Analytical considerations and plans to standardize or harmonize assays for the reference bone turnover markers PINP and β-CTX in blood.

Procollagen type I N-propeptide (PINP) and the C-terminal telopeptide of type I collagen (β-CTX) in blood have been designated as reference bone turnover markers in osteoporosis by the International Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). The IFCC Committee on Bone Metabolism (C-BM) has examined current commercial assays and performed a multicentre study to examine the agreement between assays for PINP and β-CTX in serum and plasma. The results of these studies will inform our work towards the harmonization of PINP assays and the standardization of β-CTX assays in blood, with the development of common calibrators and reference measurement procedures in collaboration with the reagent manufacturing industry.

Harmonization of commercial assays for PINP; the way forward.

Unlabelled: International Federation of Clinical Chemistry and Laboratory Medicine and The International Osteoporosis Foundation Joint Committee on Bone Metabolism believes that the harmonization of PINP assays is an achievable and practical goal.

Introduction: In order to examine the agreement between current commercial assays, a multi-center study was performed for PINP in serum and plasma.

Methods: The automated methods for PINP (Roche Cobas and IDS iSYS) gave similar results.

Reflections on Thyroid Autoimmunity: A Personal Overview from the Past into the Future.

After investigating thyroid autoimmunity for more than 40 years, we present a personal perspective on the field. Despite effective therapies for Graves' hyperthyroidism and Hashimoto's thyroiditis, cures are elusive. Novel forms of therapy are being developed, such as small molecule inhibitors of the TSH receptor (TSHR), but cure will require immunotherapy.

Structure of a Thyrotropin Receptor Monoclonal Antibody Variable Region Provides Insight into Potential Mechanisms for its Inverse Agonist Activity.

Background: The high constitutive, or ligand-independent, activity of the thyrotropin receptor (TSHR) is of clinical importance in some thyroid conditions, particularly well-differentiated thyroid carcinoma remnants following incomplete ablative therapy (surgery and radioiodine). Under these conditions, even total suppression of TSH by thyroid hormone administration does not fully reduce TSHR activity, a driver of thyrocyte growth.

Methods: CS-17 is a murine monoclonal antibody that has inverse agonist activity in that it suppresses TSHR constitutive activity.

Critical Differences between Induced and Spontaneous Mouse Models of Graves' Disease with Implications for Antigen-Specific Immunotherapy in Humans.

Graves' hyperthyroidism, a common autoimmune disease caused by pathogenic autoantibodies to the thyrotropin (TSH) receptor (TSHR), can be treated but not cured. This single autoantigenic target makes Graves' disease a prime candidate for Ag-specific immunotherapy. Previously, in an induced mouse model, injecting TSHR A-subunit protein attenuated hyperthyroidism by diverting pathogenic TSHR Abs to a nonfunctional variety.

Review: Found in Translation: International Initiatives Pursuing Interleukin-1 Blockade for Treatment of Acute Kawasaki Disease.

The decision to move forward with three clinical trials of IL-1 blockade for treatment of acute Kawasaki disease is a case study in translational science. These trials were born on the one hand from transcriptome studies of host response during the acute disease coupled with animal model investigations of key immune signaling pathways and, on the other hand, out of clinical desperation to intervene in patients with severe inflammation in the setting of acute Kawasaki disease. The convergence of laboratory science and clinical observations led to the clinical trials described here and serves as a model for how such observations can be translated into new therapies.

Withdrawn: TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective.

The TSH receptor (TSHR) on the surface of thyrocytes is unique among the glycoprotein hormone receptors in comprising two subunits: an extracellular A-subunit, and a largely transmembrane and cytosolic B-subunit. Unlike its ligand TSH, whose subunits are encoded by two genes, the TSHR is expressed as a single polypeptide that subsequently undergoes intramolecular cleavage into disulfide-linked subunits. Cleavage is associated with removal of a C-peptide region, a mechanism similar in some respects to insulin cleavage into disulfide linked A- and B-subunits with lossofaC-peptideregion.

TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective.

The TSH receptor (TSHR) on the surface of thyrocytes is unique among the glycoprotein hormone receptors in comprising two subunits: an extracellular A-subunit, and a largely transmembrane and cytosolic B-subunit. Unlike its ligand TSH, whose subunits are encoded by two genes, the TSHR is expressed as a single polypeptide that subsequently undergoes intramolecular cleavage into disulfide-linked subunits. Cleavage is associated with removal of a C-peptide region, a mechanism similar in some respects to insulin cleavage into disulfide linked A- and B-subunits with loss of a C-peptide region.

Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa.

Background: Thyrotropin receptor (TSHR) antibodies that stimulate the thyroid (TSAb) cause Graves' hyperthyroidism and TSHR antibodies which block thyrotropin action (TBAb) are occasionally responsible for hypothyroidism. Unusual patients switch from TSAb to TBAb (or vice versa) with concomitant thyroid function changes. We have examined case reports to obtain insight into the basis for "switching.

Novel acyl sulfonamide LY573636-sodium: effect on hematopoietic malignant cells.

LY573636-sodium is a promising anti-tumor agent, which causes growth arrest and apoptosis of a variety of human solid tumors in vitro and in vivo. Moreover, studies have shown that the compound is selectively toxic towards tumor cells over their normal counterparts. This targeted effect makes LY573636 a candidate for combined therapy regimens in patients with advanced or resistant cancers.

Adaptor protein Lnk associates with Tyr(568) in c-Kit.

The adaptor protein Lnk is expressed in haemopoietic cells and plays a critical role in haemopoiesis. Animal model studies demonstrated that Lnk acts as a broad inhibitor of signalling pathways in haemopoietic lineages. Lnk belongs to a family of proteins sharing several structural motifs, including an SH2 (Src homology 2) domain which binds phosphotyrosine residues in various signal-transducing proteins.

Molecular mechanisms of plaque instability.

Purpose Of Review: Coronary artery thrombosis superimposed on a disrupted atherosclerotic plaque initiates abrupt arterial occlusion and is the proximate event responsible for 60-80% cases of acute coronary syndromes. This article provides a concise update on the evolving concepts in the pathophysiology of plaque rupture and thrombosis.

Recent Findings: Over the past several years, the critical role of plaque composition rather than plaque size or stenosis severity, in plaque rupture and thrombosis have been recognized.

Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin's lymphoma, with a mean survival of only 3-5 years and suboptimal therapeutic options. MCL is characterized by a balanced translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1, a G(1) cyclin regulated by the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. As improved therapy for MCL is required and the mTOR pathway may be involved in its pathophysiology, the antiproliferative effects of RAD001 (everolimus), an mTOR inhibitor, against three MCL cell lines were investigated.

Improvement in serial cardiopulmonary exercise testing following enzyme replacement therapy in Fabry disease.

Background: Fabry disease is an X-linked genetic disorder resulting in the accumulation of glycosphingolipids in various organs, leading to exercise intolerance and early mortality. Enzyme replacement therapy (ERT) has recently been approved for use in Fabry patients. GOALS OF STUDY: To assess baseline cardiopulmonary exercise characteristics in both invasive and noninvasive tests and to study the impact of ERT on exercise.

[Immunopathology of acute rejection].

Acute transplant rejection may be the result of two immunologic mechanisms, T-cell-mediated and antibody-mediated processes, acting alone or together. Cell-mediated rejection occurs as T cells react to donor alloantigens which are expressed in context of MHC. The major forms of cellular rejection may affect tubulo-interstitium, arteries and glomeruli.

Echocardiography in cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) is a new treatment modality for eligible patients with congestive heart failure (CHF). The premise of CRT is that it decreases inter and intra ventricular inhomogeneity during systolic contraction thereby improving efficiency of cardiac pump function. Presence of cardiac dyssynchrony appears to be a prerequisite for a response to CRT.

HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo.

We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all-trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes.

Epidemiology and clinical significance of hepatotropic infections in dialysis patients. Recent evidence.

Hepatitis C virus (HCV) infection is frequent among patients receiving long-term dialysis in developed and developing countries. It is difficult to assess the natural history of HCV in the dialysis population; however, recent studies have demonstrated that positive anti-HCV status is a significant and independent risk factor for mortality among dialysis patients. Recent meta-analyses have shown that interferon (IFN) initial monotherapy is effective in the treatment of chronic hepatitis C among dialysis patients, but tolerance to IFN mono-therapy was rather poor.

High-level serum antibodies to bacterial antigens are associated with antibiotic-induced clinical remission in Crohn's disease: a pilot study.

In Crohn's disease, antibiotics are used with variable efficacy, suggesting that some patients are more likely to respond. The aim of this study was to determine whether Crohn's patients with predominant serum antibody reactivity toward bacterial antigens OmpC and/or I2 were more likely to achieve remission with antibiotics. Patients with ileal or ileal with right-sided colonic Crohn's disease were studied in a double-blind trial of budesonide alone or budesonide plus metronidazole and ciprofloxacin.

Timing affects the efficacy of LDL immunization on atherosclerotic lesions in apo E (-/-) mice.

Background: Immunization of animals with LDL reduces atherosclerosis. However, whether the timing of immunization affects its efficacy is not known. In this study, we evaluated the influence of timing of immunization on the athero-protective effects of LDL immunization in apo E (-/-) mice.

Regional ependymal upregulation of vimentin in Chiari II malformation, aqueductal stenosis, and hydromyelia.

Vimentin, glial fibrillary acidic protein (GFAP) and S-100beta protein were studied by immunocytochemistry in the ependyma of patients with Chiari II malformations, congenital aqueductal stenosis, and hydromyelia. Paraffin sections of brains and spinal cords of 16 patients were examined, 14 with Chiari II malformations, most with aqueductal stenosis and/or hydromyelia as associated features, and 2 patients with congenital aqueductal stenosis without Chiari malformation. Patients ranged in age from 20-wk gestation to 48 years.

Human mitochondrial transcription factor B1 as a modifier gene for hearing loss associated with the mitochondrial A1555G mutation.

Phenotypic expression of the deafness-associated homoplasmic A1555G mutation in the mitochondrial 12S rRNA gene varies from profound congenital hearing loss to normal hearing. It has been shown that this variability in clinical expression in most patients is due to the complex inheritance of multiple nuclear-encoded modifier genes. Human mitochondrial transcription factor B1 (TFB1M) has been proposed as a candidate for being such a modifier, since it methylates adenine residues in the adjacent loop of the A1555G mutation in the 12S rRNA gene.