Fabrication and in-vitro characterization of a polymeric aortic valve for minimally invasive valve replacement.

The valve replacement therapy is the standard treatment for severe heart valve diseases. Nowadays, two types of commercial prosthesis are available: mechanical and biological, but both of them have severe limitations. Moreover, alternative therapeutic approach for valve replacement, based on minimally invasive techniques (MIAVR), motivates the search for new valve materials. In this study a polyurethane-based self-expandable tri-leaflets heart valve compatible with MIAVR procedure is proposed. The device is based on the development, fabrication and characterization of three different elements: the leaflets, the polymeric stent for supporting the leaflets, and the external metallic stent for anchoring the valve to the native aortic root. The polymeric stent and the valve leaflets were fabricated using a thermoplastic silicone-polycarbonate-urethane using 3D printing and spray technology while the external metallic stent was made in nickel titanium (Nitinol) to obtain a self-expandable valve after the crimping process. The three elements were assembled in the completed device and tested by crimping, fatigue and fluid-dynamic test. The novel polymeric valve proposed showed promising results about valve crimping capabilities, durability and fluid dynamic performances. This approach could offer advantages such as low cost and to produce a tailor-made device basing on patient's imaging data. Moreover, the selected biomaterial offers the potential to have a device that could need of permanent anticoagulation and lack of calcification.

A Proof of Concept of a Non-Invasive Image-Based Material Characterization Method for Enhanced Patient-Specific Computational Modeling.

PURPOSE: Computational models of cardiovascular structures rely on their accurate mechanical characterization. A validated method able to infer the material properties of patient-specific large vessels is currently lacking. The aim of the present study is to present a technique starting from the flow-area (QA) method to retrieve basic material properties from magnetic resonance (MR) imaging. METHODS: The proposed method was developed and tested, first, in silico and then in vitro. In silico, fluid-structure interaction (FSI) simulations of flow within a deformable pipe were run with varying elastic modules (E) between 0.5 and 32 MPa. The proposed QA-based formulation was assessed and modified based on the FSI results to retrieve E values. In vitro, a compliant phantom connected to a mock circulatory system was tested within MR scanning. Images of the phantom were acquired and post-processed according to the modified formulation to infer E of the phantom. Results of in vitro imaging assessment were verified against standard tensile test. RESULTS: In silico results from FSI simulations were used to derive the correction factor to the original formulation based on the geometrical and material characteristics. In vitro, the modified QA-based equation estimated an average E = 0.51 MPa, 2% different from the E derived from tensile tests (i.e. E = 0.50 MPa). CONCLUSION: This study presented promising results of an indirect and non-invasive method to establish elastic properties from solely MR images data, suggesting a potential image-based mechanical characterization of large blood vessels.

Efficacy and safety of long-term management of patients with chronic post-surgical hypoparathyroidism.

PURPOSE: To evaluate adherence to European Society of Endocrinology guidelines and risk of renal complications in patients with chronic post-operative hypoparathyroidism (PO-HypoPT) treated with calcium and activated vitamin D metabolites. METHODS: We evaluated 90 adult patients (68 females and 22 males) with chronic (3 years) PO-HypoPT. Total albumin-corrected (Alb-Ca) and ionized serum calcium, phosphate, creatinine, PTH, and 24-h urinary calcium were measured; renal ultrasound was also performed. Healthy hospital employers (n = 142) were used as control. RESULTS: Complete data were available in 82 patients. Twenty-eight (34.1%) met four targets (Alb-Ca, phosphate, calcium phosphate product and 24-h urinary calcium), 36 (43.9%) three, 17 (20.7%) two, and 1 (1.2%) one. Thirteen (14.4%) had Alb-Ca value below and 18 (20.0%) above the target range and 54.9% 24-h urinary calcium above the upper normal limit. Seven (7.7%) has increased serum phosphate and none an increased calcium phosphate product. Eleven (12.2%) patients had eGFR < 60 mL/min × 1.73 m2. Nephrolithiasis was present in 27 (30%) patients. Compared with the controls, patients had lower Alb-Ca (8.9 ± 0.5 vs. 9.5 ± 0.3 mg/dL, P 0.0001) and a higher rate of kidney stones, mostly asymptomatic [27/90 (30%) vs 7/142 (5%), P < 0.0001, odd ratio 8.2 (3.4-19.9)]. Fifty-seven patients had ≥ four serum Ca2+ determinations during follow-up. Forty (70.2) patients had values within the target range in > 50% of cases, 18 in > 75%, and only 2 in 100%. Two patients never had values in the target range. CONCLUSIONS: Treatment of chronic PO-HypoPT with calcium and activated vitamin D metabolites is suboptimal and associated with an increased risk of renal complications.

Italian association of clinical endocrinologists (AME) position statement: drug therapy of osteoporosis.

Treatment of osteoporosis is aimed to prevent fragility fractures and to stabilize or increase bone mineral density. Several drugs with different efficacy and safety profiles are available. The long-term therapeutic strategy should be planned, and the initial treatment should be selected according to the individual site-specific fracture risk and the need to give the maximal protection when the fracture risk is highest (i.e. in the late life). The present consensus focused on the strategies for the treatment of postmenopausal osteoporosis taking into consideration all the drugs available for this purpose. A short revision of the literature about treatment of secondary osteoporosis due both to androgen deprivation therapy for prostate cancer and to aromatase inhibitors for breast cancer was also performed. Also premenopausal females and males with osteoporosis are frequently seen in endocrine settings. Finally particular attention was paid to the tailoring of treatment as well as to its duration.

Normocalcemic primary hyperparathyroidism: a survey in a small village of Southern Italy.

We investigated the prevalence of normocalcemic primary hyperparathyroidism (NPHPT) in the adult population living in a village in Southern Italy. All residents in 2010 (n=2045) were invited by calls and 1046 individuals accepted to participate. Medical history, calcium intake, calcium, albumin, creatinine, parathyroid hormone (PTH) and 25OHD were evaluated. NPHPT was defined by normal albumin-adjusted serum calcium, elevated plasma PTH, and exclusion of common causes of secondary hyperparathyroidism (SHPT) (serum 25OHD <30 ng/ml, estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m(2) and thiazide diuretics use), overt gastrointestinal and metabolic bone diseases. Complete data were available for 685 of 1046 subjects. Twenty subjects did not meet the inclusion criteria and 341 could not be evaluated because of thawing of plasma samples. Classical PHPT was diagnosed in four women (0.58%). For diagnosing NPHPT the upper normal limit of PTH was established in the sample of the population (n=100) who had 25OHD ≥30 ng/ml and eGFR ≥60 ml/min per 1.73 m(2) and was set at the mean+3s.d. Three males (0.44%) met the diagnostic criteria of NPHPT. These subjects were younger and with lower BMI than those with classical PHPT. Our data suggest, in line with previous studies, that NPHPT might be a distinct clinical entity, being either an early phenotype of asymptomatic PHPT or a distinct variant of it. However, we cannot exclude that NPHPT might also represent an early phase of non-classical SHPT, since other variables, in addition to those currently taken into account for the diagnosis of NPHPT, might cumulate in a normocalcemic subject to increase PTH secretion.

Cinacalcet efficacy in patients with moderately severe primary hyperparathyroidism according to the European Medicine Agency prescription labeling.

BACKGROUND: Patients with primary hyperparathyroidism (PHPT) with contraindications to parathyroidectomy (PTx) or persistent PHPT have few non surgical options. AIM: The aim of the study was to investigate the efficacy of cinacalcet in reducing serum calcium in patients with PHPT, for whom PTx would be indicated according to serum calcium levels, but in whom PTx is not clinically appropriate or is contraindicated [European Medicines Agency (EMA) prescription labeling]. SUBJECTS AND METHODS: The study (open-label prospective, conducted in a single tertiary center) included 12 sporadic and 2 multiple endocrine neoplasia type 1 PHPT patients with serum calcium greater than 11.2 mg/dl. Cinacalcet was administered in increasing doses until normal serum calcium was reached or side effects preventing a further increase occurred. Serum calcium, PTH, phosphate, 25OHD, markers of bone turnover, 24h-urinary calcium and areal bone mineral density (BMD) were measured. Safety biochemical indices and adverse events were monitored. RESULTS: The maintenance cinacalcet dose [median 30 mg twice daily (range 30 daily-60 mg twice daily)] was maintained constant during follow-up (median 12 months). Mean±SE baseline serum calcium was 12.2±0.3 mg/dl. Serum calcium decreased by at least 1 mg/dl in all patients and normalized in 10. Serum calcium at the last observation was 9.9±0.2 mg/dl (p<0.0001 vs baseline). PTH decreased by 17.1% compared to baseline (p=0.13), and never reached a normal value. BMD was unchanged. Adverse events occurred in 6 patients (43%) and required treatment withdrawal in 2. CONCLUSIONS: Cinacalcet reduced and often normalized serum calcium in PHPT patients who met the EMA labeling.

Tuning of human vestibulospinal reflexes by leg rotation.

Changing the foot position modifies the mechanical action exerted by the ankle extensor and flexor muscles over the body. We verified, in two groups of healthy subjects standing with the heels touching or apart, whether a 90° external rotation of the right leg and foot also changes the pattern of vestibulospinal reflexes elicited by electrical stimulation of the labyrinth. With the head oriented forward, leg rotation did not modify the labyrinthine-driven displacements of the center of pressure (CoP). When the head was rotated in the horizontal plane, either to the right or to the left, the CoP displacement increased along the y axis in all subjects. Changes in the x component in most instances appropriate to preserve unmodified the direction of body sway elicited by the stimulus were observed. Right leg rotation increased the basal EMG activity of ankle extensors and flexors on the left side, while the right side activity was unaffected. The EMG responses to labyrinthine stimulation were modified only on the left side, in a way appropriate to correct the effects of the altered torque pattern exerted on the body by right leg muscles. It appears, therefore, that somatosensory signals related to leg rotation and/or copy of the corresponding voluntary motor commands modify the pattern of vestibulospinal reflexes and maintain the postural response appropriate to counteract a body sway in the direction inferred by labyrinthine signals.

Role of the cholesterol biosynthetic pathway in osteoblastic differentiation.

Cholesterol (C27H46O) is the principal structural lipid of the biological membrane, but it also plays an important role in many other biological functions. Even though the majority of body cholesterol is synthesized by the liver and secreted as circulating lipoproteins, many cell types can synthesize cholesterol ex novo. The biosynthetic pathway of cholesterol proceeds through several intermediates and involves different enzymes. The rate-limiting step of cholesterol synthesis is the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that synthesizes mevalonate starting from HMG-CoA. Since natural inhibitors of HMG-CoA reductase, named statin, have been isolated, many others have been developed, which differ in their lipophilicity/ hydrophilicity. By using statins, many studies have been performed in order to shed light on the role of cholesterol on different cell types and, among these, on bone cells. In vivo studies have demonstrated that treatment of pluripotent mouse marrow stromal cells (M2-10B4) with statins inhibited the differentiation of these cells into osteoblastic cells, confirming the crucial role of cholesterol biosynthetic pathway for osteoblast differentiation. Conversely, other studies, using other cellular systems, have reported that statins may exert an anabolic effect on bone. Moreover, human and animal studies have shown that hypercholesterolemia may play an adverse effect in osteoporotic bone loss. In conclusion, it appears that cholesterol is important for different cellular activities, such as osteoblastic differentiation, if present in "normal" physiological concentration and particular experimental conditions, but it may exert adverse effects if present in excess.

The impact of thyroidectomy on parathyroid glands: a biochemical and clinical profile.

INTRODUCTION: An evaluation of PTH levels during thyroid surgery may reflect the functional status of the parathyroids and be useful in identifying patients at risk for hypocalcemia. This study aims to monitor the parathyroid function during total thyroidectomy through intra-operative serial samples for calcium and PTH. MATERIALS AND METHODS: Forty-seven patients undergoing total thyroidectomy for different diseases were selected for the study. Patients underwent serum PTH and calcium sampling at the induction of anesthesia (T0) and after the first (T1) and the second (T2) lobectomy. Serum calcium was also drafted 24 h after the operation. RESULTS: Mean PTH at T0, T1, and T2 was, respectively: 32.1 pg/ml, 19.6 pg/ml, and 11.5 pg/ml. PTH was significantly higher at T0 when compared to T1 (p<0.0001). It was also significantly higher at T1 than at T2 (p<0.0001). At T1 PTH levels were below the normal range in 20/47 cases (42.5%) and at T2 in 31/47 cases (66%). Twenty-four h after surgery, 8 patients (17%) demonstrated a biochemical hypocalcemia. A PTH value at T0 in the upper (>70 pg/ml) or in the lower (<20 pg/ml) limits of the normal range was statistically related to post-operative hypocalcemia (p=0.017). DISCUSSION: The study seems to confirm that serum PTH during thyroidectomy does not represent a sensitive tool in precociously identifying hypocalcemic patients. Nevertheless, before surgery, a PTH concentration at the higher or lower normal limit may help to identify patients "at risk" of developing hypocalcemia.

Calcium-sensing receptor gene polymorphism is not associated with bone mineral density in Italian postmenopausal women.

OBJECTIVE: Calcium-sensing receptor (CaR) is a candidate gene for osteoporosis susceptibility. Several CaR polymorphisms have been identified and an association between the A986S genotype and serum calcium levels has been found in Canadian postmenopausal women. We investigated whether the presence of 986S allele was associated with bone mineral density (BMD) and osteoporotic fractures. DESIGN: The study group consisted of 164 Italian postmenopausal women without fragility fracture (Fx(-)) and 55 women with fracture (Fx(+)). METHODS: A fragment of exon 7 of CaR gene containing three polymorphisms (A986S, R990G and Q1011E) was amplified by PCR and sequenced. Anthropometric characteristics and BMD were evaluated. RESULTS: The A986S polymorphism was the most commonly observed (27.9%), whereas the other two CaR polymorphisms, R990G and Q1011E, occurred in a minority of cases (8.8 and 5.5% respectively). There was no significant difference in the frequency distribution of any CaR allele between Fx(-) and Fx(+) patients. Body mass index was found to predict BMD at the lumbar spine and femoral neck. The A986S polymorphism and Years since menopause were not independent predictors of BMD at any site. As far as fracture occurrence, there was no statistically significant difference in the prevalence of fractures between women carrying or not carrying the 986S allele. CONCLUSIONS: Our data do not support a role of A986S CaR polymorphism in BMD and in the prevalence of fragility fractures in Italian postmenopausal women.

Calcium-sensing receptor gene polymorphisms in primary hyperparathyroidism.

The calcium-sensing receptor (CaR) polymorphism A986S has been found to be associated with higher serum calcium levels in normal subjects, suggesting that this amino acid change might decrease the inhibitory activity of the mutated receptor, render the parathyroid cells more prone to proliferate, and eventually increase the risk of developing primary hyperparathyroidism (PHPT). The aim of the present study was to investigate the frequency of this and other 2 known CaR polymorphisms (R990G and Q1011 E) in patients with PHPT and their effect on its phenotype. We studied 103 Italian patients with PHPT and 148 healthy Italian subjects and we compared the results in 50 pairs matched for sex, age and geographic provenience. A fragment of exon 7 of the CaR gene, containing the 3 polymorphic loci of interest (A986S, R990G, and Q1011E), was amplified by PCR and sequenced. Serum calcium and PTH levels, BMD and other biochemical and clinical parameters were evaluated. The frequency distribution of the A9865, R990G, and Q1011 E polymorphisms in the 103 PHPT patients was 39.8%, 5.8%, and 2.0%, respectively. There was no difference in the frequency of the 3 CaR polymorphisms in the 50 matched pairs of patients and controls. We found no significant difference in several clinical and biochemical parameters between PHPT patients carrying or not the 986S allele. Finally, no relationship was observed between the 986S genotype and total and ionized serum calcium in control subjects. The A986S CaR polymorphism is the most common in Italian PHPT patients and the allotype AS does not appear to play a relevant role in the pathogenesis of PHPT and its severity. The A986S polymorphism does not correlate with serum calcium levels in normal Italian subjects.

Biochemical and ultrasound tests for early diagnosis of active neuro-osteoarthropathy (NOA) of the diabetic foot.

OBJECTIVES: To test the effectiveness of a combined approach to an early diagnosis of neuro-osteoarthropathy (NOA) of the diabetic foot, we studied a group of outpatients with active NOA, presenting for the first time to our Diabetic Foot Clinic in 1998, by means of an integrated approach designed to assess bone turnover. PATIENTS AND METHODS: Fifteen consecutive diabetic patients (five Type 1 and ten Type 2 diabetic individuals, age 61.9+/-12.2 years, diabetes duration 18.7+/-8.9 years, HbA(1c) 8.4+/-1.5%) with active NOA (Group 1) were compared to nine diabetic patients with chronic stable NOA (Group 2), 14 neuropathic diabetic patients without NOA (Group 3), 13 non-neuropathic diabetic patients (Group 4) and 15 healthy controls (Group 5). Determination of serum carboxy-terminal collagen telopeptide (ICTP), bone alkaline phosphatase isoenzyme (B-ALP), osteocalcin (BGP) concentrations, as well as urinary excretion of deoxypyridinoline (DPD) were obtained in all individuals for assessment of bone reabsorption and new bone formation. Moreover in all individuals quantitative ultrasound (QUS) of the calcaneal bone was performed and mass density of lumbar spine and femur bone was determined by dual-energy X-ray absorptiometry (DEXA). RESULTS: QUS was significantly lower in the active NOA patients as compared with other groups (P<0.01), while ICTP was higher in both NOA groups (P<0.01). Urinary DPD was higher in the neuropathic non-NOA group (P<0.01) than the other groups, and osteocalcin was higher in healthy controls compared to diabetic patients without NOA. QUS and ICTP were inversely correlated (r=0.44, P=0.000). QUS in the active NOA group was significantly (P<0.01) lower in the affected compared to the unaffected foot. CONCLUSION: Our results indicate a possible role for an integrated approach to the diagnosis and monitoring of NOA involving the diabetic foot. DPD may identify patients at-risk for NOA, ICTP could be tested as a marker for NOA in asymptomatic cases. Finally, QUS of the calcaneal bone may be useful in discriminating active versus quiescent phases.

MEN1 gene alterations do not correlate with the phenotype of sporadic primary hyperparathyroidism.

Loss of heterozygosity (LOH) in the MEN1 region on chromosome 11q13 and MEN1 gene mutations have been found in a subset of sporadic parathyroid tumors. The question of whether these genetic abnormalities in the parathyroid tumors might influence the clinical and biochemical characteristics of primary hyperparathyroidism (PHPT) remains to be elucidated. The aim of the present study was to correlate the presence of MEN1 gene alterations in PHPT tumors with the clinical phenotype. Using microsatellite analysis for LOH at 11q13 and DNA sequencing of the coding exons, the MEN1 gene was studied in 38 parathyroid tumors of patients with sporadic PHPT. Fourteen tumors showed LOH at 11q13, and mutations of MEN1 gene were detected in 7 cases. The clinical and biochemical characteristics of patients were unrelated to the presence or absence of LOH and/or MEN1 gene mutations. In conclusion, MEN1 gene alterations are rather common in sporadic PHPT and their presence does not correlate with the clinical manifestations of the disease.

A quick intraoperative parathyroid hormone assay in the surgical management of patients with primary hyperparathyroidism: a study of 206 consecutive cases.

OBJECTIVE: The traditional surgical approach for patients with primary hyperparathyroidism (PHPT) consists of the identification of at least four glands and in the removal of all hyperfunctioning parathyroid tissue. DESIGN: To evaluate whether intraoperative parathyroid hormone (PTH) monitoring will allow a more limited surgical procedure by confirming complete removal of all hyperfunctioning tissue. METHODS: Plasma samples were obtained from 206 consecutive patients with sporadic PHPT before skin incision, during manipulation of a suspected adenoma, and 5 min (T-5) and 10 min after removal of abnormal parathyroid tissue. PTH was measured by a quick immunochemiluminescent assay (QPTH). The operative success was defined by a decrease of PTH greater than 50% of the highest pre-excision value. RESULTS: A >50% decrease of PTH occurred in 203 patients and was evident at T-5 in the majority of cases. All but three had normal serum calcium the day after surgery and afterwards. PTH concentration did not show a >50% decrease in the remaining three cases after completion of surgery. One patients had negative neck exploration and remained hypercalcemic; the other two had normal serum calcium at follow-up. Thus, the intraoperative QPTH correctly predicted the outcome of surgery in 201 patients (97.5%) (200 true positive and 1 true negative), and provided three false positive and two false negative results. CONCLUSIONS: The intraoperative QPTH measurement represents a useful tool to assist the surgeon during parathyroidectomy. It indicates whether all hyperfunctioning parathyroid tissue has been removed, limiting the procedure to a unilateral neck exploration in most cases.

Increased prevalence of primary hyperparathyroidism in treated breast cancer.

UNLABELLED: Hypercalcemia occurring in patients with advanced breast cancer (BC) is generally due to osteolytic metastases or to the activity of circulating tumor-derived products. In these conditions, the production of endogenous PTH is reduced. The frequency of hypercalcemia due to primary hyperparathyroidism in breast cancer is unknown. We examined the occurrence of primary hyperparathyroidism in a large group of women with treated BC. A total of 100 consecutive women aged 28-80 years with treated breast cancer were enrolled. One hundred and two healthy age-matched women and 60 age-matched female patients with differentiated thyroid carcinoma examined before thyroidectomy were used as controls. Intact serum PTH and serum calcium were measured in all patients and controls. Hypercalcemia associated with elevated serum PTH concentration indicating primary hyperparathyroidism was found in 7 BC patients (7%) and in none of healthy women or patients with thyroid cancer. The pre-operative staging of BC patients with primary hyperparathyroidism was I in six and II in one of them, and no patient had evidence of distant metastases. A parathyroid adenoma was found in all 6 BC patients submitted to neck exploration, one patient refused surgery. Serum calcium and PTH concentrations returned to normal levels after surgery. Two BC patients had increased serum PTH and normal calcium concentrations. One of them had low serum 25-hydroxyvitamin D [25(OH)D]. One patient with spread bone metastases had neoplastic hypercalcemia with undetectable serum PTH concentration. All remaining 90 BC patients had serum calcium and PTH concentrations within normal limits, but their mean (+/-SD) values (9.6+/-0.5 mg/dl for serum calcium, 38.0+/-16.4 mg/dl for serum PTH ) were slightly but significantly greater than in normal controls (9.3+/-0.5 mg/dl, p=0.003 and 27.9+/-10.6 pg/ml, p=0.0001, respectively) and in patients with thyroid cancer (9.2+/-0.6 mg/dl, p=0.001 and 26.2+/-11.0 pg/ml, p=0.001), with no relationship with clinical staging or anti-tumor therapy. IN CONCLUSION: 1) an increased frequency of parathyroid adenoma was found in BC patients with mildly aggressive neoplastic disease; 2) in BC patients with no evidence of primary hyperparathyroidism mean serum PTH and calcium concentrations were significantly greater than in healthy controls and in patients with thyroid carcinoma; and 3) this finding was unrelated to clinical staging or anti-tumor therapy. Thus, primary hyperparathyroidism should be considered as a possible cause of hypercalcemia in patients with non-aggressive breast cancer. We suggest that serum PTH should be determined in all BC patients with increased serum calcium concentration, especially in those with no evidence of metastatic disease.

Six novel MEN1 gene mutations in sporadic parathyroid tumors.

We report nine mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in sporadic parathyroid adenomas. Six of them have not previously been described: E60X, P32R, 261delA, 934+2T-->G, S443P, and 1593insC. The tissue samples were initially submitted to LOH analysis at 11q13 followed by SSCP screening of LOH-positive samples. Mutations were identified by direct sequencing and subcloning. Three (E60X, P32R, and 261delA) were in exon 2, one (934+2bp) in the splice junction of exon 5, one (S443P) in exon 9, and one (1593insC) in exon 10. The 3 mutations in exon 2 were associated with loss and/or creation of a restriction site. The corresponding germline sequence of the MEN1 gene was normal. Most mutations would likely result in a nonfunctional menin protein, and therefore in the loss of a tumor suppressor protein.

Effects of hormonal replacement treatment on bone mineral density and metabolism in hypogonadal patients.

We investigated 22 male patients affected by prepubertal hypogonadism with a mean age of 34.3+/-5.2. A significant reduction of bone mineral density (BMD) at both the lumbar spine (L2-L4, -14%, 1.039+/-0.11 vs. 1.217+/-0.16 g/cm(2), P=0.005) and femoral neck (-11%; 0.927+/-0.09 vs. 1.034+/-0.16 g/cm(2), P=0.01) was found in patients compared to age-matched controls. The mean Z score was -1. 55 for vertebrae and -1.33 for femur. Eleven and nine patients, respectively, had a lumbar and femoral BMD at least 1 S.D. below the normal mean; 8 and 4, respectively, 2 S.D. below. There was a strong positive correlation between BMD and duration of hormone replacement treatment (HRT) for both sites: respectively, r=0.71, P<0.005 for the vertebrae, and r=0.60, P<0.01 for the femur. A weak correlation was also present between onset of HRT and BMD: r=0.6, P<0.01 at the lumbar level, and r=0.47, P<0.05 at the femoral neck.

Parathyroid expression of calcium-sensing receptor protein and in vivo parathyroid hormone-Ca(2+) set-point in patients with primary hyperparathyroidism.

A reduced expression of calcium-sensing receptor (CaR) messenger ribonucleic acid and protein accompanied by abnormalities in parathyroid cell proliferation and PTH secretion are present in primary hyperparathyroidism. We studied the expression of CaR protein by immunohistochemistry in 36 sporadic parathyroid adenomas and investigated the relationship between CaR expression and several preoperative clinical parameters, including the set-point of Ca(2+)-regulated PTH secretion (measured in vivo). The adenomas were classified in 4 categories according to the intensity of immunohistochemical staining: 5 (14%) showed a CaR staining intensity similar to that of normal parathyroid ( ), 10 (27%) showed moderate staining (++), 16 (45%) showed weak staining (+), and 5 (14%) were negative (-). The intensity of CaR staining was not related to preoperative serum Ca(2+), PTH levels or adenoma volume. Twenty-nine patients underwent preoperatively the calcium infusion test to evaluate the PTH-Ca(2+) set-point. Individual values of PTH-Ca(2+) set-point ranged from 1.38-1.93 mmol/L and were significantly correlated with basal Ca(2+) levels (r = 0.96; P: = 0. 0001) and adenoma volume (r = 0.5; P: = 0.01). The mean PTH-Ca(2+) set-point values were significantly different in the 4 groups of patients classified according to immunohistochemical staining intensity of their adenoma (P: = 0.025; F = 3.78); the mean PTH-Ca(2+) set-point was significantly higher in the groups classified as negative than in those classified as weak or moderate. No correlation was observed between the PTH-Ca(2+) set-point and basal PTH levels or between the percent maximal PTH inhibition and adenoma volume and basal PTH or Ca(2+) levels. In summary, our data suggest that there is a relationship between apparent CaR protein expression and PTH-Ca(2+) set-point abnormality, suggesting that a reduced receptor content might have an important role in the pathogenesis of primary hyperparathyroidism.

Video-assisted versus conventional parathyroidectomy in primary hyperparathyroidism: a prospective randomized study.

BACKGROUND: Several studies demonstrated the feasibility of minimally invasive parathyroidectomy as a treatment for primary hyperparathyroidism. We compared its results with those of traditional surgery in a prospective randomized study. METHODS: From March to November 1998, 38 patients eligible for video-assisted parathyroidectomy (VAP) were referred to us. They were randomly divided into 2 groups: patients of group A underwent a conventional cervicotomy with bilateral exploration and frozen section of the removed adenoma; patients of group B underwent VAP with intraoperative measurement of parathyroid hormone. Operative time, postoperative pain, fever and hypocalcemia, cosmetic result, and costs were compared. Two cases of VAP were performed with locoregional anesthesia. RESULTS: Groups A (18 patients) and B (20 patients) were statistically balanced. Operative time was significantly shorter in group B (57 vs 70 minutes). Cosmetic result was significantly better in group B, which also experienced less postoperative pain (P < .05). No cases of persistent primary hyperparathyroidism were present in either group, but recurrent laryngeal nerve palsy occurred in 1 patient in group B. CONCLUSIONS: Compared with conventional surgery, VAP is associated with a shorter operative time, a better cosmetic result, and a less painful postoperative course.

No evidence for mutations in the calcium-sensing receptor gene in sporadic parathyroid adenomas.

Inactivating mutations of the calcium-sensing receptor gene (CaR) might explain abnormalities in the regulation of both parathyroid cell proliferation and parathyroid hormone secretion. In a previous study, using RNAse A protection assay, no mutations were identified in a series of parathyroid specimens from patients with primary and secondary hyperparathyroidism, but the analysis was incomplete, since part of exon 6 could not be analyzed. In the present study, we examined the presence of mutations in the CaR gene in 20 parathyroid adenomas using direct sequencing. The entire coding region of the CaR gene was successfully amplified by polymerase chain reaction and directly sequenced. This analysis did not identify CaR gene mutations in any tumors studied. A polymorphism that encoded a single amino acid change (Ala826Thr) was identified in 4 parathyroid adenomas and in 8 of 50 normal unrelated subjects. Loss of heterozygosity studies were also performed on adenomas using markers for the locus of the CaR gene on chromosome 3q. No allelic loss was demonstrated. In conclusion, our results extend previous observation and suggest that clonal somatic mutations of the CaR gene and allelic loss at the CaR locus on chromosome 3q do not play a major role in the pathogenesis of sporadic parathyroid tumors.