Performance of the Roche IL-6 chemiluminescent immunoassay in patients with COVID-like respiratory symptoms.

INTRODUCTION: We evaluated the Roche Elecsys IL6 assay on the Cobas immunoassay analyser. METHOD: Serum IL6 of 144 controls were compared to 52 samples from patients with COVID-like respiratory symptoms (17 SARS-CoV-2 RT-PCR positive); 25 of these were from the intensive care unit (ICU). We compared the IL6 levels to C-reactive protein (CRP) and procalcitonin (PCT) levels in all cases. RESULTS: The IL6 assay had coefficient-of-variation (CV) of 2.3 % (34.1 pg/mL) and 2.5 % (222.5 pg/mL), a limit of quantitation <1.6 pg/mL, and was linear from 1.6 to 4948 pg/mL. There was a significant difference in IL6 values between patients with COVID-like respiratory symptoms versus controls (p < 0.001). ROC analysis showed that IL6 > 6.4 pg/mL identified symptomatic cases (AUC 0.94, sensitivity 88.2 %, specificity 97.2 %). There was a significant difference between the IL6 of symptomatic ICU/non-ICU cases (median IL6 228 vs 11 pg/mL, p < 0.0001); ROC analysis showed IL6 > 75 pg/mL (sensitivity 76.0 %, specificity 88.9 %) was superior to CRP and PCT in predicting ICU admission (AUC: IL6 0.83, CRP 0.71, PCT 0.82). CONCLUSION: The performance of Elecsys IL6 assay is in keeping with the manufacturer's claims. IL6 > 6.4 pg/mL differentiates healthy from suspected COVID-19 cases and appears to be raised earlier than the other inflammatory markers in some cases. IL6 > 75 pg/mL was a good predictor of ICU admission.

The effects of cortisol and adrenal androgen on bone mass in Asians with and without subclinical hypercortisolism.

Analyses using the largest Korean cohort of adrenal incidentaloma (AI) revealed that subtle cortisol excess in premenopausal women and reduced dehydroepiandrosterone-sulfate (DHEA-S) in postmenopausal women and men are associated with bone mineral density (BMD) reduction in Asian patients with subclinical hypercortisolism (SH). INTRODUCTION: Few studies evaluated bone metabolism in Asians with SH. We investigated associations of cortisol and DHEA-S, an adrenal androgen, with BMD in Asians with AI, with or without SH. METHODS: We used cross-sectional data of a prospective multicenter study from Korea. We measured BMD, bone turnover markers, cortisol levels after 1-mg dexamethasone suppression test (1-mg DST), DHEA-S, and baseline cortisol to DHEA-S ratio (cort/DHEA-S) in 109 AI patients with SH (18 premenopausal, 38 postmenopausal women, and 53 men) and 686 with non-functional AI (NFAI; 59 premenopausal, 199 postmenopausal women, and 428 men). RESULTS: Pre- and postmenopausal women, but not men, with SH had lower BMDs at lumbar spine (LS) than those with NFAI (P = 0.008~0.016). Premenopausal women with SH also had lower BMDs at the hip than those with NFAI (P = 0.009~0.012). After adjusting for confounders, cortisol levels after 1-mg DST demonstrated inverse associations with BMDs at all skeletal sites only in premenopausal women (ß = - 0.042~- 0.033, P = 0.019~0.040). DHEA-S had positive associations with LS BMD in postmenopausal women (ß = 0.096, P = 0.001) and men (ß = 0.029, P = 0.038). The cort/DHEA-S had inverse associations with LS BMD in postmenopausal women (ß = - 0.081, P = 0.004) and men (ß = - 0.029, P = 0.011). These inverse associations of cort/DHEA-S remained significant after adjusting for cortisol levels after 1-mg DST (ß = - 0.079~- 0.026, P = 0.006~0.029). In postmenopausal women, the odds ratios of lower BMD by DHEA-S and cort/DHEA-S was 0.26 (95% CI, 0.08-0.82) and 3.40 (95% CI, 1.12-10.33), respectively. CONCLUSION: Subtle cortisol excess in premenopausal women and reduced DHEA-S in postmenopausal women and men may contribute to BMD reduction in Asians with SH.

Association of blood n-3 fatty acid with bone mass and bone marrow TRAP-5b in the elderly with and without hip fracture.

The plasma n-3 fatty acid level was 26.2% lower in patients with osteoporotic hip fracture than in those with osteoarthritis. In all patients, n-3 fatty acid was positively associated with bone mineral density and inversely associated with tartrate-resistant acid phosphatase-5b level in bone marrow aspirates, reflecting the bone microenvironment. INTRODUCTION: Despite the potential beneficial role of n-3 fatty acid (FA) on bone metabolism, the specific mechanisms underlying these effects in humans remain unclear. Here, we assessed whether the plasma n-3 level, as an objective indicator of its status, is associated with osteoporosis-related phenotypes and bone-related markers in human bone marrow (BM) samples. METHODS: This was a case-control and cross-sectional study conducted in a clinical unit. n-3 FA in the blood and bone biochemical markers in the BM aspirates were measured by gas chromatography/mass spectrometry and immunoassay, respectively. BM fluids were collected from 72 patients who underwent hip surgery because of either osteoporotic hip fracture (HF; n = 28) or osteoarthritis (n = 44). RESULTS: After adjusting for confounders, patients with HF had 26.2% lower plasma n-3 levels than those with osteoarthritis (P = 0.006), and each standard deviation increment in plasma n-3 was associated with a multivariate-adjusted odds ratio of 0.40 for osteoporotic HF (P = 0.010). In multivariate analyses including all patients, a higher plasma n-3 level was associated with higher bone mass at the lumbar spine (ß = 0.615, P = 0.002) and total femur (ß = 0.244, P = 0.045). Interestingly, the plasma n-3 level was inversely associated with the tartrate-resistant acid phosphatase-5b level (ß = - 0.633, P = 0.023), but not with the bone-specific alkaline phosphatase level, in BM aspirates. CONCLUSIONS: These findings provide clinical evidence that n-3 FA is a potential inhibitor of osteoclastogenesis that favors human bone health.

The association of cortisol and adrenal androgen with trabecular bone score in patients with adrenal incidentaloma with and without autonomous cortisol secretion.

Despite ethnic differences in cortisol sensitivity, only one study in Caucasians has assessed trabecular bone score (TBS) in patients with subclinical hypercortisolism (SH). We showed that both subtle cortisol excess and reduced adrenal androgen may contribute to impaired bone quality in Asian women with SH. INTRODUCTION: One study in Caucasians has assessed trabecular bone score (TBS), an index of bone microstructure, in adrenal incidentaloma (AI) patients with subclinical hypercortisolism (SH). There are ethnic differences in cortisol sensitivities between Caucasian and Asian populations. We investigated the associations of cortisol and the adrenal androgen dehydroepiandrosterone-sulfate (DHEA-S) with TBS in AI patients with SH, adrenal Cushing's syndrome (CS), and nonfunctional AI (NFAI). METHODS: We measured TBS, cortisol levels after the overnight 1 mg dexamethasone suppression test (1 mg DST), and cortisol/DHEA-S in 61 patients with SH (30 men; 31 women), 19 with adrenal CS (4 men; 15 women), and 355 with NFAI (213 men; 142 women). RESULTS: After adjusting for confounders, the serum cortisol level after 1 mg DST was inversely correlated with TBS in men (ß = -0.133, P = 0.045) and women (ß = - 0.140, P = 0.048). Higher cortisol/DHEA-S ratio was associated with lower TBS in women (ß = - 0.252, P < 0.001), but not men. This inverse association of cortisol/DHEA-S ratio in women remained statistically significant after adjusting for the serum cortisol level after 1 mg DST (ß = - 0.221, P = 0.008). Compared with women with NFAI, women with SH had 2.2% lower TBS (P = 0.040). Deteriorated bone microstructure (TBS < 1.230) was associated with the serum cortisol level after 1 mg DST (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.04-4.53) and cortisol/DHEA-S ratio (OR, 2.05; 95% CI, 1.03-4.08). CONCLUSIONS: Subtle cortisol excess in both genders and reduced DHEA-S, especially in women, may contribute to impaired bone quality in Asian patients with SH.

Association of circulating dipeptidyl-peptidase 4 levels with osteoporotic fracture in postmenopausal women.

Postmenopausal women with osteoporotic fracture (OF) had higher plasma dipeptidyl-peptidase 4 (DPP4) levels than those without. Furthermore, higher plasma DPP4 levels were significantly associated with higher bone turnover and a higher prevalence of OF. These results indicated that DPP4 may be associated with OF by mediating bone turnover rate. INTRODUCTION: Evidence indicates that dipeptidyl-peptidase 4 (DPP4) plays a distinct role in bone metabolism. However, there has been no report on the association, if any, between circulating DPP4 levels and osteoporosis-related phenotypes, including osteoporotic fracture (OF). Therefore, we performed a case-control study to investigate these associations in postmenopausal women. METHODS: This study was conducted in multiple centers in Korea. We enrolled 178 cases with OF and 178 age- and body mass index-matched controls. OF was assessed by an interviewer-assisted questionnaire and lateral thoracolumbar radiographs. Bone turnover markers (BTMs), bone mineral density (BMD), and plasma DPP4 levels were obtained in all subjects. RESULTS: After adjustment for potential confounders, subjects with OF had significantly higher DPP4 levels than those without (P = 0.021). Higher DPP4 levels were significantly positively associated with higher levels of all BTMs, but not with BMD at all measured sites. The differences in DPP4 levels according to OF status disappeared after an additional adjustment for each BTM, but not after adjustment for any BMD values. BTMs explained approximately half of the relationship between DPP4 and OF. The risk of OF was 3.80-fold (95% confidence interval = 1.53-9.42) higher in subjects in the highest DPP4 quartile than in those in the lowest quartile after adjustment for potential confounders, including femoral neck BMD. CONCLUSIONS: DPP4 may be associated with OF by at least partly mediating the bone turnover rate. Circulating DPP4 levels may be a potential biomarker that could increase the predictive power of current fracture risk assessment models.

The effect of sphingosine-1-phosphate on bone metabolism in humans depends on its plasma/bone marrow gradient.

BACKGROUND: Although recent studies provide clinical evidence that sphingosine-1-phosphate (S1P) may primarily affect bone resorption in humans, rather than bone formation or the osteoclast-osteoblast coupling phenomenon, those studies could not determine which bone resorption mechanism is more important, i.e., chemorepulsion of osteoclast precursors via the blood to bone marrow S1P gradient or receptor activator of NF-κB ligand (RANKL) elevation in osteoblasts via local S1P. AIM: To investigate how S1P mainly contributes to increased bone resorption in humans, we performed this case-control study at a clinical unit in Korea. METHODS: Blood and bone marrow samples were contemporaneously collected from 70 patients who underwent hip surgery due to either osteoporotic hip fracture (HF) (n = 10) or other causes such as osteoarthritis (n = 60). RESULTS: After adjusting for sex, age, BMI, smoking, alcohol, previous fracture, diabetes, and stroke, subjects with osteoporotic HF demonstrated a 3.2-fold higher plasma/bone marrow S1P ratio than those without HF, whereas plasma and bone marrow S1P levels were not significantly different between these groups. Consistently, the risk of osteoporotic HF increased 1.38-fold per increment in the plasma/bone marrow S1P ratio in a multivariate adjustment model. However, the odds ratios for prevalent HF according to the increment in the plasma and bone marrow S1P level were not statistically significant. CONCLUSION: Our current results using simultaneously collected blood and bone marrow samples suggest that the detrimental effects of S1P on bone metabolism in humans may depend on the S1P gradient between the peripheral blood and bone marrow cavity.

Psychosine inhibits osteoclastogenesis and bone resorption via G protein-coupled receptor 65.

BACKGROUND: It was recently reported that G protein-coupled receptor 65 (GPR65) suppresses ovariectomy-induced bone loss. AIM: The present study investigated the role of the lysosphingolipid psychosine, a GPR65 ligand, on osteoclastic differentiation and bone resorption. METHODS: Osteoclasts were differentiated from mouse bone marrow macrophages. Tartrate-resistant acid phosphatase-positive multinucleated cells were considered to be osteoclasts, and the resorption area was measured by incubating the cells on dentine discs. The expression levels of osteoclast differentiation markers were assessed by qRT-PCR. GPR65 siRNA and its scrambled siRNA were transfected with lipofectamine. Intracellular cyclic adenosine monophosphate (cAMP) levels were assessed using a direct enzyme immunoassay. RESULTS: Psychosine inhibited osteoclastogenesis and in vitro bone resorption without any significant effect on the viability of pre-osteoclasts, decreased the expression of osteoclast differentiation markers significantly, and increased intracellular cAMP levels. The knockdown of GPR65 by its siRNA restored osteoclastogenesis and decreased cAMP levels in the presence of psychosine. CONCLUSION: Psychosine inhibits osteoclastogenesis by increasing intracellular cAMP levels via GPR65.

Afamin stimulates osteoclastogenesis and bone resorption via Gi-coupled receptor and Ca2+/calmodulin-dependent protein kinase (CaMK) pathways.

BACKGROUND: Afamin was recently identified as a novel osteoclast-derived coupling factor that can stimulate the in vitro and in vivo migration of preosteoblasts. AIM: In order to understand in more detail the biological roles of afamin in bone metabolism, we investigated its effects on osteoclastic differentiation and bone resorption. METHODS: Osteoclasts were differentiated from mouse bone marrow cells. Tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells were considered as osteoclasts, and the resorption area was determined by incubating the cells on dentine discs. The intracellular cAMP level was determined using a direct enzyme immunoassay. Signaling pathways were investigated using western blot and RT-PCR. Recombinant afamin was administered exogenously to bone cell cultures. RESULTS: Afamin stimulated both osteoclastogenesis and in vitro bone resorption. Consistently, the expressions of osteoclast differentiation markers were significantly increased by afamin. Although afamin mainly affected the late-differentiation stages of osteoclastogenesis, the expression levels of receptor activator of nuclear factor-κB ligand (RANKL)-dependent signals were not changed. Afamin markedly decreased the levels of intracellular cAMP with reversal by pretreatment with pertussis toxin (PTX), a specific inhibitor of Gi-coupled receptor signaling. In addition, PTX almost completely blocked afamin-stimulated osteoclastogenesis. Furthermore, pretreatment with KN93 and STO609 - Ca2+/cal - mo dulin-dependent protein kinase (CaMK) and CaMK kinase inhibitors, respectively - significantly prevented decreases in the intracellular cAMP level by afamin while attenuating afamin-stimulated osteoclastogenesis. CONCLUSION: Afamin enhances osteoclastogenesis by decreasing intracellular cAMP levels via Gi-coupled receptor and CaMK pathways.

Higher serum uric acid is associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in healthy postmenopausal women.

UNLABELLED: Higher serum uric acid (UA) was associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in postmenopausal women. Furthermore, UA suppressed osteoclastogenesis and decreased production of reactive oxygen species in osteoclast precursors, indicating UA may have beneficial effects on bone metabolism as an antioxidant. INTRODUCTION: UA is known to play a physiological role as an antioxidant, and oxidative stress has detrimental effects on bone metabolism. In the present study, we investigated the association of serum UA level with the osteoporosis-related phenotypes and its direct effect on bone-resorbing osteoclasts using in vitro systems. METHODS: This is a large cross-sectional study, including 7,502 healthy postmenopausal women. Bone mineral density (BMD) and serum UA concentrations were obtained from all subjects. Data on bone turnover markers and lateral thoracolumbar radiographs were available for 1,023 and 6,918 subjects, respectively. An in vitro study investigated osteoclastogenesis and reactive oxygen species (ROS) levels according to UA treatment. RESULTS: After adjusting for multiple confounders, serum UA levels were positively associated with BMD at all sites (all p < 0.001). Compared with the participants in the highest UA quartile, the odds for osteoporosis were 40 % higher in those in the lowest quartile. The serum UA levels were inversely related to both serum C-terminal telopeptide of type I collagen and osteocalcin levels (p < 0.001 and p = 0.004, respectively). Consistently, subjects with vertebral fracture had lower serum UA levels, compared with those without it (p = 0.009). An in vitro study showed that UA decreased osteoclastogenesis in a dose-dependent manner and reduced the production of ROS in osteoclast precursors. CONCLUSION: These results provide epidemiological and experimental evidence that serum UA may have a beneficial effect on bone metabolism as an antioxidant in postmenopausal women.

Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women.

UNLABELLED: We determined whether suppression of sclerostin levels by estrogen treatment was mediated by anti-resorptive effect. Raloxifene, but not bisphosphonates, suppressed circulating sclerostin concentration, suggesting that sclerostin may mediate the action of estrogen on bone metabolism, independently of their anti-resorptive effects. INTRODUCTION: Circulating sclerostin concentrations are higher in postmenopausal than in premenopausal women, and estrogen treatment suppresses sclerostin levels in both men and women. We determined whether anti-resorptives may suppress the circulating sclerostin levels. METHODS: We conducted a retrospective observational study. Eighty postmenopausal women were treated with raloxifene for 19.4 ± 7.7 months (n = 16), bisphosphonates for 19.2 ± 6.7 months (n = 32), or were untreated (n = 32) for 17.1 ± 4.6 months. Plasma sclerostin concentrations were measured before and after treatment. RESULTS: Plasma sclerostin levels after treatment were significantly lower in the raloxifene than in the control group (55.8 ± 23.4 pmol/l vs. 92.1 ± 50.4 pmol/l, p = 0.046), but were similar between the bisphosphonate and control groups. Relative to baseline, raloxifene treatment markedly reduced plasma sclerostin concentration (-40.7 ± 22.8%, p < 0.001), with respect to both control (-7.5 ± 29.1%) and bisphosphonate (-3.1 ± 35.2%) groups. Changes in bone-specific alkaline phosphatase and osteocalcin levels showed reverse associations with sclerostin concentration changes in the raloxifene (γ = -0.505, p = 0.017) and control (γ = -0.410, p = 0.020) groups. CONCLUSIONS: Raloxifene, but not bisphosphonates, significantly suppressed circulating sclerostin concentration, suggesting that sclerostin may mediate the action of estrogen on bone metabolism, independently of their anti-resorptive effects.

The association between serum osteocalcin levels and metabolic syndrome in Koreans.

UNLABELLED: The association between serum osteocalcin levels and metabolic syndrome (MS) in Korean individuals was investigated. Serum osteocalcin levels are significantly lower in subjects with MS than in those without the disease, regardless of glucose metabolism. INTRODUCTION: Osteocalcin was recently shown to affect energy metabolism. In the present study, we investigated the possible association between serum osteocalcin concentrations and MS. METHODS: A cross-sectional community-based survey was conducted. Serum osteocalcin, type 1 collagen C-telopeptide (CTX) and total alkaline phosphatase (ALP) concentrations were determined in 567 subjects. MS was defined according to NCEP-ATP III criteria. RESULTS: Serum osteocalcin concentrations were significantly lower in subjects with MS than those without MS in postmenopausal women (18.923 ± 7.685 vs 22.513 ± 7.344 ng/ml, P<0.001) and marginally lower in subjects with MS than those without MS in men (14.550 ± 5.090 vs 16.125 ± 4.749 ng/ml, P=0.086) after adjustment for age and BMI. Further controlling with CTX or ALP did not affect this association in postmenopausal women; however, controlling with osteocalcin abolished the association between CTX and MS. Significant differences in serum osteocalcin levels by MS status were noted in subjects with normal glucose tolerance as well as those with abnormal glucose tolerance (P=0.032 and P<0.001, respectively). Compared with subjects with the highest quartile of osteocalcin, those in the lower quartile groups (Q1-Q3) had significantly increased risks of MS (ORs=5.18, CIs=1.15-23.42) in men. In postmenopausal women, the ORs for MS were significantly higher in the lowest quartile than in the highest quartile (ORs=5.25, CIs=2.42-11.36). CONCLUSIONS: These findings suggest that osteocalcin is associated with MS, independently of glucose metabolism.

Identification of novel RANK polymorphisms and their putative association with low BMD among postmenopausal women.

INTRODUCTION: Bone mineral density (BMD) is the major factor for determining bone strength, which is closely correlated to osteoporotic fracture risk and is largely determined by multiple genetic factors. The RANK (TNFRSF11A), receptor for RANKL, is a member of the tumor necrosis factor receptor (TNFR) superfamily and plays a central role in osteoclast development. METHODS: In order to investigate the effects of RANK polymorphism on BMD and osteoporosis, we directly sequenced the RANK gene in 24 Korean individuals and identified 25 sequence variants. Eleven of these polymorphisms were selected and genotyped in a larger-scale study of postmenopausal women (n = 560). Areal BMD (g/cm(2)) of the anterior-posterior lumbar spine and the nondominant proximal femur were measured using dual-energy X-ray absorptiometry. RESULTS: We found that two intronic polymorphisms in the RANK gene [RANK + 34863G > A (rs12458117) and RANK + 35928insdelC (new polymorphism found in this study) in intron 6] were significantly associated with the BMD of the lumbar spine, i.e., rare alleles were significantly associated with low BMD of the lumbar spine among Korean postmenopausal women (p = 0.04 and 0.02, respectively). These polymorphisms were also associated with low BMD of proximal femur sites, including Ward's triangle, trochanter, and total femur. Our results suggest that +34863G > A and +35928insdelC polymorphisms in RANK are possible genetic factors for low BMD in postmenopausal women.

Increased urinary albumin excretion in Cushing's syndrome: remission after correction of hypercortisolaemia.

OBJECTIVES: Increased urinary albumin excretion (UAE) in diabetic and nondiabetic subjects is frequently associated with insulin resistance syndrome and central obesity. Cushing's syndrome is also characterized by central obesity and insulin resistance. This study was undertaken to see whether increased UAE is found in Cushing's syndrome. DESIGN: Cross-sectional study. PATIENTS: Thirteen consecutive patients with Cushing's syndrome. MEASUREMENTS: Patients collected three overnight urine samples for the measurement of UAE by radioimmunoassay. UAE was also measured in 479 nondiabetic subjects who comprised the control population for this study. In the patients who had initial microalbuminuria, UAE was remeasured 2 months after successful removal of pituitary or adrenal tumours. Kidney biopsy was performed in three patients during adrenalectomy. RESULTS: Eleven out of 13 patients (84.6%) had increased UAE (> 9.6 micrograms/min), and eight patients (61.5%) had microalbuminuria or overt proteinuria (> 20 micrograms/min). Kidney biopsy revealed apparently normal glomerular structures without evidence of diabetic nephropathy. After correction of hypercortisolaemia, UAE declined profoundly in all of the patients. CONCLUSIONS: More than 80% of patients with Cushing's syndrome had increased UAE. This was almost completely reversed after successful treatment of hypercortisolaemia. These results indicate that endogenous hypercortisolaemia increases UAE by a mechanism that is presently unknown.

Prevalences of Gs alpha, ras, p53 mutations and ret/PTC rearrangement in differentiated thyroid tumours in a Korean population.

OBJECTIVE: In thyroid tumours, ras, Gs alpha, p53 mutations and ret/PTC rearrangement have been reported with variable prevalences in different geographical regions. We studied the prevalence of these mutations and rearrangement in thyroid tumours in a Korean population. As MDM2 and Bcl-1 protein expressions have been suggested to be associated with p53 protein, we also studied possible relationships among them. PATIENTS AND DESIGN: Eleven cases of adenomatous goitre, eight cases of follicular adenoma, five cases of follicular carcinoma and 37 cases of papillary carcinoma were included in this study. To find mutations and rearrangement, RT-PCR, SSCP and/or direct sequencing, after subcloning if necessary, were used, and immunohistochemical stainings were performed for p53, MDM2 and Bcl-2 proteins in cases of papillary carcinoma. RESULTS: We could not find any rearrangement for ret/PTC-1, -2, -3 and mutation of Gs alpha. For the ras oncogene, K and H-ras mutations were not found, but N-ras mutations, point mutation of CAA to CGA in codon 61, were detected in one follicular adenoma (12.5%, 1/8) and one follicular carcinoma (33%, 1/3). p53 mutations were detected in only one case of papillary carcinoma (3%, 1/31: exon 8, codon 266 GGA-->GAA). In 30 cases of papillary carcinoma without p53 mutation, the prevalences of positive immunohistochemical staining were 13.3% for p53 protein, 53.3% for MDM2 protein and 56.7% for Bcl-2 protein. While over-expression of p53 protein was not significantly related to that of MDM2 and Bcl-2 proteins, over-expression of MDM2 and Bcl-2 in papillary carcinoma were associated. CONCLUSION: ret/PTC rearrangement, Gs alpha, ras and p53 mutations are relatively rare in differentiated thyroid neoplasms from a Korean population, which may reflect genetic and environmental differences from patients in countries with high prevalences. P53 protein over-expression was noted in 13.3% of papillary carcinoma cases without p53 mutation and was not significantly related to MDM2 and Bcl-2 expression.