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Half of the women who sustain a hip fracture would not qualify for osteoporosis treatment based on current DXA-estimated bone mineral density criteria. Therefore, a better approach is needed to determine if an individual is at risk of hip fracture from a fall. The objective of this study was to determine the association between radiation-free MRI-derived bone strength and strain simulations compared to results from direct mechanical testing of cadaveric femora. Imaging was conducted on a 3-Tesla MRI scanner using two sequences: one balanced steady-state free precession sequence with 300 μm isotropic voxel size and one spoiled gradient echo with anisotropic voxel size of 234 × 234 × 1500 μm. Femora were dissected free of soft-tissue and 4350-ohm strain-gauges were securely applied to surfaces at the femoral shaft, inferior neck, greater trochanter, and superior neck. Cadavers were mechanically tested with a hydraulic universal test frame to simulate loading in a sideways fall orientation. Sideways fall forces were simulated on MRI-based finite element meshes and bone stiffness, failure force, and force for plastic deformation were computed. Simulated bone strength metrics from the 300 μm isotropic sequence showed strong agreement with experimentally obtained values of bone strength, with stiffness (r = 0.88, p = 0.0002), plastic deformation point (r = 0.89, p 0.0001), and failure force (r = 0.92, p 0.0001). The anisotropic sequence showed similar trends for stiffness, plastic deformation point, and failure force (r = 0.68, 0.70, 0.84; p = 0.02, 0.01, 0.0006, respectively). Surface strain-gauge measurements showed moderate to strong agreement with simulated magnitude strain values at the greater trochanter, superior neck, and inferior neck (r = -0.97, -0.86, 0.80; p ≤0.0001, 0.003, 0.03, respectively). The findings from this study support the use of MRI-based FE analysis of the hip to reliably predict the mechanical competence of the human femur in clinical settings.

SummaryA global rising organ shortage necessitates the use of extended criteria donors (ECD) for liver transplantation (LT). However, poor preservation and extensive ischemic injury of ECD grafts have been recognized as important factors associated with primary non-function, early allograft dysfunction, and biliary complications after LT. In order to prevent for these ischemia-related complications, machine perfusion (MP) has gained interest as a technique to optimize preservation of grafts and to provide the opportunity to assess graft quality by screening for extensive ischemic injury. For this purpose, however, objective surrogate biomarkers are required which can be easily determined at time of graft preservation and the various techniques of MP. This review provides an overview and evaluation of biomarkers that have been investigated for the assessment of graft quality and viability testing during different types of MP. Moreover, studies regarding conventional graft preservation by static cold storage (SCS) were screened to identify biomarkers that correlated with either allograft dysfunction or biliary complications after LT and which could potentially be applied as predictive markers during MP. The pros and cons of the different biomaterials that are available for biomarker research during graft preservation are discussed, accompanied with suggestions for future research. Though many studies are currently still in the experimental setting or of low evidence level due to small cohort sizes, the biomarkers presented in this review provide a useful handle to monitor recovery of ECD grafts during clinical MP in the near future.

Treatment options for arthrofibrosis following total knee arthroplasty include manipulation under anesthesia, open or arthroscopic arthrolysis, and revision surgery to correct identifiable problems. We propose preoperative low-dose irradiation and Constrained Condylar or Rotating-hinge revision for severe, idiopathic arthrofibrosis. Irradiation may decrease fibro-osseous proliferation while constrained implants allow femoral shortening and release of contracted collateral ligaments. Fourteen patients underwent fifteen procedures for a mean overall motion of 46° and flexion contracture of 30°. One patient had worsening range of motion while thirteen patients had 57° mean gain in range of motion (range 5°-90°). Flexion contractures decreased by a mean of 28°. There were no significant complications at a mean follow up of 34 months (range 24 to 74 months).

Ischemic-type biliary lesions (ITBL) are the most frequent cause of nonanastomotic biliary strictures after liver transplantation. This complication develops in up to 25% of patients, with a 50% retransplantation rate in affected patients. Traditionally, ischemia-reperfusion injury to the biliary system is considered to be the major risk factor for ITBL. Several other risk factors for ITBL have been identified, including the use of liver grafts donated after cardiac death, prolonged cold and warm ischemic times and use of University of Wisconsin preservation solution. In recent years however, impaired microcirculation of the peribiliary plexus (PBP) has been implicated as a possible risk factor. It is widely accepted that the PBP is exclusively provided by blood from the hepatic artery, and therefore, the role of the portal venous blood supply has not been considered as a possible cause for the development of ITBL. In this short report, we present three patients with segmental portal vein thrombosis and subsequent development of ITBL in the affected segments in the presence of normal arterial blood flow. This suggests that portal blood flow may have an important contribution to the biliary microcirculation and that a compromised portal venous blood supply can predispose to the development of ITBL.

The People's Republic of China foresees a target of 30 GW for installed wind power capacity by 2010 (2008: 12 GW). This paper reports on the technical and economic potentials of wind power, the recent development, existing obstacles, and related policies in China. The barriers to further commercialization of the wind power market are important and may deter the 100 GW capacity target of the Chinese government by 2020. The paper concludes that the diffusion of wind power in China is an important element for not only reducing global greenhouse gas emissions, but also for worldwide progress of wind power technology and needed economies of scale.

Activating BRAF mutations have been reported in 40% of papillary thyroid carcinomas (PTCs). The involvement of BRAF pseudogene in thyroid tumorigenesis has not previously been studied. We investigated BRAF pseudogene expression in 68 thyroid tumors: 16 multinodular goiters, 43 classic PTCs, 6 follicular variants of PTC, and 3 anaplastic thyroid carcinomas. BRAF pseudogene function was studied by Western blots, soft agar assay, and tumorigenesis in nude mice. BRAF pseudogene expression was detected in 7 multinodular goiters, 18 classic PTC, and 1 follicular variants of PTC. There is an inverse correlation between BRAF pseudogene expression and BRAF mutation. The pseudogene transcripts were more frequently detected in tumors without BRAF mutation than those with BRAF mutation. Furthermore, BRAF pseudogene expression could activate the MAP kinase signaling pathway, transform NIH3T3 cells in vitro, and induce tumors in nude mice. These data suggest that BRAF pseudogene activation may play a role in thyroid tumor development.

The rapidly escalating number of genome sequences has emphasized the basic tenants of the schema of life. By the same token comparisons according to specialized function or niche within nature expose genomic strategies to optimize the use of resources and ensure biological success. Increasing complexity may result from diversification, shuffling, and re-arrangement of an otherwise limited functional genomic complement. To further test the concept of relative structural plasticity of the TSH receptor we sequenced the TSHR gene of two Old World monkey species Macaca mulatta and Cercopithecus aethiops , evolutionary removed from Homo sapiens by >20 Myr. Both genes encoded a protein of 764 residues. This structure was 99% homologous between the two species of Old World monkeys while C. aethiops was 97% and M. mulatta was 96% homologous to H. sapiens . TSHR sequence comparisons were sought for an additional eight mammals as well as four (two Salmon, Tilapia, and Sea Bass) from teleosts. The amino-acid sequences of the 14 TSH receptors were similar. The most variable sequences were those of the intracellular tail and the distal cysteine-rich C-terminus flanking region of the ectodomain, whereas the trans-membrane domain was most preserved. Some sequences were decidedly H. sapiens specific, while others were primate specific or showed the changes expected of evolutionary descent. Others, however, exhibited “cross-species polymorphism,” sometimes at quite remarkable evolutionary distances. As opposed to H. sapiens the sequence differences may have subtle influences on TSHR function or may affect long-range compensation for radical changes in adducts. The two Old World monkeys share with other lower mammals the absence of a glycosylation site at 113–115. Sea Bass and Tilapia have four glycosylation sites, whereas the two salmon receptors have only three. Changes in some critical residues raise questions about variation in function: thus S281 is conserved in all mammals and an important determinant of negative agonist function of TSHR is replaced by R in Sea Bass. Likewise the K183, found at an important transitional region at LRR 6 conserved in all mammals, is represented by M in fish and may contribute to TSHR lutenization in fish. There is no evidence that evolutionary changes in primate receptors are more rapid than that in other mammals and the separation times of different mammals based on silent nucleotide changes of TSHR are closely parallel to archaeological estimates. Results of correlated mutation analysis, referenced to the rhodopsin crystal structure, affirms dimerization of TSHR transmembrane helices. In addition, it suggests the involvement of critical lipid-facing residues in the helices in receptor dimerization and oligomerization. We highlight the value of evolutionary informatics and set the stage for dissecting out potential subtle differences in TSHR function associated with structural variations.

p53 is a transcription factor with multifaceted regulatory functions in cell cycle progression, DNA repair, and programmed cell death. Inactivating mutations have been described in 50% of human cancers. These mutations appear to be important in tumor progression and response to chemotherapy and radiation treatment and thus clinical outcome. p53 mutations are found in 14% of malignant thyroid tumors and are more frequent in poorly differentiated and anaplastic tumors. Given that p53 is a late event in the notional multistep pathogenesis of cancer, we examined its mutation rates as a measure of genomic instability (hypermutability) of malignant thyroid tumors and also wondered whether radiation enhances that proclivity to genomic instability. To that end we have extracted all available data from the p53 mutation database (http://www.perso@curie.fr), verified, extended, where applicable, and supplemented that information from published reports. We were able to identify 100 entries. The distribution of the p53 mutational events--deletions/insertions, transitions versus transversion mutations--was similar to that of the database as a whole. The silent mutation rate of 17.8%, not different from the expected 25%, is consistent with a random occurrence of these mutations. The silent mutation rate is 120 times that expected and is 6 times that of the database. Moreover, the distribution of p53 mutations is compatible with Poisson's distribution, which taken with silent mutation rates indicates that p53 is particularly hypermutable in thyroid carcinomas. Epigenetic deamination of CpG dinucleotide at highly oncogenic DNA-contact residues is a feature of poorly differentiated tumors and thus associated with tumor progression. The rates of p53 mutations (15.4%) in radiation-related cancers were very similar to those in apparently spontaneously arising tumors, although there was a highly significant heterogeneity (P0.0005) in the residues mutated. None involved CpG deamination. It is apparent that thyroid cancer exhibits remarkable genomic instability evidenced by p53 hypermutability. Spontaneous epigenetic mutational events are involved in tumor progression and while radiation increases the absolute prevalence of thyroid cancer in the susceptible it does not increase the rate of p53 mutation and seemingly targets different non-DNA-contact residues than those in spontaneously arising tumors.

Recently, in vitro production of interleukin-2 receptor induced by mitogens have been shown to be impaired in autoimmune disorders including organo-specific autoimmune diseases. The aim of this study was to investigate serum levels of soluble interleukin-2 receptor in 20 untreated patients with Graves' disease and to follow up their changes in relation to clinical picture and TSH-receptor-, anti-thyroglobulin-, anti-microsomal as well as anti-eye muscle antibodies. Soluble interleukin-2 receptor level was significantly increased in newly-diagnosed Graves' patients compared to controls (667 +/- 270 vs. 205 +/- 45 U/ml) (P less than 0.001). Among the patients sera those with active infiltrative ophthalmopathy had higher soluble interleukin-2 receptor levels than those without eye symptoms (810 +/- 313 vs. 525 +/- 180 U/ml). Soluble interleukin-2 receptor level was normalized in Methimazole-treatment-induced remission in the majority of patients except those with ophthalopathy. In five patients the soluble interleukin-2 receptor levels were studied after interruption of thyrostatic therapy; an increase was observed in three patients; thereafter hyperthyrosis relapsed in two cases. Furthermore, a correlation was found between soluble interleukin-2 receptor levels and TSH-receptor antibodies, however, the association with other immune parameters examined was not significant. In conclusion, an enhanced level of soluble interleukin-2 receptor was detected in patients with untreated Graves' disease. This finding might play a significant role in regulation of impaired cell-mediated immune mechanism and has a prognostic value for relapse of autoreactive processes.

In Eastern Hungary, vitiligo is found to be associated with HLA-DR1. When other autoimmune disorders are also present, DR3 is also increased.

Rationale Asthma is a very complex disease whose cause remains unknown. Little is known about the possible mechanism of selenium at more basic layers of the pathogenesis of allergic disorders. Objectives We aimed to investigate the possible role of decreased selenium status in allergic diseases and to elucidate whether a correlation exists between Th1/Th2 cytokines profiles and selenium status. Methods Thirty-three patients with allergic rhinitis (AR), 21 allergic asthmatic (AA) and 28 healthy controls were included in a case control study. Serum levels of selenium, IL-4, IL-10 and IFNγ were measured. Results Mean serum selenium levels of allergic patients (84 ± 11 and 82 ± 10 μg/l in AA and AR groups respectively) were significantly lower than controls (106 ± 11μg/l) (p Conclusion This study showed that lowered selenium status may have an important role in the pathogenesis of allergic diseases and more importantly that this decreased serum level is correlated with Th2 cytokines profile predominance.

A serological survey of human T-cell lymphotropic virus type 1 (HTLV-1) antibodies was undertaken when sporadic cases of adult T-cell leukaemia were reported from Mashhad in northeastern Iran. Our findings in this study indicate that 35 of the 1511 serum samples were positive (2.3%) and the polymerase chain reaction (PCR) study showed that the virus which originated in Mashhad is classical HTLV-1 belonging to the cosmopolitan molecular group.

We studied four families with prolactin-secreting pituitary tumors as part of multiple endocrine neoplasia syndrome type I (MEN I). The propositus in family A had galactorrhea-amenorrhea and an enlarged sella turcica at the time of parathyroidectomy. Family studies showed that her mother had prolactinoma and primary hyper-parathyroidism, one of three uncles had primary hyperparathyroidism, and two sisters had prolactin-secreting adenomas, All affected family members shared the HLA haplotype: A1, B8, Cw-, DR3; linkage with HLA could not be excluded. The proband in family B had prolactinoma, primary hyperparathyroidism and primary hypothyroidism associated with a high-lying vestigial thyroid. The proband's father had primary hyperparathyroidism and thymic carcinoid, and two uncles had primary hyperparathyroidism. The proband and father shared the haplotype A2, B8, Cw-, DR3. In family C the proband had primary hyperparathyroidism and prolactinoma. Three of her sisters had primary hyperparathyroidism. One sister, who also had carcinoid tumor of the lung and a prolactinoma, married an affected member of family D; a daughter had prolactinoma and metastatic thymic carcinoid. Both proband and sister were 46 xx/xo and shared the haplotype A1, B8, Cw-, DR3. The fourth propositus, a member of family D reputed to have familial primary hyperparathyroidism, was found to have a prolactinoma four years following parathyroidectomy. One of the patient's affected uncles also had a pituitary tumor. The haplotype involved was Aw24, B35, Cw-. We conclude that (1) prolactinomas are an integral part of MEN I; (2) the syndrome may be associated with aberrant organ migration and chromosomal separation; (3) MEN I is associated with A1, B8; evidence for genetic linkage being inconclusive; (4) patients may harbor other tumors including thymic carcinoid.

We have expanded our early observation that a potent Graves' IgG preparation induces HLA-DR expression on thyroid cells, by showing that four randomly-selected Graves' IgG's were also capable of inducing DR antigens on thyroid cells. The effect of Graves' IgG was specific to thyroid cells, as it did not induce MHC Class II molecule expression on endothelial cells whereas interferon-γ and immune complexes did so. The anti-thyroid drug methimazole was capable of rapidly reducing Graves' IgG-induced DR expression but to a much lesser extent than brought about by interferon-γ. We conclude that Graves' IgG propagates thyroid-specific autoaggression by continued induction of DR antigens and than an important means whereby methimazole brings about remission is by reducing this induction.

Both positive and negative ion-molecule reactions of alkyl nitrites have been examined using the techniques of ion cyclotron resonance spectroscopy. In the case of positive ion-molecule reactions a variety of NO + transfer and hydride abstraction reactions dominate the ion chemistry. In all of the nitrites reaction sequences lead to the production of relatively stable nitrito alkyl cations. The negative ion-molecule reactions are characterized by NO 2 - production by nucleophilic displacement reactions and enolate formation via proton transfer and loss of NO. The proton affinities of each of the nitrites studied have been determined and compared to the gas phase basicities of the corresponding alcohols.

We have investigated factors which influence HLA-DR expression on thyroid cells. While bTSH (100 mU/ml) did not enhance HLA-DR expression, it increased when brought about by IFN-γ. Graves' IgG showed a dose-dependent (0.1–2 mg/ml) increase in DR expression and at a concentration of 2 mg/ml prolonged the time for which DR was expressed. The pathway of DR induction by Graves' IgG apparently differs from that by IFN-γ. The humoral response in Graves' disease, by inducing DR expression, may be instrumental in propagating thyroid specific autoimmunity.

A class of anti-idiotypes raised against antibodies specific for hormones or drugs would be anticipated to interact with their respective receptors. We have raised anti-TSH anti-idiotypic antibodies and found these to interact with the high affinity binding site for TSH on thyroid membranes, to induce adenylate cyclase activation and iodide transport into dispersed thyroid cells as well as to promote their organization into follicular structures. The anti-TSH anti-idiotypic antibody interacted with an Mr approximately 200,000 holoreceptor on protein blots of thyroid membranes resolved on SDS-PAGE in the absence of reductant. In another set of experiments we raised anti-idiotypic antibodies against monoclonal antibodies specific for the alpha and beta subunits of TSH, respectively. Neither the alpha nor beta monoclonal antibody-specific anti-idiotypic antibodies interacted with the TSH holoreceptor. The combinations of the two anti-idiotypic antibodies, however, did so and increased basal cyclase activity compared to normal IgG and individual anti-idiotypes as well as mediating TSH-specific cAMP dependent physiologic changes. As a result of the second set of experiments, we propose that the interaction of TSH with its receptor involves two cooperative signals delivered by the two subunits rather than a single signal requiring their combination. Anti-idiotypic antibodies raised against highly purified hormones can be obtained in large amounts. They facilitate simple isolation of hormone receptors and are useful as probes for hormone-receptor interactions.

Thyrocytes were isolated from porcine thyroid glands using a new method entailing two-step collagenase digestion and Percoll gradient centrifugation. Good yield and a high percentage of viabile thyrocytes free from other contaminating cells was achieved. Proteins present on the surface of thyroid cell plasma membranes were then specifically labeled using Iodogen and 125 I − . Membrane lysates were separated by electrophoresis on 10% polyacrylamide gel, under reducing and nonreducing conditions, followed by autoradiography. When the gels were stained with silver nitrate some 30 bands were visualized in both the presence and absence of reductant. Only 9 bands were found to be labeled under nonreducing conditions and 12 in the presence of reductant. Two bands involved in the thyrotropin receptor structure— M r = 66,000 and M r = 70,000, respectively—were visualized in the absence of reductant. Upon reduction the M r 66,000 band was retained and a new band ( M r = 33,000) was seen. The mild enzymatic treatment used in isolating thyrocytes and the lack of contamination with other cells allowed the consistent labeling of exposed plasma membrane components by the Iodogen method such that the orientation of thyrotropin receptor components in the plasma membrane could be deduced.

The loci determining polymorphism of genes involved in the immune response feature prominently in the susceptibility to autoimmune thyroid disease. However, disease phenotypes do not segregate perfectly with the genetic markers. The interaction between the influence of these loci on susceptibility is complex, and when taken in the context of the multilayered, multidirectional workings of the immune network and that of as-yet-unspecified environmental factors, our difficulty in predicting the susceptible phenotypes is not surprising.

A patient presenting a recurrent episode of pulmonary leiomyomatosis has been treated with the LH-RH agonist buserelin at a dosage of 200 micrograms tid SC for 7 days, then 500 micrograms SC daily for a total period of 6 months. Basal serum E2 was suppressed during treatment and varied between 62 and 180 pmol/ml (mean, 129.4 +/- 14.5). Pulmonary symptoms completely disappeared during treatment, but no objective regression of the pulmonary lesions was observed. Because of the uncertainty of response of benign metastasizing leiomyomas to castration and because of the reversibility of the medical treatment, LH-RH agonist may be preferred to surgical castration in this pathology.