SET7/9 small interfering RNA could reduce TNF-alpha-induced recruitment of NF-kappaB p65 to inflammatory gene promoters. Inflammatory gene induction by ligands of the receptor for advanced glycation end products was also attenuated in SET7/9 knockdown monocytes. In addition, we also observed increased inflammatory gene expression and SET7/9 recruitment in macrophages from diabetic mice. Microarray profiling revealed that, in TNF-alpha-stimulated monocytes, the induction of 25% NF-kappaB downstream genes, including the histone H3-lysine 27 demethylase JMJD3, was attenuated by SET7/9 depletion. These results demonstrate a novel role for SET7/9 in inflammation and diabetes.

Survival following HIV infection of a cohort followed up from seroconversion in the UK.

OBJECTIVES: To estimate changes over calendar time in survival following HIV seroconversion in the era of HAART and to provide updated survival estimates. METHODS: Using data from a UK cohort of persons with well estimated dates of HIV seroconversion, we analysed time from seroconversion to death from any cause using Cox models, adjusted for prognostic factors. Kaplan-Meier methods were then used to determine the expected survival in each calendar period. RESULTS: 2275 seroconverters were included with 18 695 person-years of follow up. A total of 444 (20%) died. The relative risk of death, compared with pre-1996, decreased over time to 0.63 [95% confidence interval (CI), 0.48-0.81], 0.24 (0.17-0.34), 0.14 (0.10-0.21), 0.08 (0.05-0.13) and 0.03 (0.02-0.06) in 1996-1997, 1998-1999, 2000-2001, 2002-2003 and 2004-2006, respectively. An elevated risk of death was associated with older age at seroconversion [hazard ratio (HR), 1.49; 95% CI, 1.34-1.66 per 10-year increase] and HIV infection through injecting drug use (HR, 1.53; 95% CI, 1.17-2.00). In 2000-2006, the proportion of individuals expected to survive 5, 10 and 15 years following seroconversion was 99%, 94% and 89%, respectively. CONCLUSIONS: Survival following HIV seroconversion has continued to improve over calendar time in our cohort, even in the more recent years of HAART availability. HIV seroconverters, by definition identified early in their infection, are likely to have the greatest opportunity for intervention; if similar high survival expectations are to be seen in the wider HIV-infected population, early diagnosis is likely to be crucial.

The importance of audiologic red flags in patient management decisions.

BACKGROUND: It is essential that nonbenign forms of hearing impairment are recognized and addressed before audiological management is entertained. PURPOSE: To present an illustrative case and focused literature review of early red flag indicators for retrocochlear impairment, as might be discerned from a patient's history or physical examination. RESULTS: The presenting history and clinical course of a female patient with fatal adenocarcinoma presenting as a suspected retrocochlear mass is reviewed over the last four months of her life. Clinical signs, symptoms and test results pointing to the diagnosis of "acoustic neuroma" and then "metastatic neoplasm" are reviewed along with selected supporting reference literature. The ambiguous clinical pictures at various points in her history are analyzed, with an effort to point out how early audiological decisions may significantly impact patient's overall health. CONCLUSIONS: Clear communication with primary care physicians, vigilance when audiological results are ambiguous for active disease, and pre-established referral relationships with practitioners in the neurologic and otologic disciplines are stressed as important requirements for audiologists who serve as entry points into hearing healthcare.

Choosing the appropriate antithrombotic agent for the prevention and treatment of VTE: a case-based approach.

OBJECTIVE: To review the risk of venous thromboembolism (VTE) in various patient populations and evaluate the agents available for the prevention and treatment of VTE using a case-based approach. DATA SOURCES: A MEDLINE search (1995-July 2006) was conducted to identify relevant literature. Additional references were reviewed from selected articles. STUDY SELECTION AND DATA EXTRACTION: Articles related to the prevention of VTE in orthopedic surgery, general surgery, and medically ill patients, as well as the treatment of VTE, were reviewed. DATA SYNTHESIS: Pharmacologic options for the prevention and treatment of VTE include warfarin, unfractionated heparin (UFH), low-molecular-weight heparins (LMWH), and fondaparinux. Current guidelines support the use of warfarin, LMWH, or fondaparinux for VTE prophylaxis following lower limb major orthopedic surgery. For VTE prophylaxis in hospitalized medical patients or patients undergoing general surgery, use of UFH and LMWH is supported; however, recent data on fondaparinux suggest that it is also effective in these patient populations. The use of UFH or LMWH (both in conjunction with warfarin) for treatment of acute deep venous thrombosis or nonmassive pulmonary embolism is recommended. Recent data suggest that fondaparinux (in conjunction with warfarin) is also effective for the treatment of VTE. A variety of pharmacokinetic, pharmacodynamic, and pharmacoeconomic factors differentiate each agent for the various indications. CONCLUSIONS: Currently, a "one-size-fits-all" anticoagulant is not available for treatment of VTE. A variety of patient factors, including type of surgery, medical indication, thrombotic risk factors, bleeding risk, history of heparin-induced thrombocytopenia, and a variety of comorbid conditions can affect the safety, efficacy, and selection of appropriate VTE therapy.

Regulation of the human Sox9 promoter by the CCAAT-binding factor.

Sox9 is an essential transcriptional regulator of chondrogenesis and chondrocyte-specific gene expression; however, the identity and function of transcription factors that regulate Sox9 gene expression are not well understood. Here, we have undertaken an analysis of the human Sox9 proximal promoter region in an effort to elucidate the function and identity of transcriptional regulators that are important for controlling Sox9 gene transcription. By transfection analysis, we show that elements residing between -256 bp and +67 bp are important for the overall level of Sox9 promoter activity. Previously, two CCAAT boxes were identified in the Sox9 mouse and human promoters (position -60 bp and -100 bp) by sequence analysis (Kanai, Y., Koopman, P., 1999. Structural and functional characterization of the mouse Sox9 promoter: implications for campomelic dysplasia. Hum. Mol. Genet., 8: 691-696). We demonstrate by electrophoretic mobility shift (EMSA) competition and supershift assays that the CCAAT-binding factor (CBF) can form a complex with both Sox9 CCAAT boxes in nuclear extracts from multiple cell lines. Transfection of human Sox9 promoter-luciferase constructs containing mutated or deleted CCAAT boxes demonstrated that both CCAAT boxes are important for Sox9 promoter activity in chondrogenic cell lines and primary chondrocytes. Chromatin immunoprecipitation (ChIP) experiments demonstrated that CBF interacts with the Sox9 promoter in vivo. Together, these studies show that the Sox9 promoter is regulated by CBF through its interaction with two functional CCAAT boxes.

The role of oral direct thrombin inhibitors in the prophylaxis of venous thromboembolism.

Venous thromboembolism, which is manifested as deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a significant cause of death, disability, and discomfort. Two million people/year are affected by VTE, making it the third most common cardiovascular disease after coronary heart disease and stroke. The rationale for VTE prophylaxis stems from the clinically silent presentation of the disease and its prevalence among hospitalized patients. At greatest risk are patients undergoing major orthopedic surgery and those admitted to the intensive care unit with acute myocardial infarction, heart failure, ischemic stroke, respiratory disease, systemic infection, or other medical conditions that immobilize patients for 5 days or longer. Several anticoagulant regimens have been effective in reducing the risk of VTE after major orthopedic surgery. For patients undergoing total hip or knee replacement, treatment with adjusted-dose warfarin, low-molecular-weight heparins, or fondaparinux may be used. Warfarin, which has been around for more than 50 years, is the only oral anticoagulant available for VTE prophylaxis. Ximelagatran, a new low-molecular-weight oral prodrug of the direct thrombin inhibitor melagatran, has advantages over warfarin that may make it the drug of choice for prevention of VTE.

Pharmacoeconomics of thrombosis management.

Venous thromboembolism (VTE) is the cause of significant morbidity and mortality and may lead to other complications, including recurrent VTE and long-term postthrombotic syndrome. Venous thromboembolism represents a huge health economic burden of nearly 500 million dollars/year in the United States. Without adequate prophylaxis, patients undergoing major orthopedic surgery are at high risk of developing VTE. Prophylaxis with either unfractionated heparin or warfarin not only substantially reduces the risk of VTE after orthopedic surgery, but also is more cost-effective than no prophylaxis. Low-molecular-weight heparins (LMWHs) have been shown to be superior to unfractionated heparin or warfarin, and despite the fact that they are more expensive, they are cost-effective. Large-scale clinical trials have shown that fondaparinux further reduces the likelihood of VTE complications after major orthopedic surgery. A review of the pharmacoeconomic evaluations of fondaparinux leads to the conclusion that fondaparinux is a cost-effective alternative to LMWHs in VTE prophylaxis.

Atherothrombosis: epidemiology, pathophysiology, and prevention.

OBJECTIVES: To review the pathophysiology of atherothrombosis (atherosclerosis with superimposed platelet-rich thrombus formation) and the measures that can be taken to prevent its clinical sequelae through lifestyle modifications and pharmacotherapy, with emphasis on the role of antiplatelet agents. DATA SOURCES: Recent (1995-2003) published scientific literature, as identified by the authors through Medline searches using the terms atherothrombosis, pathophysiology, risk factors, prevention, and reviews on treatment. STUDY SELECTION: Recent systematic English-language review articles were screened for relevant material. DATA SYNTHESIS: Atherothrombosis is a generalized and diffuse progressive process affecting multiple vascular beds; its clinical consequences, including acute coronary syndromes (unstable angina, acute myocardial infarction, and sudden cardiac death), ischemic stroke, and peripheral arterial disease, are unpredictable in their time course and potentially life-threatening. Atherothrombosis rather than arterial stenosis appears to account for most of the acute ischemic manifestations of the atherosclerotic process. Interventions that can favorably influence atherosclerotic progression include lifestyle modifications (dietary control, exercise, and smoking cessation) and pharmacotherapy (lipid-lowering, antihypertensive, antiglycemic, and antiplatelet drugs). The pivotal role played by the platelet in thrombus formation provides the rationale for employing antiplatelet drugs with complementary modes of action (e.g., aspirin, clopidogrel) to prevent atherothrombosis. CONCLUSION: Ischemic cerebrovascular, coronary, and peripheral arterial disease can be regarded as diverse manifestations of a common underlying systemic pathology, namely atherothrombosis. Secondary prevention of an ischemic event in an affected arterial bed confers the added benefit of primary prevention against potential ischemic events in other arterial beds.