Estrogen receptor α CA dinucleotide repeat polymorphism is associated with rate of bone loss in perimenopausal women and bone mineral density and risk of osteoporotic fractures in postmenopausal women

Summary The association between a newly identified CA repeat polymorphism of the estrogen receptor alpha gene (ESR1) with osteoporosis was investigated. Postmenopausal women with <18 CA repeats had low BMD, increased rate of bone loss and increased fracture risk. Introduction Studies have shown that intronic dinucleotide repeat polymorphisms in some genes are associated with disease risk by modulating mRNA splicing efficiency. D6S440 is a newly identified intronic CA repeat polymorphism located downstream of the 5’-splicing site of exon 5 of ESR1. Methods The associations of D6S440 with bone mineral density (BMD), rate of bone loss and fracture risk were evaluated in 452 pre-, 110 peri- and 622 postmenopausal southern Chinese women using regression models. Results Post- but not premenopausal women with less CA repeats had lower spine and hip BMD. The number of CA repeats was linearly related to hip BMD in postmenopausal women (β = 0.008; p = 0.004). Postmenopausal women with CA repeats <18 had higher risks of having osteoporosis (BMD T-score<−2.5 at the spine: OR 2.46, 95% CI 1.30–4.65; at the hip: OR 3.79(1.64–8.74)) and low trauma fractures (OR 2.31(1.29–4.14)) than those with ≥18 repeats. Perimenopausal women with <18 CA repeats had significantly greater bone loss in 18 months at the hip than those with ≥18 repeats (−1.96% vs. −1.61%, p = 0.029). Conclusions ESR1 CA repeat polymorphism is associated with BMD variation, rate of bone loss and fracture risk, and this may be a useful genetic marker for fracture risk assessment. Funding Source: This project is supported by CRCG Grant, Bone Health Fund, Matching Grant and Osteoporosis and Endocrine Research Fund of the University of Hong Kong.     

Quantitative assessment of impaired postevacuation brain re-expansion in bilateral chronic subdural haematoma: Possible mechanism of the higher recurrence rate

IntroductionRecurrence of chronic subdural haematoma (CSDH) occurs in up to 30% of patients. The rate of recurrence is higher in bilateral versus unilateral CSDH and the reason for this has not been fully elucidated. There are few quantitative studies of temporal changes in brain re-expansion after haematoma evacuation. The aim of this study is to use a simple volumetric image analysis method to quantify temporal changes of postoperative brain re-expansion in unilateral and bilateral CSDH.MethodsWe reviewed computed tomography (CT) scans of 20 consecutive patients (16 men, 4 women; median age, 73.5 years) with CSDH (unilateral, n = 10; bilateral, n = 10) who underwent surgery (burr hole drainage on one or both sides) at our institutions during the period from June 2006 to August 2008. Haematoma volume was quantified preoperatively and on postoperative days 14 and 30 by computer-based image analysis (PACS Web 1000 System) of CT scans. We then calculated the brain re-expansion rate (BRR) for postoperative days 14 and 30.ResultsHaematoma volume remained significantly higher (p < 0.001) in bilateral versus unilateral CSDHs at both postoperative time points, and the BRR was significantly greater (p < 0.001) in unilateral versus bilateral CSDH at both time points.ConclusionResults of this quantitative analysis provide definitive evidence for a poor BRR in bilateral compared to unilateral CSDH. This impairment may result in shifting of the brain and shearing of blood vessels, resulting in a higher recurrence rate.     

Ethnic difference of clinical vertebral fracture risk

Summary

Vertebral fractures are the most common osteoporotic fractures. Data on the vertebral fracture risk in Asia remain sparse. This study observed that Hong Kong Chinese and Japanese populations have a less dramatic increase in hip fracture rates associated with age than Caucasians, but the vertebral fracture rates were higher, resulting in a high vertebral-to-hip fracture ratio. As a result, estimation of the absolute fracture risk for Asians may need to be readjusted for the higher clinical vertebral fracture rate.

Introduction

Vertebral fractures are the most common osteoporotic fractures. Data on the vertebral fracture risk in Asia remain sparse. The aim of this study was to report the incidence of clinical vertebral fractures among the Chinese and to compare the vertebral-to-hip fracture risk to other ethnic groups.

Methods

Four thousand, three hundred eighty-six community-dwelling Southern Chinese subjects (2,302 women and 1,810 men) aged 50 or above were recruited in the Hong Kong Osteoporosis Study since 1995. Baseline demographic characteristics and medical history were obtained. Subjects were followed annually for fracture outcomes with a structured questionnaire and verified by the computerized patient information system of the Hospital Authority of the Hong Kong Government. Only non-traumatic incident hip fractures and clinical vertebral fractures that received medical attention were included in the analysis. The incidence rates of clinical vertebral fractures and hip fractures were determined and compared to the published data of Swedish Caucasian and Japanese populations.

Results

The mean age at baseline was 62?±?8.2?years for women and 68?±?10.3?years for men. The average duration of follow-up was 4.0?±?2.8 (range, 1 to 14) years for a total of 14,733 person-years for the whole cohort. The incidence rate for vertebral fracture was 194/100,000 person-years in men and 508/100,000 person-years in women, respectively. For subjects above the age of 65, the clinical vertebral fracture and hip fracture rates were 299/100,000 and 332/100,000 person-years, respectively, in men, and 594/100,000 and 379/100,000 person-years, respectively, in women. Hong Kong Chinese and Japanese populations have a less dramatic increase in hip fracture rates associated with age than Caucasians. At the age of 65 or above, the hip fracture rates for Asian (Hong Kong Chinese and Japanese) men and women were less than half of that in Caucasians, but the vertebral fracture rate was higher in Asians, resulting in a high vertebral-to-hip fracture ratio.

Conclusions

The incidences of vertebral and hip fractures, as well as the vertebral-to-hip fracture ratios vary in Asians and Caucasians. Estimation of the absolute fracture risk for Asians may need to be readjusted for the higher clinical vertebral fracture rate.     

Determinants of peak bone mineral density and bone area in young women

Osteoporosis is a disease caused by compromised bone strength, and individuals with a high peak bone mass at a young age are likely to have a high bone mass in old age. To identify the clinical determinants of peak bone mass in young adult women, 418 southern Chinese women, aged 20–39 years, were studied. Low bone mass was defined as areal bone mineral density (aBMD) Z-score < −1 at either the spine or total hip. Within the cohort, 62 (19.0%) and 86 (26.4%) women had low aBMD at the spine and hip, respectively. Regression model analysis revealed that low body weight (<44 kg) was associated with an 8.3-fold (95% CI, 3.7–18.9) and a 6.8-fold (95% CI, 3.0–15.6) risk of having low aBMD at the spine and hip, respectively. Low body weight was also predictive of low volumetric BMD (vBMD) at the spine (odds ratio (OR) 7.8, 95% CI, 3.1–20.1) and femoral neck (OR 3.0, 95% CI, 1.3–7.1). A body height below 153 cm was associated with a 4.8-fold risk in the small L2–4 bone area (95% CI, 2.3–9.8) and a 3.9-fold risk in the small femoral neck area (95% CI, 1.9–8.1). Delayed puberty (onset of menstruation beyond 14 years) was associated with a 2.2-fold (95% CI, 1.0–4.9) increased risk of having low aBMD at the hip. Physical inactivity was associated with a 2.8-fold risk of low spine vBMD (OR 2.8, 95% CI, 1.1–6.7) and a 3.3-fold risk of low hip aBMD (95% CI, 1.0–10.0). Pregnancy protected against low spine aBMD (OR 0.4, 95% CI, 0.1–1.2) and spine vBMD (OR 0.1, 95% CI, 0.0–1.0), low femoral neck vBMD (OR 0.3, 95% CI, 0.1–1.1) and small L2–4 bone area vBMD (OR 0.3, 95% CI, 0.1–1.1). In conclusion, this study identified a number of modifiable determinants of low peak bone mass in young adult women. Maintaining an ideal body weight, engaging in an active lifestyle, and diagnosing late menarche may enable young women to maximize their peak bone mass and so reduce their risk of osteoporosis in later life.     

Total thyroidectomy replaces subtotal thyroidectomy as the preferred surgical treatment for Graves' disease

BACKGROUND: Total thyroidectomy is increasingly being adopted for patients requiring surgical treatment for Graves' disease based on a comparable surgical risk and the lack of recurrence, as well as the questionable ability of subtotal thyroidectomy to maintain euthyroidism. The purpose of the present paper was to evaluate its safety and efficiency. METHODS: Total thyroidectomy was adopted as part of the routine surgical treatment for Graves' disease from 2000. Patients who underwent subtotal thyroidectomy (STT) from 1995 to 1999 (n = 119) were compared with those who underwent total thyroidectomy (TT) from 2000 to 2003 (n = 98) with respect to immediate postoperative morbidity and long-term outcome. RESULTS: Fourteen (11.8%) and 22 patients (22.4%) required calcium supplement on discharge in the STT and TT groups, respectively (P < 0.05). One (0.8%) and three patients (3.1%) developed permanent hypocalcaemia, respectively. Transient recurrent laryngeal nerve palsy occurred in 9.2% (n = 11) and 5.1% (n = 5) of patients or 5.0% and 2.6% of nerves at risk after STT and TT, respectively. None of the patients had permanent nerve palsy. The estimated blood loss was less and hospital stay shorter after TT. During a mean follow up of 64 months, 86 patients (72.3%) in the STT group required thyroxine replacement and seven patients (5.9%) developed relapse. CONCLUSION: Subtotal thyroidectomy was associated with relapse as well as hypothyroidism in a significant proportion of patients during long-term follow up. Total thyroidectomy can be performed as safely as STT and should be recommended as the procedure of choice for patients requiring surgical treatment for Graves' disease.     

The use of yeast to understand TRP-channel mechanosensitivity

Mechanosensitive (MS) ion channels likely underlie myriad force-sensing processes, from basic osmotic regulation to specified sensations of animal hearing and touch. Albeit important, the molecular identities of many eukaryotic MS channels remain elusive, let alone their working mechanisms. This is in stark contrast to our advanced knowledge on voltage- or ligand-sensitive channels. Several members of transient receptor potential (TRP) ion channel family have been implicated to function in mechanosensation and are recognized as promising candidate MS channels. The yeast TRP homolog, TRPY1, is clearly a first-line force transducer. It can be activated by hypertonic shock in vivo and by membrane stretch force in excised patches under patch clamp, making it a useful model for understanding TRP channel mechanosensitivity in general. TRPY1 offers two additional research advantages: (1) It has a large (∼300 pS) unitary conductance and therefore a favorable S/N ratio. (2) Budding yeast allows convenient and efficient genetic and molecular manipulations. In this review, we focus on the current research of TRPY1 and discuss its prospect. We also describe the use of yeast as a system to express and characterize animal TRP channels.     

Use of monoclonal antibodies as sensitive and specific probes for biologically active human gamma-interferon.

Mouse monoclonal antibodies B1 and B3 are specific for natural and Escherichia coli-derived recombinant human gamma-interferon (IFN-gamma). The two antibodies recognize different epitopes of the IFN-gamma molecule and do not compete with each other's binding. We have used these two antibodies to construct a solid-phase, sandwich immunoradiometric assay for human IFN-gamma. Purified antibody B1 was coated on polystyrene beads (0.64 cm in diameter) and used as the solid-phase immunoadsorbent and antibody B3 was labeled with 125I and used as tracer. This assay can be completed in about 4 hr and is capable of detecting IFN-gamma levels in human serum or tissue culture fluids as low as 0.1 NIH reference unit/ml. Recombinant human IFN-gamma derived from E. coli was detectable at a concentration of 0.02 ng/ml. The assay appears to be specific for the biologically active forms of IFN-gamma, since after exposure to pH 2, 37 degrees C, or 56 degrees C, biological activity and reactivity in the immunoradiometric assay decreased in parallel. The immunoradiometric assay can be employed for the analysis of the structural characteristics of the human IFN-gamma molecule.     

Goitrogenesis during pregnancy and neonatal hypothyroxinaemia in a borderline iodine sufficient area

OBJECTIVE: Severe iodine deficiency disorders (IDDs) may have been eradicated in many parts of the world, but milder forms still exist and may escape detection. We evaluated the impact of pregnancy on the maternal and fetal thyroid axis in Hong Kong, a coastal city in southern China with borderline iodine intake. DESIGN: A prospective study performed in a maternity hospital. PATIENTS: Two hundred and thirty pregnant women were prospectively studied and their neonates assessed at birth. MEASUREMENTS: Urine iodine concentration, thyroid function tests and thyroid volume (TV) by ultrasound were determined in the mothers during pregnancy and up to 3 months postpartum and in the neonates. RESULTS: Increased urinary iodine concentration was seen from first trimester onwards and the proportion of women having urine iodine concentration of < 0.4 micromol/l decreased from 11.3% in the first trimester to 4.7% in the third trimester. There was progressive reduction in circulating fT4 and fT3 concentrations and free thyroxine index (FTI) with increasing gestation and the percentage of women having subnormal levels at term were 53.2%, 61.1% and 4.8%, respectively. The serum TSH concentration during pregnancy doubled towards term. In the first trimester, multiparous women had significantly larger TV than the nulliparous women (P < 0.001). By the third trimester, TV had increased by 30% (range 3-230%) so that the goitre incidence was 14.1%, 21.8%, 25.9% during the three trimesters of pregnancy, and 24.3% and 21.9% at 6 weeks and 3 months postpartum (ANOVA, P < 0.05). The change in thyroid volume during pregnancy correlated positively with the change in thyroglobulin (r = 0.225, P < 0.002) and negatively with urinary iodine concentration (r = - 0.149, P < 0.02). Fourteen women with excessive thyroidal stimulation in the second trimester (defined as those with thyroglobulin (Tg) concentrations in the highest tertile and FTI in the lowest tertile) were found to have lower urine iodine concentrations and larger TV (both P < 0.005) throughout pregnancy, and their neonates had higher cord TSH (P < 0.05), Tg (P < 0.05) and slightly larger TV (P = 0.06) as compared to the findings in 216 pregnant women without evidence of thyroid stimulation. Seven neonates (50%) born to these women had subnormal fT4 levels at birth. CONCLUSION: In a borderline iodine sufficient area, pregnancy posed an important stress resulting in higher rates of maternal goitrogenesis as well as neonatal hypothyroxinaemia and hyperthyro- trophinaemia. An adequate iodization program is necessary to eliminate iodine deficiency disorders during pregnancy.