Effect of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women.

Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low. INTRODUCTION: Selective estrogen receptor modulators may be an alternative to bisphosphonates for treating rebound resorption after discontinuing denosumab. This study aimed to investigate the effects of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women. METHODS: This retrospective observational study included 61 patients who received 12-month follow-up raloxifene therapy after denosumab discontinuation. The primary endpoint was the bone mineral density change. The secondary endpoints were the changes in bone turnover markers and the incidence of new vertebral fractures. RESULTS: Raloxifene administration for 12 months after denosumab discontinuation resulted in a significantly lower bone mineral density at all sites compared to the level at 6 months after the last denosumab treatment (lumbar spine, - 5.48%; femoral neck, - 2.95%; total hip, - 3.52%; all, p < 0.001). The decrease in lumbar bone mineral density was particularly evident when the body mass index was low, there were previous vertebral fractures, or lumbar bone mineral density before denosumab administration was low. Marked increases in the bone turnover markers from baseline were noted after switching to raloxifene. However, no new vertebral fractures occurred during raloxifene treatment. CONCLUSIONS: Follow-up raloxifene therapy after denosumab discontinuation resulted in a decrease in bone mass to the pre-denosumab levels and a rebound increase of bone turnover markers. Therefore, raloxifene administered sequentially after denosumab discontinuation was not effective in preventing rebound phenomenon.

Comparison of fracture risk between type 1 and type 2 diabetes: a comprehensive real-world data.

Population-based cohort study of 6,548,784 Korean subjects demonstrates that the risk of fracture was higher in patients with diabetes than in nondiabetic subjects. Furthermore, patients with type 1 diabetes were associated with a higher risk of fracture than patients with type 2 diabetes for all measurement sites. INTRODUCTION: Diabetes mellitus is associated with increased fracture risk. Although the pathophysiologic effect on bone metabolism differs according to the type of diabetes, a higher risk of fracture in patients with diabetes than in nondiabetic patients has been consistently demonstrated. Considering the ever-increasing number of patients with diabetes, we aimed to provide updated information on whether this phenomenon remains valid in real-world settings by using large-scale population datasets. METHODS: We conducted a retrospective longitudinal study using data from the Korean National Health Insurance Service dataset of preventive health check-ups between January 2009 and December 2016. The hazard ratios were calculated for any fracture, vertebral fracture, and hip fracture and were analyzed according to the presence and type of diabetes. Among 10,585,818 subjects, 6,548,784 were eligible for the analysis (2418 patients with type 1 diabetes mellitus [T1DM] and 506,208 patients with type 2 diabetes mellitus [T2DM]). RESULTS: The mean follow-up duration (in years) was 7.0 ± 1.3 for subjects without diabetes, 6.4 ± 2.0 for those with T1DM, and 6.7 ± 1.7 for T2DM. Patients with T1DM had a higher incidence rate for all types of fractures per 1000 person-years. The fully adjusted hazard ratios (HRs) for any fracture, vertebral fracture, and hip fracture were higher in T1DM than in T2DM (1.37 [95% confidence interval (CI): 1.23-1.52] for any fracture, 1.33 [95% CI: 1.09-1.63] for vertebral fracture, and 1.99 [95% CI: 1.56-2.53] for hip fracture). CONCLUSIONS: In this large-scale population analysis, diabetes was associated with a higher risk of all types of fractures. Patients with T1DM had a higher risk of fracture than those with T2DM for all measurement sites, and hip fractures had the highest risk. Therefore, fracture prevention training for patients with diabetes is advisable.

The prevalence of osteoporosis and the rate of bone loss in Korean adults: the Chungju metabolic disease cohort (CMC) study.

Because the rate of bone loss is an important risk factor for fracture, we studied longitudinal changes in bone mineral density (BMD). Although the BMD of the hip decreased over time, spine BMD remained largely stable or increased. Therefore, spine BMD may not be appropriate for assessing BMD change. INTRODUCTION: The rate of age-dependent bone loss has been shown to be an important risk factor for fracture. However, longitudinal rates of BMD loss in Korea have not yet been reported. The objective of this study was to evaluate longitudinal changes in BMD in Korea. METHODS: This cohort study was performed in a population of individuals 40 years of age or older living in the rural area of Chungju City, Korea. A second BMD examination was conducted approximately 4 years after a baseline examination. A total of 3755 of the 6007 subjects completed the follow-up visit, corresponding to a follow-up rate of 62.51%. RESULTS: The age-standardized osteoporosis prevalence was 12.81% in males and 44.35% in females. In males, the average annual BMD loss at the total hip increased from -0.25% per year in their 40s to -1.12% per year in their 80s. In females, the average annual BMD loss at the total hip increased from -0.69% per year in their 40s to -1.51% per year in their 80s. However, the average annual percentage change in spine BMD in females increased from -0.91% per year in their 40s to +1.39% per year in their 80s. CONCLUSIONS: A substantial number of subjects had osteoporosis, even though we standardized the prevalence of osteoporosis. In total hip, the mean BMD was decreased during the follow-up period; in addition, the annual percentage loss increased with age. However, spine BMD remained approximately stable or increased over time and therefore may not be appropriate for assessing BMD change.

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.

Association of bone mineral density and diabetic retinopathy in diabetic subjects: the 2008-2011 Korea National Health and Nutrition Examination Survey.

UNLABELLED: Because diabetic retinopathy increases fracture risk, we studied the association between bone mineral density (BMD) and diabetic retinopathy in a nationally representative sample. A significant association between the presence of diabetic retinopathy and low BMD was observed. Therefore, diabetic retinopathy might be considered as a marker of low BMD. INTRODUCTION: Several diabetic complications, including nephropathy, retinopathy, and peripheral neuropathy, are associated with a higher fracture risk in diabetic subjects. However, in contrast to diabetic nephropathy and peripheral neuropathy, which are associated with low bone mineral density (BMD), little is known about the association between BMD and diabetic retinopathy. The aim of the present study was to determine whether the prevalence of diabetic retinopathy is associated with BMD. METHODS: This cross-sectional study included a nationally representative sample consisting of 4357 men aged 50 years and older and 4392 postmenopausal women who participated in the Korea National Health and Nutritional Examination Survey (KNHANES) from 2008 to 2011 and underwent BMD measurement by dual-energy X-ray absorptiometry (DXA) and diabetic retinopathy assessments using seven standard gradable photographs. RESULTS: The diabetic women with retinopathy had lower mean BMD at all measured sites than those without retinopathy, although the BMD difference between the two groups was small (3-5 %). In addition, the diabetic women with retinopathy were 2.27 times more likely to have osteoporosis following adjustments for all clinically relevant covariates. However, the prevalence of diabetes mellitus (DM) or diabetic retinopathy was not associated with the prevalence of osteoporosis in men. CONCLUSIONS: This study has shown that the presence of diabetic retinopathy is significantly associated with a reduced BMD and increased prevalence of osteoporosis in diabetic women.

Serum preadipocyte factor 1 concentrations and risk of developing diabetes: a nested case-control study.

AIM: To determine whether preadipocyte factor 1 could be a predictive marker for the development of diabetes in people without diabetes at baseline. METHODS: We conducted a population-based, nested case-control study of individuals who progressed to diabetes (n = 43) or prediabetes (n = 345) and control participants matched on age, sex and fasting plasma glucose concentration, who maintained normal glucose tolerance (n = 389) during a 4-year follow-up using data from the Chungju Metabolic disease Cohort Study. Circulating levels of preadipocyte factor 1 were measured using an enzyme-linked immunosorbent assay. RESULTS: Baseline serum preadipocyte factor 1 levels showed a stepwise decrease across the glucose tolerance status groups at follow-up (normal glucose tolerance: 10.02 ± 3.02 ng/ml; prediabetes: 9.48 ± 3.35 ng/ml; diabetes: 8.66 ± 3.29 ng/ml; P for trend, 0.0151). Individuals whose fasting plasma glucose level had increased or whose homeostasis model assessment of ß-cell function had decreased at follow-up showed significantly lower levels of preadipocyte factor 1 compared with their control group counterparts. After adjusting for age, BMI, fasting plasma glucose, serum insulin levels, systolic blood pressure and triglycerides, the incidence of diabetes was nearly threefold higher in the lowest vs. the upper three quartiles of circulating preadipocyte factor 1 (relative risk 2.794; 95% CI 1.188-6.571; P = 0.0185). Notably, these findings were significant in women but not in men. CONCLUSIONS: Levels of circulating preadipocyte factor 1 may be a useful biomarker for identifying women at high risk of developing diabetes.

Antimicrobial resistance of enterococci isolated from mastitic bovine milk samples in Korea.

The aim of this study was to determine the antimicrobial resistance of various species of enterococci isolated from mastitic bovine milk samples. A total of 105 enterococci isolates were examined: Enterococcus faecalis (n = 47), Enterococcus faecium (n = 39), Enterococcus gallinarum (n = 6), Enterococcus avium (n = 6), Enterococcus hirae (n = 5) and Enterococcus durans (n = 2). All the isolates were susceptible to ampicillin, gentamicin and vancomycin, and only a single E. hirae isolate was resistant to ampicillin. In general, the most frequently observed resistance among the enterococcal isolates was to tetracycline (69.5%), followed by penicillin (64.7%), erythromycin (57.1%) and cephalothin (44.7%). A similar antimicrobial resistance pattern was observed among individual species except E. durans, which exhibited only tetracycline resistance. Resistance observed among isolates of E. hirae and E. gallinarum was almost as high as E. faecium and E. faecalis. Of 105 isolates, only six (5.7%) strains of E. faecium were susceptible to all the antimicrobials tested and about 52% (55/105) showed resistance to more than three antimicrobials. The most common multiple resistance pattern was penicillin, tetracycline and erythromycin, which was observed in 32 of 105 (30.4%) isolates. This study demonstrates that enterococcal isolates belonging to minor species showed antimicrobial resistance rates as high as those of E. faecium and E. faecalis, and that monitoring of antimicrobial resistance should not be restricted only to those two major species.

Subclinical Cushing's syndrome associated with an adrenocortical oncocytoma.

Oncocytoma is a neoplasm that can arise in several organs, and it has been more commonly described in the kidney, salivary gland and thyroid. Oncocytoma arising in the adrenal gland is a rare finding. Moreover, functioning adrenocortical oncocytoma is exceptionally rare. A 47-yr-old man was incidentally discovered to have a right adrenal mass. The patient had no clinical features suggestive of increased adrenal function. However, hormonal evaluation showed a disturbed cortisol circadian rhythm, supranormal urinary cortisol excretion, a low level of ACTH, and a lack of suppressibility of cortisol secretion after dexamethasone. Right adrenalectomy was performed, and this revealed a well-circumscribed dark-brown tumor that measured 2.4x2.2 cm. The tumor consisted almost exclusively of large eosinophilic and epitheloid cells whose cytoplasm was packed with eosinophilic granulations, which corresponded to the numerous mitochondria confirmed on electron microscopy. This is a rare case of subclinical Cushing's syndrome that was caused by adrenocortical oncocytoma.

Feed contaminated with classical swine fever vaccine virus (LOM strain) can induce antibodies to the virus in pigs.

In November 2004, antibodies to classical swine fever virus (csfv) were detected in finishing pigs during the annual serological surveillance in Jeju Province, Korea. In addition, csf vaccine viruses (lom strain) had recently been isolated from pigs raised on farms known to have csfv antibody-positive pigs. In contrast with mainland Korea, Jeju Province had been csf free and its pigs had not been vaccinated against csf for more than five years. An epidemiological investigation team from the National Veterinary Research and Quarantine Service investigated the current status of csf prevention on the Korean mainland and in Jeju Province to determine possible routes of introduction of the virus into the province. It was concluded that improperly processed blood meals, manufactured on mainland Korea, had been contaminated with the csf vaccine lom strain, and that the lom strain had been transmitted to pigs fed feed or feedstuffs containing the contaminated meal.

Pancytopenia and secondary myelofibrosis could be induced by primary hyperparathyroidism.

Hyperparathyroidism may be a precipitating factor important to the development of myelofibrosis: however, there has been only a few reports regarding myelofibrosis secondary to primary hyperparathyroidism. Recently, a rare case of pancytopenia caused by myelofibrosis in a 41-year-old woman who complained of general weakness and arthralgia presented to our clinical service. The patient was diagnosed with primary hyperparathyroidism with pancytopenia. Bone marrow biopsy revealed myelofibrosis. Right parathyroidectomy was performed and a parathyroid adenoma was totally excised. After surgery, the CBC counts and other clinical abnormalities gradually improved without further intervention. We concluded that the pancytopenia was because of bone marrow fibrosis resulting from primary hyperparathyroidism. Therefore, physicians should consider myelofibrosis secondary to primary hyperparathyroidism as a cause of pancytopenia in hypercalcemic patients, even though it is rare.

Dual enteric and respiratory tropisms of winter dysentery bovine coronavirus in calves.

Although winter dysentery (WD), which is caused by the bovine coronavirus (BCoV) is characterized by the sudden onset of diarrhea in many adult cattle in a herd, the pathogenesis of the WD-BCoV is not completely understood. In this study, colostrum-deprived calves were experimentally infected with a Korean WD-BCoV strain and examined for viremia, enteric and nasal virus shedding as well as for viral antigen expression and virus-associated lesions in the small and large intestines and the upper and lower respiratory tract from 1 to 8 days after an oral infection. The WD-BCoV-inoculated calves showed gradual villous atrophy in the small intestine and a gradual increase in the crypt depth of the large intestine. The WD-BCoV-infected animals showed epithelial damage in nasal turbinates, trachea and lungs, and interstitial pneumonia. The WD-BCoV antigen was detected in the epithelium of the small and large intestines, nasal turbinates, trachea and lungs. WD-BCoV RNA was detected in the serum from post-inoculation day 3. These results show that the WD-BCoV has dual tropism and induces pathological changes in both the digestive and respiratory tracts of calves. To our knowledge, this is the first detailed report of dual enteric and respiratory tropisms of WD-BCoV in calves. Comprehensive studies of the dual tissue pathogenesis of the BCoV might contribute to an increased understanding of similar pneumoenteric CoV infections in humans.

Disseminated visceral coccidiosis in a wild white-naped crane (Grus vipio).

Disseminated visceral coccidiosis (DVC) was unexpectedly recognized in a wild white-naped crane (Grus vipio) killed by phosphamidon insecticide. On gross pathologic examination, widely disseminated white nodules were found on the serosa of the pro-ventriculus, gizzard, and intestine, as well as on the surface and in the parenchyma of liver, spleen, and cardiac muscle. Microscopically, asexual stages of a coccidia were observed in some nodules. However, the species of coccidia could not be determined because no oocysts were found on fecal examination. This is believed to be the first reported case of DVC in a wild white-naped crane infected with Eimeria spp.

Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women.

BACKGROUND: Recently, klotho has been proposed as a link between cardiovascular diseases and premature aging, but the relationship between KLOTHO genes and cardiovascular risk factors, especially glucose metabolism, in humans is unclear. OBJECTIVES: We investigate the relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. MATERIAL AND METHODS: In 251 women (mean age 51.3+/-6.9 yr), body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose, insulin and lipid profiles were measured. The genotyping of polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene was performed by allelic discrimination using a 5' nuclease polymerase chain reaction assay. RESULTS: Allele frequencies of G395A polymorphism was 0.829 for the G allele and 0.171 for the A allele and allele frequencies of C1818T polymorphism were 0.804 for the C allele and 0.196 for the T allele, both of which were in compliance with Hardy-Weinberg equilibrium and the two polymorphisms were in linkage disequilibrium (D'=0.43, p<0.01). Mean systolic blood pressure was significantly higher in A allele carriers of G395A polymorphism compared with non-carriers, and the significance was persistent even after adjustment for age and BMI. Mean fasting plasma glucose was significantly higher in T allele carriers of C1818T polymorphism compared with non-carriers, and the significance was persistent even after adjustment for age and BMI. Subjects without any minor allele from either single nucleotide polymorphisms (SNP) had significantly lower mean values for systolic, diastolic blood pressure and fasting plasma glucose levels compared with subjects with both minor allele from either SNP. CONCLUSIONS: We observed that KLOTHO G395A polymorphism was associated with blood pressure and KLOTHO C1818T polymorphism was associated with glucose metabolism in Korean women. Further studies are needed to clarify this relationship.

Rabies, an emerging disease in Korea.

Since the first rabies case was reported in a dog in 1907, the disease was enzootic up to 1975 in Korea. After a steady decrease in the number of rabies cases from 1976 to 1984, no case was reported for 8 years from 1985 to 1992. Then, a resurgence of the disease was noted in 1993, and a continuous increase of rabies cases was observed during the following years. This report provides information on rabies in South Korea during the reemerging period 1993-2003. A total of 364 rabies cases in five different animal species and five deaths in human beings as a result of rabies were reported. Cattle and dogs accounted for 46.4% and 40.4% of total animal cases, respectively, and raccoon dogs commanded an overwhelming majority (44/48) of rabies cases in wildlife animal species. All animal and human rabies cases occurred only in two provinces, Gyeonggi and Gangwon; majority of them in two counties of Gyeonggi and one county of Gangwon province that border the demilitarized zone. From the three counties, the disease continued to expand to the other areas of the two provinces. The average monthly frequency of animal rabies cases during the 11-year period peaked in January, and the incidence was highest during winter. There were three major rabies outbreaks in animals and the number of animal rabies cases increased with time. Data indicate that the temporal patterns were attributable to the ethology of raccoon dogs in the areas of outbreak.

Highly pathogenic avian influenza in magpies (Pica pica sericea) in South Korea.

Highly pathogenic avian influenza (HPAI) is an extremely infectious, systemic viral disease of birds that produces high mortality and morbidity. HPAI was diagnosed in the three dead magpies (Pica pica sericea) submitted to the National Veterinary Research and Quarantine Service. At necropsy, the prominent lesions were multifocal or coalescing necrosis of the pancreas with enlargement of the livers and spleens. Microscopically, there were severely necrotizing pancreatitis and lymphocytic meningoencephalitis. Influenza viral antigen was also detected in areas closely associated with histologic lesions. Avian influenza virus was isolated from cecal tonsils and feces of the magpies. The isolated virus was identified as a highly pathogenic H5N1, with hemagglutinin proteolytic cleavage site deduced amino acid sequence of QREKRKKR/GLFGAIAG. To determine the pathogenicity of the isolate, eight 6-wk-old specific-pathogen-free chickens were inoculated intravenously with the virus, and all birds died within 24 hr after inoculation. This is the first report of HPAI in magpies.

Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation.

Cytokines including IL-6 and TNF-alpha play an important role in the pathogenesis of postmenopausal osteoporosis. However, the relationship between changes in the cytokine levels and subsequent bone loss in patients undergoing a bone marrow transplantation (BMT) is unclear. A total of 46 patients undergoing an allogeneic BMT were prospectively investigated. The bone turnover markers and the serum cytokines were measured before BMT and serially after BMT. Bone mineral density (BMD) was measured before and 1 year after BMT. At 1 year after BMT, the lumbar spine BMD had decreased by 4.8%, and the total proximal femoral BMD had decreased by 12.3%. The serum IL-6 and TNF-alpha levels increased until 2 and 3 weeks after BMT, respectively. The lumbar BMD was significantly decreased as the serum IL-6 and TNF-alpha levels increased by post-BMT 3 weeks. The lumbar BMD decreased significantly as the cumulative prednisolone and cyclosporine dose increased. Patients with GVHD > or =grade II had higher lumbar bone loss than patients with GVHD

Relationship between circulating cytokine levels and thyroid function following bone marrow transplantation.

The relation between thyroid hormone changes and cytokines in bone marrow transplantation (BMT) patients has not been studied. This prospective study was designed to determine the relation between thyroid hormones and cytokine levels after BMT and their effects on the mortality. We studied 80 patients undergoing allogeneic BMT. Serum thyroid hormone parameters and cytokine levels were measured before and serially during 6 months after BMT. Serum T(3) decreased to a nadir 3 weeks post-BMT and serum T(4) was lowest at 3 months post-BMT. Serum thyroid stimulating hormone (TSH) sharply decreased to a nadir at 1 week and recovered. Serum interleukin-6 increased for 2 weeks after BMT and declined thereafter. Serum tumor necrosis factor-alpha increased for 3 weeks after BMT and declined thereafter. After 3 weeks post-BMT, both cytokine levels were negatively correlated with serum T(3) and T(4) levels. A total of 29 patients died before 1 year post-BMT and 51 patients survived longer than 1 year. Those patients who died before 1 year post-BMT had significantly lower levels of T(4) at 3 weeks, 3 and 6 months than surviving patients. In conclusion, increased levels of serum IL-6 and TNF-alpha were negatively correlated with thyroid hormone concentrations in BMT recipients suggesting the role of these cytokines in euthyroid sick syndrome.

Outbreak of Fowl cholera in Baikal teals in Korea.

Fowl cholera (FC) caused by Pasteurella multocida was diagnosed in waterfowl, Baikal teals (Anas formosa), submitted to the National Veterinary Research and Quarantine in Korea. The total number of mortalities was 13,228 out of approximately 100,000 birds that wintered in Cheonsoo Bay, the most important habitat area of Baikal teals in the world. Clinical signs were detected in only a few birds because of sudden death. Grossly, the dead Baikal teals had lesions consistent with FC, including multifocal necrotic foci in the liver with enlargement, petechial or ecchymotic hemorrhages on the heart, and mucoid exudates in the duodenal mucosa. Microscopically, there were hepatocytic necrosis with bacterial colonization, hemorrhage and necrosis in the myocardium, and hemorrhagic enteritis. Pasteurella multocida was isolated from the liver and the heart of all birds examined, and the isolate (P-627) was the serotype 1 X 12 X 13 by the agar gel immunodiffusion test. In order to estimate the virulence of P-627, 5-wk-old commercial ducks were exposed intramuscularly or intratracheally to the bacterium. On the basis of mortality rate, the isolate, P-627, was found to be highly virulent. This is the first report of an outbreak of FC in Baikal teals in Korea.

The role of cytokines in the changes in bone turnover following bone marrow transplantation.

Osteoporosis is a common disease among patients undergoing transplantation and a loss of bone mass is usually detected after bone marrow transplantation (BMT), particularly during the immediate post-BMT period. Post-BMT bone loss is primarily related to gonadal dysfunction and immunosuppression. Cytokines, especially interleukin 6, play an important role in the pathogenesis of postmenopausal osteoporosis. However, the pathogenetic role of cytokines in post-BMT bone loss is unknown and data on the changes of cytokines in accordance with bone turnover markers are scarce. The aim of this study was to assess the relationship between bone turnover markers and cytokines, which are regularly sampled at peripheral blood and bone marrow before and after allogeneic BMT. This prospective study included two analyses. The first was a study of 46 BMT recipients (M/F 28/18), examining the relationship between bone turnover markers and serum cytokines that were measured before and at 1 week, 2 weeks, 3 weeks, 4 weeks and 3 months after BMT. Serum intact parathyroid hormone was measured before BMT and at 3 weeks after BMT and its relation to other cytokines and bone turnover markers was evaluated. The second analysis was a study of 14 (M/F 9/5) of 46 patients in whom bone marrow plasma cytokines [interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha)] were measured at 3 weeks after BMT. The relationship between bone marrow plasma cytokines and bone turnover markers was studied because bone marrow is the microenvironment where the real changes in bone turnover occur. Serum type I collagen carboxyterminal telopeptide (ICTP), a bone resorption marker, increased progressively until 4 weeks (peak) after BMT and then decreased thereafter. Serum osteocalcin, a bone formation marker, decreased progressively until 3 weeks after BMT and then increased thereafter. Serum IL-6 increased until 2 weeks after BMT and declined thereafter. Serum TNF-alpha increased until 3 weeks after BMT and declined thereafter. There was a significant positive correlation between serum ICTP and bone marrow IL-6 levels at 3 weeks after BMT, when a marked change in bone metabolism occurs following BMT. However, a correlation between bone turnover markers and bone marrow TNF-alpha or peripheral blood cytokines was not found. At 3 months after BMT, there was a significant negative correlation between the mean daily steroid dose and the serum osteocalcin level (r = -0.43, p < 0.05). The correlation between the Mean daily steroid dose and serum ICTP was also significant (r = 0.41, p < 0.05). Our data suggest that the progressive increase in bone resorption during the immediate post-BMT period is related to both steroid dose and the increase in bone marrow IL-6, which is a potent stimulator of bone resorption in vivo.

Hypodipsic hypernatremia with intact AVP response to non-osmotic stimuli induced by hypothalamic tumor: a case report.

Anatomical lesions of hypothalamic area associated with hypodipsic hypernatremia have been reported only rarely. We report here a case of hypodipsic hypernatremia induced by a hypothalamic lesion. A 25-yr-old man, who had been treated with radiation for hypothalamic tumor 5-yr before, was admitted for evaluation of hypernatremia and hypokalemia. He never felt thirst despite the elevated plasma osmolality and usually refused to drink intentionally. Plasma arginine vasopressin (AVP) level was normal despite the severe hypernatremic hyperosmolar state and urine was not properly concentrated, while AVP secretion was rapidly induced by water deprivation and urine osmolality also progressively increased to the near maximum concentration range. All of these findings were consistent with an isolated defect in osmoregulation of thirst, which was considered as the cause of chronic hypernatremia in the patient without an absolute deficiency in AVP secretion. Hypokalemia could be induced by activation of the renin-angiotensin-aldosterone system as a result of volume depletion. However, inappropriately low values of plasma aldosterone levels despite high plasma renin activity could not induce symptomatic hypokalemia and metabolic alkalosis. The relatively low serum aldosterone levels compared with high plasma renin activity might result from hypernatremia. Hypernatremia and hypokalemia were gradually corrected by intentional water intake only.