Bone turnover markers in HIV disease

Biomarkers are being increasingly used in basic and clinical research of HIV disease as well as clinical management of infected individuals. Bone metabolism can be assessed by measurement of bone turnover markers, molecules released during bone formation and removal of old bone (resorption). In HIV-infected adults, there is a higher prevalence of low bone mineral density and fractures compared to the general population. This review discusses the findings regarding bone turnover markers in HIV-uninfected and -infected populations and their potential role in assessing fracture risk and predicting bone loss. Studies in postmenopausal women and elderly men show that increased bone turnover markers levels are associated with bone loss, and high levels of resorption markers may predict fractures independently of bone mineral density. Several HIV-related factors, including HIV infection and inflammation, have been found to affect the balance between bone formation and resorption. Some clinical studies found increased levels of bone turnover markers in HIV-infected adults compared to uninfected controls. Furthermore, bone turnover marker levels increased following initiation or switch to different antiretroviral agents in recent randomized trials. The clinical value of bone turnover markers is currently limited due to different sources of variability and limited data from studies in HIV-infected populations. Further research is needed to explore the potential value of bone turnover markers as additional measurements to bone mineral density in fracture risk assessment and monitoring treatment-induced bone effects in HIV-infected patients.     

Predictive markers in breast cancer--the present

Breast cancer is a heterogeneous disease and there is a continual drive to identify markers that will aid in predicting prognosis and response to therapy. To date, relatively few markers have established prognostic power. Oestrogen receptor (ER) is probably the most powerful predictive marker in breast cancer management, both in determining prognosis and in predicting response to hormone therapies. Progesterone receptor (PR) is also a widely used marker, although its value is less well established. HER-2 status has also become a routine prognostic and predictive factor in breast cancer. Given the importance of these biological markers in patient management, it is essential that assays are robust and quality controlled, and that interpretation is standardized. Furthermore, it is important to be aware of the limitations in their predictive power, and how this may be refined through addition of further biological markers. The aim of this review is to provide an overview of the established role of ER, PR and HER-2 in patient management, the current standards for assessing these markers, as well as highlighting the controversies that still surround their use and methods of assessment.     

Small intestinal stem cell markers

Stem cells hold great promise for regenerative medicine but remain elusive in many tissues, including the small intestine, where it is well accepted that the epithelium is maintained by intestinal stem cells located in the crypts. The lack of established markers to prospectively identify intestinal stem cells has necessitated the use of indirect analysis, e.g. long-term label retention, which is based on the hypothesis that intestinal stem cells are slow-cycling. Several intestinal stem cell markers have been proposed, including Musashi-1, BMPR1α, phospho-PTEN, DCAMKL1, Eph receptors and integrins, but their validity, using functional and/or lineage tracing assays, has yet to be confirmed. Recently, Lgr5 has been identified by lineage tracing as an intestinal stem cell marker. In this review we summarize what is known about the currently reported intestinal stem cell markers and provide a rationale for developing model systems whereby intestinal stem cells can be functionally validated.     

S100 proteins in the pathogenesis and diagnosis of inflammatory bowel disease

Crohn’s disease and ulcerative colitis (the inflammatory bowel diseases) are two well characterized conditions featuring inflammation of the gastrointestinal tract. Gut inflammation may be detected, assessed and measured by a variety of methods but their utility varies extensively. Over the past decade, calprotectin, belonging to a family of S100 proteins, has been shown to be a reliable marker of gut inflammation that corresponds to neutrophil migration. In addition, other members of the S100 family have important roles in inflammation and may also be useful markers of gut inflammation. Furthermore, these proteins may have functional roles in gut defense or in the pathogenesis of inflammatory bowel disease.     

Cartilage degradation products as markers for evaluation of patients with rheumatic disease

Markers of cartilage degradation hold a great, but so far underutilized potential in the research and clinical management of joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). With the rapid pace of development of such markers, they are likely to emerge as promising clinical tools for several uses. These roles may include: improving preclinical and clinical development in arthritis research; differentiation of patients with high and low turnover states at disease diagnosis; selection of optimal therapy and therapy dose for the individual patient; monitoring disease progression; and predicting disease outcome.This review focuses on the cartilage matrix components and the metabolites from this very special tissue that have been proposed as biochemical markers. Special attention is focused on the challenges facing the development of such markers to the standards required for widespread practical use. Examples are provided on the current use of cartilage derived biochemical markers and perspectives for the future use of markers and required clinical documentation are presented.     

Assessment of serological markers associated with rheumatoid arthritis: Diagnostic autoantibodies and conventional disease activity markers

Progress in the detection and quantitation of autoantibodies associated with rheumatoid arthritis (RA) indicates an expanding role for serology in the diagnosis and predicting the prognosis of the disease. The advent of enzyme-linked immunoadsorbant assay (ELISA) methods for the quantitation of rheumatoid factor (RF) isotypes offers significant RA disease information substantially above that gained using traditional measurements of total RF. The ability to quantitate isotypes adds specificity for the diagnosis of RA and identifies those individuals that will tend to exhibit progressive, erosive disease. Other autoantibodies that are highly specific for RA recognize epitopes associated with proteins containing citrulline (e.g., antikeratin and antiperinuclear factor). A highly specific (92-98%) and relatively sensitive (∼80%) second-generation ELISA has been developed and marketed for the diagnosis of RA using cyclic citrullinated peptide as antigen (CCP). Population based studies indicate that finding multiple RF isotypes or antifilaggrin antibodies (synonymous with anti-CCP) in apparently normal individuals is highly predictive for the development of RA in subsequent years. More importantly, these markers are being recognized as indicative of disease course. Monitoring C-reactive protein and erythrocyte sedimentation rate continue to be a mainstay for determining RA disease activity, although acute-serum amyloid A may be a more sensitive marker for synovial inflammation.     

Advances in clinical hepatology and what the hepatologist expects from a liver biopsy result

Liver disease is increasing. Traditionally, there have been several main indications for liver biopsy.First, to establish the aetiology of disease, second, to stage disease and third to grade severity of disease in terms of activity to establish prognosis. Biopsy can also be used to monitor progress serially and to diagnose cancers and other focal pathology. Each of these long established uses for liver biopsy is now besieged by new technology.New serological markers and clinical scoring systems, complement biopsy to assist us with diagnosis, in some cases making biopsy unnecessary. Non-invasive markers of liver fibrosis are entering clinical practice and replacing the need for biopsy to stage disease and diagnose cirrhosis.Increasingly the static nature of a biopsy and other point in time measures gives way to measurements that reflect prognosis. As other modalities replace biopsy there is potential for “diagnostic drift” away from the classic pathology of the condition. Despite this, the rising tide of liver disease means that the importance of liver biopsies will not decrease and the nature of questions being asked by the hepatologist are likely to become more difficult.     

How do we monitor asthma control?

The present consensus on asthma management includes avoidance of triggers, education, regular follow-up, and an action plan that relies on symptoms and lung function measurements for the monitoring of disease severity. Inclusion of objective measurements for monitoring seems to be important because patients and physicians may not always recognize asthma symptoms or their severity. However, the additional value of monitoring peak flow and symptoms in guiding asthma therapy has not been well established. Furthermore, it can be questioned whether a treatment strategy which is solely based on optimizing symptoms and lung function leads to optimal control of asthma in each individual patient, since airway hyperresponsiveness (AHR) and airways inflammation may persist. The chronicity of such abnormalities may lead to airways remodelling, thereby worsening the long-term outcome of asthma. It has been shown that AHR provides prognostic information on asthma control, because it can serve as a valuable noninvasive surrogate marker of airways inflammation when added to the guides of asthma therapy. A limited increase in dose of inhaled steroids, instead of applying an increased dose indiscriminately, can be successfully tailored to the needs of the individual patient based on the degree of AHR. Such a strategy leads to both a better clinical outcome and a better histologic outcome. The present worldwide effort is to find alternative markers of airways inflammation in asthma that can be easily implemented in routine practice. In the near future, longitudinal studies will determine which parameter is potentially most useful in guiding asthma management.     

Serum tumour markers in gynaecological cancers

Serum tumour markers have had a role in screening, diagnosis and monitoring of some gynaecological cancers. Women with suspected ovarian malignancies have as routine a CA125 serum test, and in conjunction with scans, the risk of malignancy can be calculated. Equally, this CA125, if elevated pre-operatively can be used to predict chemotherapeutic responses, and even disease relapse prior to any symptoms or clinical findings. Other useful markers in ovarian cancer are βHCG and AFP produced by germ cell tumours. βHCG is also of extreme importance in both the diagnosis and management of choriocarcinomas. The level of βHCG determines the need, and with other indicators, the type of chemotherapeutic intervention. Other serum markers are known in cervical cancer, and possibly endometrial and vulval cancer—but their clinical utility is very limited. Novel markers may help in managing patients, and in the future permit screening for certain diseases.     

Cells and mediators in bronchoalveolar lavage of asthmatic patients: the example of eosinophilic inflammation

Bronchoalveolar lavage (BAL) greatly improved our understanding of asthma allowing to demonstrate the key role of inflammation in the pathogenesis of the disease. BAL is a safe procedure, even in severe patients when properly performed. BAL samples large and small airways and alveoli. Cells and mediators may be measured in BALF but they only represent an indirect estimation of the bronchial inflammation. Before performing BAL, the clinical status of the patients should be ascertained and drugs taken may have to be withdrawn. BALF markers should follow some requirements: (I) markers should be released by cells that are pertinent to airways inflammation (and reparation) in asthma, and, if possible they should be specific of a single cell type, (2) the enumeration of cells or titration of the marker or of its metabolites should be specific and sensitive, (3) if possible the titration should not be modified by the sampling procedure, (4)pilot studies should have demonstrated that the cell is incrcased or the secretory product is released during challenge in asthmatic subjects, (5) studies in a large number of patients should have demonstrated that the levels of the marker are increased in chronic asthmatics, that these levels are correlated with the severity of the disease and are decreased during effective anti-inflammatory treatment, and (6) if possible the cell or marker should be specific to asthma (but at present there is no such cell or marker). Eosinophils and granule secretory products follow most of these requirements. BAL represents an important research tool to assess the effects of therapeutic interventions.     

Immunohistochemistry in melanocytic proliferative lesions

Melanoma incidence is rising worldwide. Early diagnosis is very important, as the most effective treatment for melanoma still consists of excision of the tumour before onset of the metastatic growth phase. Immunohistochemistry is a valuable tool for (dermato)pathologists to aid establishing diagnosis. Melanoma markers can be classified into two main categories: melanocytic differentiation markers and melanoma progression markers. Melanocytic differentiation markers are mostly used to distinguish poorly differentiated melanomas from non-melanocytic tumours and for staging of melanocytic proliferative lesions. Melanoma progression markers are most suitable to determine the level of malignancy and/or aggressiveness of tumour cells. This review describes the classification of melanoma markers, including commonly used and recently identified antigens with potential marker function. We characterize their expression profile in melanocytic proliferative lesions and their potential usefulness for diagnosis, prognosis, microstaging, immunotherapeutic purposes and evaluation of therapies.     

Tryptase as an inflammatory marker in allergic disease and asthma

Asthma is a chronic inflammatory disease of the airways, varying from occasional episodes of wheezing and shortness of breath, to an irreversible, life-threatening obstructive disease. While many cases are managed with relative ease, others do not respond to the traditional inhaled therapy or even to oral glucocorticosteroids. Although it cannot be cured as yet, asthma can be controlled if properly diagnosed. Usually, functional clinical parameters form the basis for estimation of the disease severity. In addition, the growing database of cytokine and mediator profiles have allowed their exploitation as molecular markers for processes underlying airway inflammation in asthma. Tryptase is a potent and versatile mediator in allergic inflammation, orchestrating both acute and chronic events by acting on a vast array of cells and tissue components. For more than a decade, tryptase has been used as a marker for allergic inflammation in asthma as well as in a variety of other airway diseases. In this review, the current advantages and disadvantages of the use of tryptase as an inflammatory marker in asthma will be discussed.     

Disease activity assessment of rheumatic diseases during pregnancy: a comprehensive review of indices used in clinical studies

Pregnancy requires a special management in women with inflammatory rheumatic diseases (RDs), with the aim of controlling maternal disease activity and avoiding fetal complications. Despite the heterogeneous course of RDs during pregnancy, their impact on pregnancy largely relates to the extent of active inflammation at the time of conception. Therefore, accurate evaluation of disease activity is crucial for the best management of pregnant patients. Nevertheless, there are limitations in using conventional measures of disease activity in pregnancy, as some items included in these instruments can be biased by symptoms or by physiological changes related to pregnancy and the pregnancy itself may influence laboratory parameters used to assess disease activity. This article aims to summarize the current literature about the available instruments to measure disease activity during pregnancy in RDs. Systemic lupus erythematosus is the only disease with instruments that have been modified to account for several adaptations which might interfere with the attribution of signs or symptoms to disease activity during pregnancy. No modified-pregnancy indices exist for women affected by other RDs, but standard indices have been applied to pregnant patients.The current body of knowledge shows that the physiologic changes that occur during pregnancy need to be either adapted from existing instruments or developed to improve the management of pregnant women with RDs. Standardized instruments to assess disease activity during pregnancy would be helpful not only for clinical practice but also for research purposes.     

Pediatric biomarkers in asthma: exhaled nitric oxide, sputum eosinophils and leukotriene E4

PURPOSE OF REVIEW: Markers of disease status that provide a numerical measure of disease activity, biomarkers, have come into more routine use in medicine. This is evidenced by troponin and brain natriuretic peptide when measuring cardiac function or glomerular filtration rate in relation to kidney function. Similar markers to assess inflammation in the asthmatic lung have emerged as possible tools to guide treatment. Three biomarkers, fractional exhaled nitric oxide, sputum eosinophils and leukotriene E4 in the urine and exhaled breath condensate, have been heavily investigated. RECENT FINDINGS: Recent literature indicates that exhaled nitric oxide, sputum eosinophils and leukotriene E4 in the urine, and exhaled breath condensate could serve as good markers of inflammation in the asthmatic airway. These markers, when combined with conventional measures of lung function--forced expiratory flow in 1 s, peak flow or methacholine challenge--will be of benefit in improving asthma control in the pediatric population. SUMMARY: Exhaled nitric oxide and urinary leukotriene E4 are relatively easy to attain in the clinical setting. Sputum eosinophils are an excellent tool for assessing inflammation, however sputum induction can be challenging for a young child. Despite small limitations, all three biomarkers are potentially valuable when used in conjunction with conventional methods for airway control.     

Use of prognostic markers in early rheumatoid arthritis to identify patients at risk of destructive disease

As the benefits of early aggressive treatment of rheumatoid arthritis have become clear, and with the availability of newer (and more expensive) therapies, we need to be able to identify which patients are most at risk of destructive disease and poorer outcomes, and therefore, pinpoint which patients are most likely to benefit from intensive intervention at an early stage. A need for reliable prognostic markers is paramount in identifying these patients. Anticyclic citrullinated peptide antibody and serum inflammatory markers can precede the onset of disease by months and aid in both diagnosis and prognosis. Newer imaging modalities are now available and add to information gained from conventional radiography. This article reviews laboratory markers and imaging currently used in recognizing those patients at risk of nonreversible, destructive disease.     

Noninvasive monitoring of airway inflammation and steroid reduction in children with asthma

PURPOSE OF REVIEW: Management of pediatric asthma is currently based on symptoms (often a second-hand report from parents) and lung function. Inhaled steroids are the mainstay of asthma management targeted at controlling airway inflammation. They should be used in the lowest possible doses. A number of noninvasive methods to assess inflammation have been developed in an effort to optimize anti-inflammatory treatment. RECENT FINDINGS: The first longitudinal studies have been published demonstrating an improvement in asthma control in children by adding noninvasive monitoring of inflammation into the clinical management. New methods include exhaled nitric oxide measurements, induced sputum and markers in exhaled breath condensate. SUMMARY: Further studies will show the practicability of including these measurement methods into everyday clinical practice. Their addition to the conventional assessment of asthma control appears promising. Using these methods to evaluate the current inflammatory state seems obligatory in research into new asthma therapeutics and management strategies. Managing asthma in children in specialist practice relying only on symptoms and lung function is no longer state of the art.     

肿瘤标志物在乳腺癌诊断及预后中的应用

肿瘤标志物已广泛应用于乳腺癌的诊断及预后.本综述总结了肿瘤抗原15-3 (CA15-3)、人表皮生长因子受体2( HER2)、雌激素受体(ER)及黄体酮受体(PR)等经典乳腺癌标志物的临床应用现状及新兴乳腺癌生物标志的临床价值.多标志物的联合检测较单一标志物有更高的灵敏度及特异性,将成为今后乳腺癌标志物的临床应用趋势.     

炎症性肠病与肌肉减少症

溃疡性结肠炎 (Ulcerative Colitis，UC) 是慢性炎症性肠病 (Inflammatory Bowel Disease，IBD) 的一种，病因和发病机制尚不完全明确，目前认为是多种致病因素相互作用的共同结果，主要包括环境、遗传、肠道微环境和免疫等因素，其中肠道免疫系统紊乱所致肠粘膜持续性慢性炎症在UC中发挥着重要作用。通过文献复习，并结合临床实际工作中所遇到的病例，本文系统论述了 UC的临床流行病学特征、内镜、影像、实验室检查以及 UC的治疗和预后，重点阐述 UC的病理学形态和鉴别诊断。     

Pulse wave velocity

Pulse wave velocity (PWV) reflects arterial stiffness. PWV correlates with other markers reflecting the severity of atherosclerosis such as the findings of ultrasound examination of carotid artery. In addition, several studies demonstrated that increased PWV is a predictor of future cardiovascular events in patients with either hypertension or diabetes mellitus. Thus, PWV is thought to be applicable as a marker relating with the severity of atherosclerosis and/or predicting future atherosclerotic cardiovascular events. Age and blood pressure is a major determinant of PWV, and the influence of these factors should be taken into account to use PWV as a marker of cardiovascular risk. On the other hand, while anti-hypertensive medication or statins improve PWV, it has not been fully evaluated whether these improvement reflect the improvement of prognosis. Therefore, the significance of PWV as a surrogate marker for the treatment of atherosclerotic cardiovascular risk has not been fully established. Carotid-femoral PWV is used as a conventional method. Recently, more simple method: brachial-ankle PWV is available in clinical settings. This method is simple fully enough to apply in a large population. However, brachial-ankle PWV includes peripheral component of artery in its assessment of arterial stiffness, and it has not been fully concluded that brachial-ankle PWV has a similar potential as a marker using the management of atherosclerotic cardiovascular disease as carotid-femoral PWV. Further study is proposal to evaluate the clinical significance of brachial-ankle PWC as a tool using the management of cardiovascular disease.     

Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. Biomarker Working Group Report.

Biology-based markers that can be used to confirm the diagnosis of chronic graft-versus-host disease (GVHD) or monitor progression of the disease could help in the evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biologic or pathogenic process, a pharmacologic response to a therapeutic intervention, or a surrogate end point intended to substitute for a clinical end point. The following applications of biomarkers could be useful in chronic GVHD clinical trials or management: (1) predicting response to therapy; (2) measuring disease activity and distinguishing irreversible damage from continued disease activity; (3) predicting the risk of developing chronic GVHD; (4) diagnosing chronic GVHD: (5) predicting the prognosis of chronic GVHD; (6) evaluating the balance between GVHD and graft-versus-leukemia effects (graft-versus-leukemia or GVT); and (7) serving as a surrogate end point for therapeutic response. Such biomarkers can be identified by either hypothesis-driven testing or by high-throughput discovery-based methods. To date, no validated biomarkers have been established for chronic GVHD, although several candidate biomarkers have been identified from limited hypothesis-driven studies. Both approaches have merit and should be pursued. The consistent treatment and standardized documentation needed to support biomarker studies are most likely to be satisfied in prospective clinical trials.