Suppressed bone turnover in obesity: a link to energy metabolism? A case-control study.

CONTEXT: Observations in rodents suggest that osteocalcin (OC) participates in glucose metabolism. Based on human studies, it remains unclear whether circulating OC is simply a bone turnover marker (BTM) or also a mediator in interactions between the skeleton and glucose homeostasis. OBJECTIVE: The objective of the study was to determine the responses of BTMs, including OC, to oral glucose tolerance test (OGTT) in a case-control setting. DESIGN AND PATIENTS: Thirty-four normoglycemic young adults [mean age 19 y (SD 2.3)] with severe childhood-onset obesity and their gender- and age-matched nonobese controls underwent a standard 2-hour OGTT. MAIN OUTCOME MEASURES: Glucose, insulin, and six BTMs including total and carboxylated OC (cOC) were determined at baseline and at 30, 60, 90, and 120 minutes during OGTT. RESULTS: The obese and control subjects were similar in height; the mean body mass indices were 40.4 and 21.9 kg/m(2), respectively. The homeostasis model assessment index was 2.7 times greater in the obese subjects. All BTMs, except bone-specific alkaline phophatase, were lower in the obese subjects compared with the controls: the differences at baseline were 40%, 35%, 17%, 31%, and 32% for N-terminal propeptides of type I collagen, cross-linked telopeptides of type I collagen, tartrate-resistant acid phosphatase, total OC, and carboxylated OC (P < .05 for all) after adjusting for whole-body bone area. All BTMs decreased during OGTT. The relative values for the OGTT responses for total, but not for cOC (measured as area under the curve) differed between the two groups (P = .029 and P = .139, respectively): the decrease in total OC during the OGTT was less pronounced in the obese subjects. Responses in other BTMs were similar between the groups. No associations were observed between glucose metabolism and OCs during OGTT with linear regression. CONCLUSIONS: Bone turnover markers were substantially lower in obese subjects compared with controls. Total OC and cOC showed less pronounced decrease during the OGTT in obese subjects compared with controls, whereas other BTMs responded similarly in the two groups. The role of OC, if anything, in glucose homeostasis is indirect and may be mediated via other factors than glucose or insulin.

[Diabetic microangiopathic hemolytic anemia--rare complication of a common disease]. / Diabeettinen mikroangiopaattinen hemolyyttinen anemia--tavallisen taudin harvinainen komplikaatio.

It is well-known that long-standing diabetes damages the vasculature. It is less frequently known that the plasticity of red blood cells may also be impaired so that they do not always survive intact in a vasculature roughened by diabetes, but are instead lysed. Lysis of red blood cells results in fragmentation hemolysis, which may lead to anemia if formation of red blood cells is deficient. We describe two patients with this rare complication, both of whom were diagnosed with diabetic microangiopathic hemolytic anemia (DMHA) during pregnancy.

Plasmodium falciparum--malaria in pregnant African immigrants often goes unrecognized.

We report four cases of asymptomatic Plasmodium falciparum malaria in pregnant African women. They had immigrated to Finland 3 to 13 months earlier. The disease was revealed only by anemia. The diagnosis relied on blood smear which showed a parasitemia <0.2% in three cases. Medical personnel should be informed about the possibility of afebrile forms of malaria in pregnant women even months after immigration. Very low levels of parasitemia may call for a more sensitive diagnostic approach such as polymerase chain reaction.

[Thirst and extensive bone lesions in a previously basically healthy woman]. / Aiemmin terveen naisen jano ja laaja-alaiset luustomuutokset.

A previously quite healthy 65-year-old woman sought emergency hospital care due to fatigue, weight loss and sensation of thirst appearing over a couple of months. Further analysis revealed a process affecting the neurohypophysis and extensive lytic sclerotic bone lesions. Eventually a rare generalized underlying disease was unraveled: the diagnosis included both Langerhans cell histiocytosis and Erdheim-Chester disease.

Prevalence of vitamin D deficiency and secondary hyperparathyroidism during winter in pre-menopausal Bangladeshi and Somali immigrant and ethnic Finnish women: associations with forearm bone mineral density.

Secondary hyperparathyroidism (SHPT) is one of the outcomes of vitamin D deficiency that negatively affects bone metabolism. We studied the ethnic differences in vitamin D status in Finland and its effect on serum intact parathyroid hormone (S-iPTH) concentration and bone traits. The study was done in the Helsinki area (60°N) during January-February 2008. A total of 143 healthy women (20-48 years of age) from two groups of immigrant women (Bangladeshi, n 34 and Somali, n 48), and a group of ethnic Finnish women (n 61) were studied in a cross-sectional setting. Serum concentrations of 25-hydroxyvitamin D (S-25OHD) and S-iPTH were measured. Peripheral quantitative computed tomography measurements were taken at 4 and 66 % of the forearm length. In all groups, the distribution of S-25OHD was shifted towards the lower limit of the normal range. A high prevalence of vitamin D insufficiency (S-25OHD < 50 nmol/l) was observed (89·6 %) in the Somali group. The prevalence of SHPT (S-iPTH>65 ng/l) was higher (79·1 %) in Somali women than in Finnish women (16 %). There was a significant association between S-25OHD and S-iPTH (r - 0·49, P < 0·001). Ethnicity and S-25OHD together explained 30 % of the variation in S-iPTH. The total bone mass at all sites of the forearm, fracture load and stress-strain index was higher (P < 0·001) in Bangladeshi and Finnish women than in Somali women. The high prevalence of hypovitaminosis D, SHPT and low bone status in Somali women indicates a higher risk of osteoporosis.

Elevated hydroxyacylcarnitines in a carrier of LCHAD deficiency during acute liver disease of pregnancy - a common feature of the pregnancy complication?

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a mitochondrial fatty acid beta-oxidation defect characterized by accumulation of long-chain hydroxyacylcarnitine intermediates and female carriers of this disorder are in risk for pregnancy complications. We found elevated blood long-chain hydroxyacylcarnitine species in a carrier of LCHAD deficiency at 31weeks of pregnancy with a LCHAD deficient fetus during acute fatty liver of pregnancy-like liver involvement, but had been within the normal range at 25weeks of pregnancy. This finding supports the hypothesis of acylcarnitine accumulation in pathogenesis of AFLP in carriers of LCHAD and MTP deficiencies.

[No thyroxin dose seemed sufficient--why?]. / Miksi mikään tyroksiiniannos ei tuntunut riittävän?

The health status of a woman with type 1 diabetes was followed during pregnancy in a maternity hospital. In addition to insulin, thyroxine therapy was applied due to hypothyreosis as a consequence of Basedow disease. Nephropathy and significant proteinuria had developed as complications of diabetes, with the proteinuria increasing considerably during pregnancy. Simultaneously thyroxine doses increased to exceptionally high levels. The cause of increasing doses was found to be secretion of thyroxine into urine. The phenomenon has been described earlier, but it is not generally recognized.

Long-term outcome of 495 TNM stage I or II patients with differentiated thyroid carcinoma followed up with neck ultrasonography and thyroglobulin measurements on T4 treatment.

OBJECTIVE: Recent guidelines for surveillance of patients with differentiated thyroid carcinoma emphasize TSH-stimulated serum thyroglobulin (Tg) measurements and neck ultrasonographies (US) over Tg measurements on T(4) and diagnostic whole body scans (DxWBS). We evaluated the safety and efficacy of a surveillance paradigm comprising yearly T(4)-suppressed Tg measurements and neck US every second year, with an increase in Tg to a detectable level being a prompt indication for DxWBS. DESIGN: A retrospective study with a median follow-up of 11.6 years. PATIENTS AND MEASUREMENTS: Recurrences, cancer-specific deaths and number of neck US, fine needle aspiration biopsies (FNABs) and operations performed were evaluated in 495 low-risk (TNM stage I and II) patients, the majority of whom had total thyroidectomy and radioactive iodine remnant ablation as initial treatment. RESULTS: Forty-four patients (8.9%) experienced a recurrence in the neck and one patient died. Recurrences were established histopathologically in 26 and by a new uptake in DxWBS in 16 cases. A combination of neck US and high Tg revealed 42 of 44 recurrences. Of 993 ultrasonographies, 149 led to FNAB and 28 FNABs to surgery. Serum Tg was elevated 173 times, indicating a recurrence in 23 patients. CONCLUSIONS: Although longer follow-up is still needed, monitoring low-risk differentiated thyroid carcinoma patients with neck US and T(4)-suppressed Tg appears to be safe, provided radioactive iodine remnant ablation has been given and a low-alarm threshold for Tg indicating further evaluation, is used. The number of additional studies caused by this surveillance paradigm was reasonable. DxWBS was helpful in selected cases. Comparative studies are warranted to show how much rhTSH-stimulation tests add to this surveillance scheme.

Increased calcium intake does not completely counteract the effects of increased phosphorus intake on bone: an acute dose-response study in healthy females.

A high dietary P intake is suggested to have negative effects on bone through increased parathyroid hormone secretion, as high serum parathyroid hormone (S-PTH) concentration increases bone resorption. In many countries the P intake is 2- to 3-fold above dietary guidelines, whereas Ca intake is too low. This combination may not be optimal for bone health. In a previous controlled study, we found that dietary P dose-dependently increased S-PTH and bone resorption and decreased bone formation. The aim of the present study was to investigate the dose-response effects of Ca intake on Ca and bone metabolism with a dietary P intake higher than recommended. Each of the twelve healthy female subjects aged 21-40 years attended three 24-h study sessions, which were randomized with regard to a Ca dose of 0 (control day), 600 or 1200 mg, and each subject served as her own control. The meals on each study day provided 1850 mg P and 480 mg Ca. S-PTH concentration decreased (P < 0.001) and serum ionized Ca concentration increased (P < 0.001) with increasing Ca doses. The bone formation marker, serum bone-specific alkaline phosphatase, did not differ significantly (P = 0.4). By contrast, the bone resorption marker, urinary N-terminal telopeptide of collagen type I, decreased significantly with both Ca doses (P = 0.008). When P intake was above current recommendations, increased Ca intake was beneficial for bone, as indicated by decreased S-PTH concentration and bone resorption. However, not even a high Ca intake could affect bone formation when P intake was excessive.

Efficacy and safety of orbital decompression in treatment of thyroid-associated ophthalmopathy: long-term follow-up of 78 patients.

OBJECTIVE: To study the long-term results of decompression surgery in patients with thyroid-associated ophthalmopathy (TAO). DESIGN AND METHODS: Retrospective analysis and clinical re-examination of TAO patients with comparison to healthy controls in Helsinki University Central Hospital. PATIENTS: Seventy-eight patients who had undergone orbital decompression due to TAO by transantral or endonasal technique between the years 1985 and 2000 were invited for re-examination. For comparison, 79 healthy age- and sex-matched controls underwent a similar examination. RESULTS: In comparison to the patients' preoperative state, proptosis was reduced by 4.7 (2.6) mm (mean (SD)) in the right and 4.4 (2.9) mm in the left globe (P < 0.0001) but did not reach the level of the controls' globe (P < 0.0001). In the right and left eye of patients, visual acuity improved in 44-55%, remained stable in 27-36% and worsened in 18-20%, but remained significantly worse than in controls (P =0.02-0.001). Prevalence of diplopia was high at the re-examination (N = 39, 50%), but 54% of those patients considered it less difficult than before the surgery. Among patients and controls, maxillary sinusitis and facial neuralgias were equally common. Sensory disturbances were significantly more frequent in patients (P < 0.0001). In assessment of overall satisfaction with present eye status, the median of the visual analogue scale (VAS) was lower for the patients than the controls (P < 0.0001). The majority of the patients considered the operation very helpful regardless of the technique used. CONCLUSION: For patients with TOA, orbital decompression seems to be an effective and safe treatment.

Meconium contaminated amniotic fluid and infant otitis media. Is it a risk factor in children surviving aspiration and initial distress of respiration?

OBJECTIVE: Histological studies show that amniotic fluid cellular content (AFCC) causes in the middle ear a foreign body reaction, the extent and severity of which depends upon the massiveness of contamination. We studied how factors related to birth and environment affect proneness to acute otitis media (AOM) in infants born through meconium contaminated amniotic fluid. METHODS: From the birth records of infants born from 1996 to 2000 a list was made of those born through meconium contaminated amniotic fluid with pulmonary aspiration and tracheal suctioning, followed by treatment in a neonatal intensive care unit. Thirty-seven such children formed the study group, 43 children matching the study cases but born through clear fluids formed the control group. Birth and environmental factors together with the frequency and number of episodes of AOM were analyzed in all, based on a verified questionnaire. In addition, 27 children in the study group and 21 in the control group received a specialist ENT examination, hearing tests and tympanometry. RESULTS: The events at delivery were highly significantly different between the two groups, manifested by the lower Apgar points in the study group (p<0.001) while other birth and environmental factors appeared equalized. The first episode of AOM in the study group came earlier than in the control group and their frequency was significantly higher during the 1st and 2nd year of life and during the entire observation period (p<0.001). Tympanostomy was performed more often in the study group. Tympanometry showed more cases of reduced static admittance and negative pressure than in the control group and hearing was poorer. CONCLUSIONS: Cases with compromised delivery through meconium contaminated fluids, resulting in pulmonary aspiration and in need of intensive care treatment, form a risk group, which should be closely followed. Early nasopharyngeal suctioning of AFCC may reduce its entry into the middle ear. A prolonged episode of AOM suggests mucosal involvement of several middle ear compartments, shown by histological studies to occur in all cases of massive contamination. Placement of a ventilation tube after the first prolonged AOM allows regression of the granulation tissue in the air spaces together with the secretory elements in the mucosa.

Effects of grapefruit juice on the absorption of levothyroxine.

AIMS: Our aim was to study the effect of grapefruit juice on the pharmacokinetics of levothyroxine. METHODS: In a randomized cross-over study with two phases, 10 healthy subjects ingested 200 ml grapefruit juice or water (control) three times daily for 2 days. On day 3, a single 600 microg dose of levothyroxine was administered with 200 ml grapefruit juice or water, which was also ingested 1 h before and 1 h after levothyroxine. Serum concentrations of total thyroxine (T4) and thyroid-stimulating hormone (TSH) were measured up to 24 h. RESULTS: Grapefruit juice decreased slightly (11%; P < 0.01) the maximal increase of T4 concentration after ingestion of levothyroxine from 66.4 nmol l(-1) to 59.4 nmol l(-1) (95% CI on the difference -11.3, -2.7). The incremental areas under the serum T4 concentration-time curve (dAUC) during the first 4 and 6 h were also decreased slightly: dAUC(0,4 h) by 13% (P < 0.05), from 195 nmol l(-1) h to 169 nmol l(-1) h (95% CI -51, -1) and dAUC(0,6 h) by 9% (P = 0.085), from 298 nmol l(-1) h to 271 nmol l(-1) h (95% CI -58, 4). The decrease in the serum concentration of TSH (1.25 mU l(-1)) measured 24 h after ingestion of levothyroxine, was not altered by grapefruit juice. CONCLUSIONS: Grapefruit juice may slightly delay the absorption of levothyroxine, but it seems to have only a minor effect on its bioavailability. Accordingly, the clinical relevance of the grapefruit juice-levothyroxine interaction is likely to be small.

Prevention of bone loss after allogeneic stem cell transplantation by calcium, vitamin D, and sex hormone replacement with or without pamidronate.

CONTEXT: In controlled studies, bisphosphonates have been used to prevent bone loss after solid organ transplantations but not in conjunction with stem cell transplantation (SCT). OBJECTIVE: The objective of the study was to test whether additional iv pamidronate would prevent bone loss associated with SCT more effectively than the combination of calcium, vitamin D, and sex steroid replacement therapy alone. SETTING: The study was carried out at the Helsinki University Central Hospital. PATIENTS, DESIGN, INTERVENTION: Ninety-nine adult recipients of allogeneic SCT were randomized by age and gender into two groups. In one group, the patients received 1000 mg calcium carbonate and 800 IU vitamin D daily, and females received estrogen and males received testosterone replacement therapy. In another group, the patients received the same treatments plus six iv infusions of 60 mg pamidronate before and 1, 2, 3, 6, and 9 months after SCT. MAIN OUTCOME MEASURES: Bone mineral density (BMD) of the lumbar spine and the upper femur, measured by dual-energy x-ray absorptiometry, and bone turnover markers were followed for 12 months. RESULTS: In the pamidronate group, lumbar spine BMD remained stable but decreased in the other group by 2.9% at 12 months (P = 0.0084 between the groups over time). Total hip BMD reduced 5.1% in the pamidronate group and 7.8% in the other group by 12 months (P = 0.0015), and femoral neck BMD reduced 4.2 and 6.2%, respectively (P = 0.074). In the pamidronate group, serum type I procollagen amino-terminal propeptide (P = 0.032 between the groups over time) and urinary type I collagen amino-terminal telopeptide (P = 0.035) decreased 79 and 68% during the first 3 months, and remained lowered thereafter, but did not change in the other group. CONCLUSIONS: The recipients of allogeneic SCT receiving additional pamidronate sustain less bone loss than those treated with calcium, vitamin D, and sex steroid replacement alone. Despite all the efforts, however, bone loss is not totally abolished at the hip.

Effects of isolated isoflavonoids on lipids, lipoproteins, insulin sensitivity, and ghrelin in postmenopausal women.

The low cardiovascular risk in Asian women has been thought to result from high isoflavonoid intake. In a double-blind, randomized, placebo-controlled trial, we studied the effects of isolated isoflavonoids (114 mg/d) on lipids, lipoproteins, insulin sensitivity, and ghrelin in 56 nondiabetic postmenopausal women with a history of breast cancer. Isoflavonoid or placebo tablets were given for 3 months, and the treatment regimens crossed over after a 2-month washout period. The concentrations of total cholesterol, high- and low-density lipoprotein cholesterol, triglycerides, apolipoproteins B and A1, and lipoprotein (a) were not affected by isoflavonoids. However, during the isoflavonoid regimen, women with low-density lipoprotein cholesterol level above the median (4.20 mmol/liter) showed a rise [0.65 +/- 0.60 (sd) mmol/liter], which was statistically different from the fall during the placebo regimen (-0.45 +/- 0.67 mmol/liter, P = 0.009). Isoflavonoids did not affect insulin sensitivity as assessed by an oral 2-h glucose tolerance test (75 g). Changes in ghrelin levels differed (P = 0.048) during the isoflavonoid (-7.1 +/- 151 micromol/liter) and placebo regimens (+47.9 +/- 198 micromol/liter). In conclusion, we found no effects of isolated isoflavonoids on lipids, lipoproteins, or insulin sensitivity in postmenopausal women, implying no vascular benefit. Isoflavonoids may reduce ghrelin levels and thus hunger and weight.

Effects of alendronate and hormone replacement therapy, alone and in combination, on bone mass and markers of bone turnover in elderly women with osteoporosis.

The aim of the study was to compare alendronate, hormone replacement therapy (HRT), and their combination in treatment of osteoporosis in elderly postmenopausal women. Ninety patients, aged 65-80 yr (mean 71), with a T-score of bone mineral density (BMD) of 2.5 or less at either the lumbar spine or the femoral neck were randomized to receive daily 10 mg alendronate (n = 30), 2 mg estradiol plus 1 mg norethisterone acetate (n = 30) (HRT), or their combination (n = 30) for 2 yr. BMD of the lumbar spine and the upper femur was measured at baseline and after 1 and 2 yr of treatment. Urinary excretion of type I collagen aminoterminal telopeptide as related to creatinine and serum type I procollagen aminoterminal propeptide was assayed at baseline and at 6-month intervals thereafter. Increases of 9.1-11.2% in lumbar spine BMD at 2 yr were similar in the study groups. Only HRT increased femoral neck BMD statistically significantly (P < 0.0001 for a change from baseline) at both 1 (+4.9%; P =NS vs. the other groups) and 2 yr (+5.8%; P < 0.05 vs. the other groups). Total hip BMD increased similarly in all study groups. Percentage reductions in urinary type I collagen aminoterminal telopeptide in the HRT group (60.2-62.7%) were significantly smaller than those in the combination group (78.1-80.4%) (P < 0.0001-0.0069) and the alendronate-only group (72.4-76.1%) (P = 0.047 at 24 months). Serum type I procollagen aminoterminal propeptide decreased less in the HRT group (53.6-59.8%) than in the other groups [73.0-75.0% in the alendronate group (P < 0.001 at 12 months); 67.0-71.5% in the combination group (P < 0.0001 at 12 months, P = 0.013 at 24 months)]. We conclude that in elderly postmenopausal women with osteoporosis, the combination of HRT and alendronate did not offer an extra gain of bone mass over either treatment alone. In terms of BMD changes, the single treatments were equally effective, but the reductions in bone markers were less with HRT than with alendronate.

The effects of transdermal estrogen therapy on bone mass and turnover in early postmenopausal smokers: a prospective, controlled study.

OBJECTIVE: The purpose of this study was to investigate whether smoking reduces the effects of transdermal estrogen replacement therapy on bone. STUDY DESIGN: One hundred forty-eight women (0.5-5 years after menopause, aged 46-58 years) completed the study. Smokers were assigned randomly to receive either 1.0 mg (n=32 women) or 1.5 mg (n=31 women) of transdermal estradiol in gel daily, and nonsmokers (n=46 women) were assigned to receive 1.0 mg of transdermal estradiol for 2 years. The control group consisted of 17 smokers and 22 nonsmokers. Bone mineral density was measured by dual-energy x-ray absorptiometry. Bone turnover was assessed by measurements of urinary aminoterminal telopeptide of type I collagen and serum aminoterminal propeptide of type I procollagen. RESULTS: Lumbar spine bone mineral density increased similarly in smoking (+3.6%) and nonsmoking (+2.6%) estrogen users (P<.0001 to a decrease of 2.5% in the control group). Femoral neck bone mineral density increased 2.2% to 2.4% in smoking and nonsmoking estrogen users but decreased 0.2% in control subjects (P<.05). Urinary aminoterminal telopeptide of type I collagen decreased similarly in all estrogen-using groups (P<.05 to control group), but serum aminoterminal propeptide of type I procollagen decreased more in smoking than in nonsmoking estrogen users (P=.006). Serum 25-hydroxyvitamin D was 20% lower (P=.004) in smokers than in nonsmokers. CONCLUSION: Transdermal estrogen treatment protects smoking women as effectively as nonsmokers from osteoporosis. Smoking worsens the vitamin D state of postmenopausal women.

High rate of monoclonal gammopathy among immunocompetent subjects with primary cytomegalovirus infection.

Serum samples from immunocompetent adults with primary cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection and from solid-organ or bone marrow transplant recipients with primary CMV infection were examined for paraproteins. Several immunocompetent patients with CMV infection but none with EBV infection presented with an M component, which implies that the M component connects CMV infection to a risk of B cell malignancy.