Advances in Clinical Chemistry最新文献

Dysfunctional visceral fat plays a key role in the initiation and maintenance of chronic inflammation, liver steatosis and subsequent systemic insulin resistance that primes the body for development of metabolic syndrome. These changes, occurring with or without obesity, lead to type 2 diabetes. In this chapter, we first provide a brief overview of the factors that lead to dysfunctional visceral fat and their relative importance. Adipose tissue has a great plasticity which allows for cell hypertrophy and, when needed, angiogenesis to sustain hypertrophy. Due to the prevalence of inexpensive and widely available "junk food," i.e., those enriched in fat, carbohydrate and sugar, this response becomes maladaptive. Hypertrophied adipocytes become hypoxic. Some undergo necrosis which induces macrophage recruitment forming crown structures wherein macrophages and leukocytes surround injured adipocytes. This leads to the ominous triad: inflammation, fibrosis (extracellular matrix hypertrophy) and impaired angiogenesis as well as consequent unresolved hypoxia. Adipokines and cytokines secreted by these crown structures as well as the palmitate fluxes due to excessive lipolysis are released from visceral adipose tissue to portal blood. They inundate the liver causing insulin resistance. In this review we explore the actions of adipokines, proteins and macrophage cytokines (adiponectin, leptin, FABP4, resistin, PAI-1, ANGPT3/4, IL-6 and TNFα) that normally intervene but whose action goes awry in the presence of inflammation and insulin resistance. We provide an assessment of their relative clinical utility as well as challenges associated with their use as biomarkers.

Muscle invasive bladder cancer (MIBC) carries a poor prognosis with a 5-year overall survival rate of 40-50%. For localized disease, radical treatment options are cystectomy or radiotherapy with or without a radiosensitiser. Neoadjuvant or adjuvant chemotherapy is often delivered in addition to either. Metastatic disease can be treated with palliative systemic chemotherapy or immunotherapy. Standard clinicopathological information is insufficient to guide treatment decisions in several clinical scenarios in MIBC and there has been substantial effort to identify predictive and prognostic biomarkers. Despite this, no biomarker has been sufficiently qualified in prospective clinical trials to justify routine use. In this chapter we discuss these biomarkers and provide insight into the significant unmet need for robust biomarkers to inform treatment decisions and ultimately improve outcomes for bladder cancer patients.

Oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) represent an indicator of IgG and IgM immunoglobulins intrathecal synthesis in the central nervous system (CNS). The techniques and detection methods for their determination have evolved from the beginning to isoelectric focusing on an agarose gel as the gold standard technique and immunodetection as the reference method. The evolution, both in techniques and methods for detection of IgG and IgM OCBs is evaluated in this review. In addition to the significance of the presence of a single band of IgG immunoglobulin in CSF, IgG OCBs within the diagnostic criteria of multiple sclerosis (MS), the prevalence of IgG OCBs and the effect of latitude in MS, as well as the clinical and immunological involvement of OCBs (IgG and IgM) in MS and other neurological diseases.

Cysteine, homocysteine, glutathione and cysteinylglycine are metabolically related low molecular weight aminothiols involved in antioxidant defense and in thiol redox control in many cellular and extracellular processes. Alterations in plasma aminothiol profiles are evident in pathologic conditions associated with oxidative stress and accordingly can be considered potential biomarkers. More recently, cysteine has received special attention on this regard and several methodologies for the separation and measurement of cysteine as well as other related aminothiols have been developed and refined. In this review, we provide insight into characteristics, biologic functions, and metabolic interactions of aminothiols (including their involvement in thiol redox status). We highlight cysteine and review methodologic approaches to elucidate its potential role as a risk factor as well as a biomarker in cardiovascular disease, obesity and insulin resistance.

Metabolic syndrome (MetS) is increasing globally and is clinically significant due to its association with cardiovascular disease, type 2 diabetes and cancer. Although the pathogenesis of MetS has not been clearly elucidated, insulin resistance and chronic low-grade inflammation derived from central obesity are the most widely accepted as underlying pathophysiology. Accordingly, insulin resistance indices, adipokines and various inflammatory markers have been suggested as reliable biomarkers for MetS. Others, such as uric acid, alkaline phosphatase, γ-glutamyl transferase, are also known to positively correlate with MetS and could be diagnostically useful. In this review, we provide a comprehensive overview of MetS biomarkers and the development of a systematic approach to laboratory analysis.

Biotin (vitamin B₇ or vitamin H), a member of vitamin B complex, acts as a cofactor for five biotin-dependent carboxylases, thus playing critical roles in gluconeogenesis, fatty acid synthesis and amino acid catabolism. Although rare inborn errors of metabolism may cause biotin deficiency, these can be successfully treated with biotin supplementation. In general, normal individuals do not get any benefit from taking biotin supplement. Nevertheless, biotin use remains widespread for growing healthy hair and nail. Unfortunately, the use/overuse of supplemental biotin may interfere with immunoassays that incorporate biotinylated antibody in assay design. Biotin if present in elevated concentration in serum or plasma, may falsely increase analyte concentration using competitive immunoassay (positive interference). In contrast, biotin shows negative interference if sandwich immunoassay format is used. Such interferences may cause diagnostic error, most commonly in cases of hyperthyroidism due to (1) positive interference of biotin in free triiodothyronine (FT3) and free thyroxine (FT4) assays (competitive format) and (2) negative interference in thyroid stimulating hormone (TSH) assay (sandwich format). In this review, I explore the biochemistry of biotin and discuss its role as a potential interferent in immunoassay formats that are biotin based.

Orexin A and B, also known as hypocretin 1 and 2, are excitory neuropeptides synthesized in the perifornical and lateral hypothalamic areas. Following their discovery in 1998, orexins are now known to be involved in feeding, sleep, stress response, and reward processing. Most importantly, orexin deficiency has been linked to narcolepsy, a neurological sleep-wake disorder. Patients with narcolepsy also present overlapping symptoms with psychiatric disorders, such as anxiety and depressed mood, and even hallucinations, which often lead to misdiagnosis in the initial assessment. In this article, we aim to review studies of the orexin system associated with the three major psychiatric disorders: schizophrenia, major depressive disorder (MDD), and bipolar disorder. In addition to animal and clinical reports, studies of the orexin system in treatment, symptoms and side effects would also be reviewed. Thus far, relatively robust evidence suggests a connection of the orexin system with MDD. Findings of orexin involvement in schizophrenia are inconsistent and only studies in bipolar disorder are limited. While the orexin system might not be firmly associated with diagnosis, it may be useful to target specific symptom within the diagnosis or treatment, such as insomnia, weight gain and polydipsia.

Metabolism is a highly regulated process that provides nutrients to cells and essential building blocks for the synthesis of protein, DNA and other macromolecules. In healthy biological systems, metabolism maintains a steady state in which the concentrations of metabolites are relatively constant yet are subject to metabolic demands and environmental stimuli. Rare genetic disorders, such as inborn errors of metabolism (IEM), cause defects in regulatory enzymes or proteins leading to metabolic pathway disruption and metabolite accumulation or deficiency. Traditionally, the laboratory diagnosis of IEMs has been limited to analytical methods that target specific metabolites such as amino acids and acyl carnitines. This approach is effective as a screening method for the most common IEM disorders but lacks the comprehensive coverage of metabolites that is necessary to identify rare disorders that present with nonspecific clinical symptoms. Fortunately, advancements in technology and data analytics has introduced a new field of study called metabolomics which has allowed scientists to perform comprehensive metabolite profiling of biological systems to provide insight into mechanism of action and gene function. Since metabolomics seeks to measure all small molecule metabolites in a biological specimen, it provides an innovative approach to evaluating disease in patients with rare genetic disorders. In this review we provide insight into the appropriate application of metabolomics in clinical settings. We discuss the advantages and limitations of the method and provide details related to the technology, data analytics and statistical modeling required for metabolomic profiling of patients with IEMs.

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in the ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in the selective excretion of plant sterols from the liver and intestine, leading to a failure to excrete plant sterols. Sitosterolemia, which is currently considered a rare genetic disorder, has been described as a phenocopy of homozygous familial hypercholesterolemia (FH). Typical phenotypes of sitosterolemia, including elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary artery disease, overlap those of homozygous FH; however, there are substantial differences between these two diseases in terms of treatments and prognoses. Moreover, it is of note that sitosterolemia appears to be quite underdiagnosed, although accurate diagnosis and appropriate interventions will likely to lead to better prognoses compared with homozygous FH. Unlike cases of homozygous FH, dietary counseling is quite effective in reducing the LDL cholesterol as well as sitosterol of patients with sitosterolemia. In this chapter, we summarize the current understandings of this disease and provide useful tips for the diagnosis as well as better treatment of patients with sitosterolemia.

A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) are major mediators in extracellular matrix (ECM) turnover and have gained increasing interest over the last years as major players in ECM remodeling during tissue homeostasis and the development of diseases. Although, ADAMTSs are recognized in playing important roles during tissue remodeling, and loss of function in various member of the ADAMTS family could be associated with the development of numerous diseases, limited knowledge is available about their specific substrates and mechanism of action. In this chapter, we will review current knowledge about ADAMTSs and their use as disease biomarkers.