Clinical features of bone metastases resulting from thyroid cancer: a review of 28 patients over a 20-year period

Bone is the second most frequent site of metastasis resulting from thyroid cancer. Many studies have investigated clinical features and prognostic factors of distant metastases stemming from thyroid cancer in Western countries. The purpose of this study was to review clinical characteristics of Korean patients with bone metastasis originating from thyroid cancer. Between January 1985 and August 2004, 28 patients with thyroid cancer were diagnosed with bone metastases at the Yonsei Severance Hospital in Seoul, Korea. Their clinical characteristics were analyzed retrospectively. Incidence of bone metastasis from follicular thyroid cancer was 6.8% (9 of 132 patients), and 0.4% (13 of 3,154 patients) from papillary thyroid cancer, with an odds ratio of 17.67 (95% confidence interval; 7.41-42). Twelve patients had no symptoms of bone metastasis. Overall mean number of metastasis sites was 2.6 +/- 1.9, and 12 patients had a solitary bone metastasis. Survival rates between the synchronous and metachronous metastasis groups were not significantly different, and the number of metastasis sites did not affect survival. However, the survival of patients that underwent curative treatment was longer than those with palliation (P = 0.0317). In Korea, the overall incidence of bone metastasis resulting from thyroid cancer was less than our expectation. Many patients were asymptomatic, and had a tendency of undergoing less aggressive or palliative treatment, even though the long-term survival of distant metastasis resulting from thyroid cancer with active treatment is relatively good. Further studies of the prognostic factors and effectiveness of various treatments of these patients are needed to enhance survival.     

Mutation in hepatocyte nuclear factor-1α is not a common cause of MODY and early-onset type 2 diabetes in Korea

Maturity-onset diabetes of the young (MODY)-3 with a mutation in hepatocyte nuclear factor (HNF)-1α has been identified in most races, but the prevalence of Korean MODY and early-onset type 2 diabetes with a mutation in this gene is unknown. To determine the prevalence of MODY and early-onset type 2 diabetes with the mutation of HNF-1α gene in Korea, we analyzed this gene in 69 Korean early-onset type 2 diabetics and in 35 healthy persons using the single-strand conformation polymorphism (SSCP) technique and direct sequencing. We identified one mutation in exon 4 (C900A) in only one of the 69 Korean subjects with early-onset type 2 diabetes; this mutation was silent and did not change the amino acid (Pro300). Additionally, we identified four polymorphisms: S487N, AAC→AGC, intron 2 (nt −23), intron 7: (nt +7) and intron 9 (nt −24). However, there was no significant difference in frequencies of the four polymorphisms between the type 2 diabetes and control groups. Among type 2 diabetics, codon 487 variant showed no relationship to age at onset, body mass index, fasting blood glucose. HbA1c, lipid profile, basal C-peptide and 2 hour C-peptide. We concluded that this genetic mutation in HNF-1α gene may not be a common contributor to MODY and early-onset type 2 diabetes susceptibility in Korea. Received: October 2000 / Accepted in revised form: August 2001     

Interleukin-1beta regulates urokinase plasminogen activator (u-PA), u-PA receptor, soluble u-PA receptor, and plasminogen activator inhibitor-1 messenger ribonucleic acid expression in cultured human endometrial stromal cells

The interleukin-1 (IL-1) system plays an integral role in local intercellular interactions during implantation. In addition, the plasminogen activator system, especially urokinase plasminogen activator (u-PA), plasminogen activator inhibitor (PAI-1), and u-PA receptor (u-PAR), are crucial during embryo implantation. Decidualization and implantation are complex processes dependent upon several proteases, including u-PA, and IL-1 is known to affect PA activity in several cell types. We investigated the role of IL-1beta in regulating u-PA, PAI-1, u-PAR, and soluble u-PAR messenger ribonucleic acid (mRNA) expression in cultured human endometrial stromal cells using quantitative competitive PCR. For confirmation of the mRNA data, we measured PAI-1 and u-PAR protein by enzyme-linked immunosorbent assay. Confluent stromal cell cultures treated with progesterone and estradiol for 9 days were stimulated with IL-1beta, and IL-1beta plus IL-1beta antibody for an additional 24 h. Total RNA was extracted, reverse transcribed, and coamplified using quantitative and competitive PCR with internal standards. IL-1beta increased PAI-1, u-PAR, and soluble u-PAR expression in a dose-dependent manner, and this result was reversed by anti-IL-1beta antibody treatment. u-PA mRNA expression was not dependent on IL-1beta. These results suggest that IL-1 may be important in regulating PAI-1 and u-PAR during stromal cell decidualization before implantation.     

Prognosis of congestive heart failure after prior myocardial infarction in older persons with atrial fibrillation versus sinus rhythm

In a prospective study of 651 older persons with congestive heart failure after prior myocardial infarction, persons with atrial fibrillation had a significantly higher mortality than those with sinus rhythm if they had an abnormal (p = 0.005) or normal (p = 0.0001) left ventricular ejection fraction. The Cox regression model showed that significant independent risk factors for total mortality were age (risk ratio 1.03 for an increment of 1 year of age), hypertension (risk ratio 1.2), diabetes mellitus (risk ratio 1.4), abnormal left ventricular ejection fraction (risk ratio 2.1), and atrial fibrillation (risk ratio 1.5).     

Aortobronchial fistula presenting as recurrent hemoptysis and successfully treated with an endovascular stent graft.

Aortobronchial fistula (ABF) (aortopulmonary fistula) may cause a massive fatal hemoptysis. We have recently seen a patient with ABF presenting with recurrent, massive hemoptysis. She was successfully treated with an endovascular stent graft. The endovascular stent graft may provide an alternative treatment of in patients considered to be poor surgical candidates.     

Prevalence, awareness, treatment, control and risk factors of hypertension in Korea: the Ansan study

OBJECTIVES: To determine prevalence, awareness, treatment, and control of hypertension, and its risk factors in an urban Korean population. DESIGN AND SETTING: A cross-sectional survey in Ansan-city, Korea. SUBJECTS AND METHODS: Population-based samples of people aged 18-92 years in Ansan-city, Korea, were selected, yielding 2278 men and 1948 women, and their blood pressures were measured using a highly standardized protocol. Hypertension was defined as a systolic BP > or = 140 mmHg or diastolic BP > or = 90 mmHg or reported treatment with antihypertensive medications, and subclassified according to 1999 WHO-ISH guidelines. Isolated systolic hypertension (ISH) defined as a systolic BP > or = 140 mmHg and diastolic BP < 90 mmHg was also examined. Data were stratified by age and sex. RESULTS: The overall prevalence of hypertension in this study was 33.7%. Among these, 64.9% had Grade 1 hypertension, 22.5% Grade 2, and 12.5% Grade 3. Age-specific prevalence of hypertension increased progressively with age, from 14.19% in 18 to 24 year-olds to 71.39% in those 75 years or older. Hypertension prevalence was significantly higher in men (41.5%) than in women (24.5%) (P < 0.001). Isolated systolic hypertension had significantly lower prevalence (4.33%) within the population, although in the elderly aged 55 years or more it rose by 11.13%. Overall, 24.6% of hypertensive individuals were aware that they had high blood pressure, as much as 78.6% were being treated with antihypertensive medications, and 24.3% were under control. Hypertension awareness as well as treatment and control rates varied by sex, with women higher in all three rates. Multivariate analysis revealed that age, body mass index and abdomen circumference were significantly associated with prevalence of hypertension both in men and women. CONCLUSIONS: Hypertension is highly prevalent in Korea. Despite the high rate of treatment, the rates of awareness and control are relatively low, suggesting the nationwide demand for preventing and controlling high blood pressure in Korea in order to avert an epidemic of cardiovascular disease.     

Transcription factor decoy for activator protein-1 (AP-1) inhibits high glucose- and angiotensin II-induced type 1 plasminogen activator inhibitor (PAI-1) gene expression in cultured human vascular smooth muscle cells

AIMS/HYPOTHESIS: Multiple factors, including hyperglycaemia and angiotensin II (Ang II), stimulate plasminogen activator inhibitor-1 (PAI-1) gene expression in human vascular smooth muscle cells. This study tested the hypothesis that hyperglycaemia and Ang II stimulate PAI-1 gene expression through activator protein-1 (AP-1) binding sites. METHODS: We evaluated the role of AP-1 in PAI-1 gene expression in human vascular smooth muscle cells under high D-glucose and Ang II stimulation using a double-stranded cis-element AP-1 oligodeoxynucleotide (decoy ODN). RESULTS: Activator protein 1 activity was stimulated by high glucose and Ang II treatment and the AP-1 decoy ODN, but not a mismatched decoy ODN, competed for AP-1 activity. The increase in PAI-1 expression by high glucose and Ang II was significantly attenuated by the AP-1 decoy ODN (p <0.05 or p < 0.01). The increase in PAI-1 expression by high glucose and Ang II action on AP-1 sites was also confirmed by promoter analysis of PAI-1. Activator protein 1 activation in response to either high glucose or co-stimulation with high glucose and Ang II was inhibited completely by calphostin C (a PKC inhibitor) and partially by genistein (a protein tyrosine kinase inhibitor). CONCLUSION/INTERPRETATION: This study shows that high glucose and Ang II stimulate PAI-1 expression through AP-1 binding sites. Signal transduction after AP-1 activation by both high glucose and Ang II largely depends on PKC activation. These data indicate an important role for AP-1 in PAI-1 expression.     

Phosphorylation releases constraints to domain motion in ERK2

Protein motions control enzyme catalysis through mechanisms that are incompletely understood. Here NMR ¹³C relaxation dispersion experiments were used to monitor changes in side-chain motions that occur in response to activation by phosphorylation of the MAP kinase ERK2. NMR data for the methyl side chains on Ile, Leu, and Val residues showed changes in conformational exchange dynamics in the microsecond-to-millisecond time regime between the different activity states of ERK2. In inactive, unphosphorylated ERK2, localized conformational exchange was observed among methyl side chains, with little evidence for coupling between residues. Upon dual phosphorylation by MAP kinase kinase 1, the dynamics of assigned methyls in ERK2 were altered throughout the conserved kinase core, including many residues in the catalytic pocket. The majority of residues in active ERK2 fit to a single conformational exchange process, with k_ex ≈ 300 s⁻¹ (k_AB ≈ 240 s⁻¹/k_BA ≈ 60 s⁻¹) and p_A/p_B ≈ 20%/80%, suggesting global domain motions involving interconversion between two states. A mutant of ERK2, engineered to enhance conformational mobility at the hinge region linking the N- and C-terminal domains, also induced two-state conformational exchange throughout the kinase core, with exchange properties of k_ex ≈ 500 s⁻¹ (k_AB ≈ 15 s⁻¹/k_BA ≈ 485 s⁻¹) and p_A/p_B ≈ 97%/3%. Thus, phosphorylation and activation of ERK2 lead to a dramatic shift in conformational exchange dynamics, likely through release of constraints at the hinge.The MAP kinase, extracellular signal-regulated kinase 2 (ERK2), is a key regulator of cell signaling and a model for protein kinase activation mechanisms (1). ERK2 can be activated by MAP kinase kinases 1 and 2 (MKK1 and 2) through dual phosphorylation of Thr and Tyr residues located at the activation loop (Thr183 and Tyr185, numbered in rat ERK2) (1, 2). Phosphorylation at both sites is required for kinase activation, resulting in increased phosphoryl transfer rate and enhanced affinity for ATP and substrate (3).Conformational changes accompanying the activation of ERK2 have been documented by X-ray structures of the inactive, unphosphorylated (0P-ERK2) and the active, dual-phosphorylated (2P-ERK2) forms (4, 5). Phosphorylation rearranges the activation loop, leading to new ion-pair interactions between phospho-Thr and phospho-Tyr residues and basic residues in the N- and C-terminal domains of the kinase core structure. This leads to a repositioning of active site residues surrounding the catalytic base, enabling recognition of the Ser/Thr-Pro sequence motif at phosphorylation sites and exposing a recognition site for interactions with docking sequences in substrates and scaffolds (6).Less is known about how changes in internal motions contribute to kinase activation. Previous studies using hydrogen-exchange mass spectrometry (HX-MS) and electron paramagnetic resonance spectroscopy (7–9) led to a model where conformational mobility at the hinge linking the N- and C-terminal domains is increased by phosphorylation, therefore releasing constraints needed for activation. Such a model differs from other types of autoinhibitory mechanisms in protein kinases, which involve interactions with domains outside the kinase core (10, 11). However, how hinge flexibility regulates ERK2 is unknown.NMR relaxation dispersion methods enable protein dynamics to be monitored by measuring exchange between conformational states (12). In particular, Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion experiments report on motions on slow (100–2,000 s⁻¹) timescales (13), which are often important for enzymatic function (13–16). In the CPMG experiment, exchange between different conformational states is probed with varying times between “refocusing” pulses. Conformational exchange leads to imperfect refocusing, thus decreasing the intensity of the NMR signal. Increasing the pulse frequency allows less chance for conformational exchange, and therefore increased NMR signal intensity. For a given pulse frequency, analysis of the signal intensity yields the effective relaxation rate for the resonance, R_2,eff. This is typically plotted as a relaxation dispersion curve, which can be fit to a two-state conformational exchange process (e.g., A ⇌ B interconversion). Fitting extracts the populations and the exchange rates between states, thus reflecting the thermodynamics and kinetics of the system (17, 18).Here we performed CPMG relaxation dispersion experiments at multiple field strengths to compare the dynamic properties of [¹³C]methyl-labeled ERK2 in its phosphorylated and unphosphorylated states. The results demonstrate that phosphorylation causes a significant change in exchange dynamics throughout the kinase core, consistent with a global domain motion. Increasing hinge mobility by introducing mutations at the hinge also promotes domain motion within the core but with differing kinetics and populations. Taken together, the results show that large changes in dynamics accompany ERK2 phosphorylation, which are influenced by conformational mobility at the hinge. We propose that the activation of ERK2 involves removing inhibitory constraints to domain motion, which are conferred by the internal architecture of the kinase.     

Central metabotropic glutamate receptors differentially participate in interleukin-1beta-induced mechanical allodynia in the orofacial area of conscious rats.

The present study investigated the role of central metabotropic glutamate receptors (mGluRs) in interleukin-1beta (IL-1beta)-induced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Experiments were carried out on male Sprague-Dawley rats weighing 230 to 280 g. After administration of 0.01, 0.1, 1, or 10 pg of IL-1beta into a subcutaneous area of the vibrissa pad, we examined the withdrawal behavioral responses produced by 10 successive trials of an air-puff ramp pressure applied ipsilaterally or contralaterally to the IL-1beta injection site. Subcutaneous injection of IL-1beta produced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Intracisternal administration of CPCCOEt, a mGluR1 antagonist, or MPEP, a mGluR5 antagonist, reduced IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia. Intracisternal administration of APDC, a group II mGluR agonist, or L-AP4, a group III mGluR agonist, reduced both IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia. The antiallodynic effect, induced by APDC or L-AP4, was blocked by intracisternal pretreatment with LY341495, a group II mGluR antagonist, or CPPG, a group III mGluR antagonist. These results suggest that groups I, II, and III mGluRs differentially modulated IL-1beta-induced mechanical allodynia, as well as mirror-image mechanical allodynia, in the orofacial area. PERSPECTIVE: Central group I mGluR antagonists and groups II and III mGluR agonists modulate IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Therefore, the central application of group I mGluR antagonists or groups II and III mGluR agonists might be of therapeutic value in treating pain disorder.     

Long-term remission from life-threatening hypercoagulable state associated with lupus anticoagulant (LA) following rituximab therapy

Rituximab, a chimeric monoclonal CD20 antibody, is useful in the treatment of B-cell lymphomas and certain autoimmune diseases. We report a successful outcome of rituximab for life threatening hypercoagulable state associated with lupus anticoagulant (LA). A 30-year-old woman initially presented 10 years ago with DVT and positive serology for SLE and LA. While on Coumadin, she suffered from recurrent DVT in the legs and arms, pulmonary emboli, Budd-Chiari syndrome, mesenteric vein thrombosis, bone infarcts, recurrent strokes, and chronic ITP. All measures including plasmapheresis and monthly IV cyclophosphamide were of no benefit. She was recently admitted with spontaneous subdural hematoma with INR of 3.8. Upon discontinuation of anticoagulation for surgical drainage, she developed acute abdomen from thrombosis and recurrent DVT. Because she had failed prior standard measures, 4 weekly infusions of rituximab (375 mg/m2) were given following 2 rounds of plasmapheresis. Subsequently, she made a remarkable recovery over the next month and has been free of thrombosis on Coumadin for over 15 months. LA, IgM antibodies to cardiolipin, and B2GP1 were consistently positive. After rituximab therapy, LA became negative and IgM antibodies to cardiolipin decreased and ITP went into remission. Rituximab induced a lasting remission in a woman suffering from life-threatening hypercoagulable state associated with LA. Her clinical remission was associated with disappearance of LA.