Treatment of Obesity with Thyroid hormones in Europe. Data from the THESIS* Collaboration.

PURPOSE: The use of thyroid hormones (TH) to treat obesity is unsupported by evidence as reflected in international guidelines. We explored views about this practice, and associations with respondent characteristics among European thyroid specialists. METHODS: Specialists from 28 countries were invited to a survey via professional organisations. The relevant question was whether "Thyroid hormones may be indicated in biochemically euthyroid patients with obesity resistant to lifestyle interventions". RESULTS: Of 17,232 invitations 5695 responses were received (33% valid response rate; 65% women; 90% endocrinologists). Of these, 290 (5.1%) stated that TH may be indicated as treatment for obesity in euthyroid patients. This view was commoner among non-endocrinologists (8.7% vs. 4.7%, p < 0.01), private practice (6.5% vs. 4.5%, p < 0.01), and varied geographically (Eastern Europe, 7.3%; Southern Europe, 4.8%; Western Europe, 2.7%; and Northern Europe, 2.5%). Respondents from Northern and Western Europe were less likely to use TH than those from Eastern Europe (p < 0.01). Gross national income (GNI) correlated inversely with this view (OR 0.97, CI: 0.96-0.97; p < 0.001). Having national guidelines on hypothyroidism correlated negatively with treating obesity with TH (OR 0.71, CI: 0.55-0.91). CONCLUSIONS: Despite the lack of evidence, and contrary to guidelines' recommendations, about 5% of respondents stated that TH may be indicated as a treatment for obesity in euthyroid patients resistant to life-style interventions. This opinion was associated with (i) respondent characteristics: being non-endocrinologist, working in private practice, treating a small number of hypothyroid patients annually and (ii) national characteristics: prevalence of obesity, Eastern Europe, low GNI and lack of national hypothyroidism guidelines.

Applying machine learning methods for the analysis of two-dimensional mass spectra.

In a measurement of isomeric yield-ratios in fission, the Phase-Imaging Ion-Cyclotron-Resonance technique, which projects the radial motions of ions in the Penning trap (JYFLTRAP) onto a position-sensitive micro-channel plate detector, has been applied. To obtain the yield ratio, that is the relative population of two states of an isomer pair, a novel analysis procedure has been developed to determine the number of detected ions in each state, as well as corrections for the detector efficiency and decay losses. In order to determine the population of the states in cases where their mass difference is too small to reach full separation, a Bayesian Gaussian Mixture model was implemented. The position-dependent efficiency of the micro-channel plate detector was calibrated by mapping it with 133Cs+ ions, and a Gaussian Process was trained with the position data to construct an efficiency function that could be used to correct the recorded distributions. The obtained numbers of counts of excited and ground-state ions were used to derive the isomeric yield ratio, taking into account decay losses as well as feeding from precursors.

Simvastatin downregulates adipogenesis in 3T3-L1 preadipocytes and orbital fibroblasts from Graves' ophthalmopathy patients.

BACKGROUND: Smoking is a strong risk factor for the development of Graves' ophthalmopathy (GO). Immediate early genes (IEGs) are overexpressed in patients with active GO compared to healthy controls. The aim of this study was to study the effects of tobacco smoking and simvastatin on preadipocytes and orbital fibroblasts (OFs) in the adipogenic process. METHODS: Cigarette smoke extract (CSE) was generated by a validated pump system. Mouse 3T3-L1 preadipocytes or OFs were exposed to 10% CSE with or without simvastatin. Gene expression was studied in preadipocytes and OFs exposed to CSE with or without simvastatin and compared to unexposed cells or cells treated with a differentiation cocktail. RESULTS: In 3T3-L1 preadipocytes, Cyr61, Ptgs2, Egr1 and Zfp36 expression levels were two-fold higher in cells exposed to CSE than in unexposed cells. Simvastatin downregulated the expression of these genes (1.6-fold, 5.5-fold, 3.3-fold, 1.4-fold, respectively). CSE alone could not stimulate preadipocytes to differentiate. Scd1, Ppar-γ and adipogenesis were downregulated in simvastatin-treated preadipocytes compared to nontreated preadipocytes 18-, 35- and 1.7-fold, respectively. In OFs, similar effects of CSE were seen on the expression of CYR61 (1.4-fold) and PTGS2 (3-fold). Simvastatin downregulated adipogenesis, PPAR-γ (2-fold) and SCD (27-fold) expression in OFs. CONCLUSION: CSE upregulated early adipogenic genes in both mouse 3T3-L1 preadipocytes and human OFs but did not by itself induce adipogenesis. Simvastatin inhibited the expression of both early and late adipogenic genes and adipogenesis in preadipocytes and human OFs. The effect of simvastatin should be investigated in a clinical trial of patients with GO.

Proteomics of Orbital Tissue in Thyroid-Associated Orbitopathy.

CONTEXT: A potentially altered protein expression profile in orbital tissue from patients with thyroid-associated orbitopathy (TAO) is suspected. OBJECTIVE: To detect for the first time changes in proteomic patterns of orbital connective tissue in TAO and compare these with control tissue using mass spectrometry. DESIGN: Proteomics cross-sectional, comparative study. SETTING: Two academic endocrine institutions. SAMPLES: A total of 64 orbital and peripheral adipose tissue samples were collected from 39 patients with TAO and 25 control subjects. METHODS: Samples were analyzed and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technology. MAIN OUTCOME MEASURES: Mean intensity values of all identified peptides per protein. RESULTS: Thirty-one proteins were identified, of which 16 differentiated between controls and patients with TAO. Different protein patterns between orbital and peripheral adipose tissue were observed. Compared to controls, 10 proteins were markedly up-regulated (≥ 2-fold) in the orbital tissue of untreated patients: beta IV spectrin (6.2-fold), GTP binding G protein 2 (5.6-fold), POTE ankyrin domain family member F (5.4-fold), xylulokinase (4.1-fold), kinesin family member 1A and lipocalin 1 (both 3.6-fold), semicarbazide-sensitive metalloproteinase amine oxidase 3 and polymerase I transcript release factor (both 3.4-fold), cell-cycle protein elongin A binding protein 1 (3.3-fold), annexin A2 and cavin (both 3-fold), protein pointing to cell proliferation histone H4 (2.8-fold), and ADAM metallopeptidase with thrombospondin type 1 motif 14 (2.7-fold). The highest protein up-regulations were noted in the orbital tissue of medically untreated patients. Steroid therapy markedly reduced up-regulation of these proteins, foremost in nonsmokers. CONCLUSIONS: Proteins involved in tissue inflammation, adipose tissue differentiation, lipid metabolism, and tissue remodeling were up-regulated in orbital tissue of untreated patients with TAO. Steroids decreased the expression of these proteins, whereas smoking attenuated such effect.

Prevalence of migraine headache in an in-patient stroke population.

INTRODUCTION: Migraine, especially with aura, is a risk factor for ischemic stroke. In this study, we investigated descriptive data and prevalence of migraine in an in-patient stroke population. MATERIALS AND METHODS: Patients with acute cerebrovascular disease (CVD) admitted to the stroke unit during a 6-month period were recruited. Prevalence of migraine was assessed using a structured questionnaire. Additional clinical data regarding risk factors for CVD were evaluated for all responding patients. RESULTS: A total of 229 patients received a questionnaire and 175 answers were collected (response frequency of 76.4%). Responders matched the initial cohort regarding distribution of age, sex, and type of stroke. Thirty-six cases (20.6%) fulfilled the criteria for migraine or probable migraine according to the 2nd edition of the International Headache Classification (ICHD-2). Sixty percent of migraine patients had migraine with aura. Stroke patients with migraine were younger (P = 0.007), the presence of patent foramen ovale (PFO) was significantly increased (P = 0.008), and atrial fibrillation was less common (P = 0.048). There were no other differences between patients with and without migraine headache regarding conventional risk factors. CONCLUSIONS: The prevalence of migraine in this hospital-based stroke cohort was comparable to the estimated prevalence of migraine usually described in population studies. In our study population, the prevalence of migraine with aura was higher than expected. The increased prevalence of PFO in patients with migraine headache corresponds well to previous population studies.

First observation of the unbound nucleus 15Ne.

We report on the first observation of the unbound proton-rich nucleus 15Ne. Its ground state and first excited state were populated in two-neutron knockout reactions from a beam of 500 MeV/u 17Ne. The 15Ne ground state is found to be unbound by 2.522(66) MeV. The decay proceeds directly to 13O with simultaneous two-proton emission. No evidence for sequential decay via the energetically allowed 2- and 1- states in 14F is observed. The 15Ne ground state is shown to have a strong configuration with two protons in the (sd) shell around 13O with a 63(5)% (1s1/2)2 component.

Increased TRAb and/or low anti-TPO titers at diagnosis of graves' disease are associated with an increased risk of developing ophthalmopathy after onset.

Patients with low thyroid peroxidase antibodies (anti-TPO) and increased TSH-receptor antibodies (TRAb) at diagnosis of Graves' disease (GD) have been suggested to have an increased risk to develop Graves' ophthalmopathy (GO). The aim was to evaluate if GO development can be predicted.This is an observational study with registration of possible GD and GO risk factors.399 patients with GD were registered 2003-2008 in Malmö, Sweden and out of these 310 were retrospectively followed up to 6 years. The main outcome measures were anti-TPO titer, TRAb titer, smoking habits, radioiodine treatment and GO development.TRAb was assessed with a third generation assay at GD diagnosis in 231 patients. The proportion of patients with GO increased above the median 6.3 IU/L both at diagnosis of GD (p=0.001) and at follow-up (p=0.0001).The distribution of GO patients anti-TPO above or below 20 kIU/L at diagnosis of GD was similar between groups (p=0.239). However at follow-up anti-TPO<20 kIU/L was associated with an increased proportion of newly developed GO as compared to the cohort with anti-TPO>20 kIU/L (p=0.018).87% of patients who developed GO after GD diagnosis had TRAb above 6.3 IU/L and/or anti-TPO below 20 kIU/L. The proportion of GO was doubled in GD patients treated with radioiodine but could not explain the described findingsAnti-TPO<20 kIU/L and/or TRAb>6.3 IE/L at the time of GD diagnosis were associated with an increased risk to develop GO after diagnosis of GD.

Migraine-related ischemic stroke?

INTRODUCTION: Migraine, especially migraine with aura, has been described to be associated with an increased risk for ischemic stroke. An increased incidence of silent lesions in the posterior circulation has also been described. METHOD: Six cases with migraine and stroke in close relation over time were retrospectively reviewed. RESULTS: All patients had previously known MA or MO and suffered from a stroke within the first 24-hour period after an acute migraine attack. None of the patients fulfilled the IHS criteria for migrainous infarction. Four out of these six patients had a patent foramen ovale (PFO) or an atrial septal defect (ASD). DISCUSSION: None of these cases can be categorized as migrainous infarctions according to IHS. However, the migraine attack might have been involved in the mechanisms for the development of the infarctions.

Quantized thermal transport across contacts of rough surfaces.

Heat transport across interfaces is often discussed in terms of the transmission probability of the heat-carrying phonons through the contact zone. Although interface roughness influences the true contact area and affects phonon scattering within the contact zone, its effect on nanoscale heat transport remains poorly understood. Here, we report experimental data on the pressure dependence of thermal transport across polished nanoscale contacts. The data can be quantitatively explained by a model of thermal conductance across interfaces that incorporates the effect of nanoscale roughness through the quantized thermal conductance across individual atomic-scale contacts within the contact zone.

Precise determination of the unperturbed 8B neutrino spectrum.

A measurement of the final state distribution of the (8)B ß decay, obtained by implanting a (8)B beam in a double-sided silicon strip detector, is reported here. The present spectrum is consistent with a recent independent precise measurement performed by our collaboration at the IGISOL facility, Jyväskylä [O. S. Kirsebom et al., Phys. Rev. C 83, 065802 (2011)]. It shows discrepancies with previously measured spectra, leading to differences in the derived neutrino spectrum. Thanks to a low detection threshold, the neutrino spectrum is for the first time directly extracted from the measured final state distribution, thus avoiding the uncertainties related to the extrapolation of R-matrix fits. Combined with the IGISOL data, this leads to an improvement of the overall errors and the extension of the neutrino spectrum at high energy. The new unperturbed neutrino spectrum represents a benchmark for future measurements of the solar neutrino flux as a function of energy.

Maternal autoimmune thyroid disease and the fetal immune system.

OBJECTIVE: Several studies indicate that in utero exposure to maternal autoimmune diseases and transplacental passage of autoantibodies affect the risk of autoimmunity in the offspring, e. g., maternally derived GAD65 autoantibody correlates with decreased risk of type 1 diabetes, whereas thyroid peroxidase autoantibody (TPOAb) positivity at birth is associated with increased incidence of autoimmune thyroid disease later in life. The aim of this study was to identify immunological changes in children born to mothers with thyroid autoimmunity that may be related to in utero exposure to autoantibodies. DESIGN AND METHOD: Open label prospective analysis of cord blood lymphocytes and serum cytokines by Flow Cytometry in children born to mothers with autoimmune thyroiditis (AIT) (n=31) and to healthy mothers (n=76) and titers of thyroid autoantibodies were determined in cord blood and in maternal peripheral blood at delivery. RESULTS: We found an increase (almost 30%) in the frequency of cord blood natural killer (NK) cells (p=0.0016) and a minor increase in the subset of T cells expressing NK markers (p=0.028), in children born to AIT mothers. There were no detectable differences in the phenotype or frequency of cord blood memory/activated T cells, including CD4 (+)CD25 (+) T cells, between the 2 groups. The levels of pro-inflammatory cytokines TNF-α, IL-10, IL-12p70, IFN-γ and IL-1ß were significantly decreased in offspring of AIT mothers as compared to healthy controls. CONCLUSIONS: Maternal thyroid autoimmunity and transplacental passage of autoantibodies against thyroid antigens may affect the generation or expansion of cells with NK activity and the secretion of inflammatory cytokines.

Spectroscopy of 32Ne and the "Island of Inversion".

We report on the first spectroscopic study of the N=22 nucleus 32Ne at the newly completed RIKEN Radioactive Ion Beam Factory. A single gamma-ray line with an energy of 722(9) keV was observed in both inelastic scattering of a 226 MeV/u 32Ne beam on a carbon target and proton removal from 33Na at 245 MeV/u. This transition is assigned to the deexcitation of the first Jpi=2+ state in 32Ne to the 0+ ground state. Interpreted through comparison with state-of-the-art shell-model calculations, the low excitation energy demonstrates that the "island of inversion" extends to at least N=22 for the Ne isotopes.

One-neutron removal measurement reveals 24O as a new doubly magic nucleus.

The first measurement of the momentum distribution for one-neutron removal from (24)O at 920A MeV performed at GSI, Darmstadt is reported. The observed distribution has a width (FWHM) of 99 +/- 4 MeV/c in the projectile rest frame and a one-neutron removal cross section of 63 +/- 7 mb. The results are well explained with a nearly pure 2s_{1/2} neutron spectroscopic factor of 1.74 +/- 0.19 within the eikonal model. This large s-wave probability shows a spherical shell closure thereby confirming earlier suggestions that (24)O is a new doubly magic nucleus.

Immunization of Macaca fascicularis against experimental periodontitis using a vaccine containing cysteine proteases purified from Porphyromonas gingivalis.

INTRODUCTION: Periodontitis is a common infectious disease to which Porphyromonas gingivalis has been closely linked, in which the attachment tissues of the teeth and their alveolar bone housing are destroyed. We conducted a study to determine if immunization using a purified antigen could alter the onset and progression of the disease. METHODS: Using the ligature-induced model of periodontitis in Macaca fascicularis, we immunized five animals with cysteine protease purified from P. gingivalis and used an additional five animals as controls. Alveolar bone loss was measured by digital subtraction radiography. RESULTS: Immunization induced high titers of specific immunoglobuin G serum antibodies that were opsonic. Total bacterial load, levels of P. gingivalis in subgingival plaque and levels of prostaglandin E(2) in gingival crevicular fluid were significantly reduced. Onset and progression of alveolar bone loss was inhibited by approximately 50%. No manifestations of toxicity were observed. CONCLUSIONS: Immunization using a purified protein antigen from P. gingivalis inhibits alveolar bone destruction in a ligature-induced periodontitis model in M. fascicularis.

Differential display analysis of Porphyromonas gingivalis gene activation response to heat and oxidative stress.

BACKGROUND/AIMS: The etiologic relationship between periodontitis and Porphyromonas gingivalis is attributed to the ability of the organism to express a variety of virulence factors, many of which are cell surface components including lipopolysaccharide and arginine-specific cysteine proteases (Arg-gingipains, RgpA, and RgpB). P. gingivalis responds to the stress of rapid elevation in temperature by activating a set of genes to produce heat shock proteins that mediate the effects of sudden changes in environmental temperatures by repairing or eliminating cellular proteins denatured by that stress. METHODS: We used restriction fragment differential display (RFDD) to identify and measure the genes expressed by surrogates of environmental stresses, heat and oxidative stress. The results were then confirmed using quantitative reverse-transcription polymerase chain reaction. RESULTS: We selected 16 genes differentially induced from over 800 total expression fragments on the RFDD gels for further characterization. With primers designed from those fragments we found that a + 5 degrees C heat shock caused a statistically significant increase in expression compared 12 of 18 untreated genes tested. The exposure of P. gingivalis to atmospheric oxygen resulted in statistically significant increases in five of the target genes. These genes are likely involved in transport and synthesis of components of the lipopolysaccharide biosynthetic pathway important in anchoring the Arg-gingipains required for virulence-related activities. CONCLUSION: These results emphasize the need for studies to measure the coordinated responses of bacteria like P. gingivalis which use a multitude of interrelated metabolic activities to survive the environmental hazards of the infection process.

Educating the next generation of dentists.

A new vision for dental education is being shaped by (1) future dentists' need to keep pace with rapid developments in medicine and biomedical science, and changing health-care delivery mechanisms that will transform dentistry; (2) dissatisfaction with unintended, undesirable consequences of traditional approaches to dental education that do not integrate biomedical/clinical, behavioral, ethical, and population perspectives in clinical practice, and fail to cultivate the skills and values which support lifelong learning; (3) new developments in cognitive science demonstrating learning environments' need to be more student-centered, to emphasize active learning strategies, and teach students to use the scientific method to resolve clinical problems. These changes will require efforts in faculty development, and have implications for the administration and function of dental schools.

Reliability and validity of a chronic care facility adaptation of the Clinical Dementia Rating scale.

OBJECTIVE: This study investigated the reliability and validity of a chronic care facility adaptation of the Clinical Dementia Rating scale (CDR-CC). METHOD: Sixty-two residents in a chronic care facility participated in an inter-rater and 1 month test-retest reliability study. The instrument was validated against the Mini-Mental State Examination (MMSE). RESULTS: Inter-rater and 1 month test-retest reliability for the global CDR-CC score were excellent (intraclass correlation coefficients 0.99 and 0.92, respectively). The CDR-CC domain and global scores were negatively correlated with the MMSE. CONCLUSIONS: The CDR-CC is a global assessment tool that reliably and validly measures cognitive and functional impairment in a chronic care setting.

Suicide in late life. Identifying and managing at-risk older patients.

The patient in this case displayed multiple risk factors for suicide, including depression, loneliness following recent widowhood, use of alcohol, and distribution of possessions to other people. In retrospect, it was found that he was stockpiling old medications and refused to comply with his plan of care. The patient's outcome was tragic despite numerous attempts to provide a support system to meet his needs. Although he appeared to improve with therapy, the patient may have had a suicidal agenda that he managed to hide from everyone, including his family and multiple healthcare professionals. The patient's daughter was offered bereavement counseling services, which she appreciated.

Alternative medicine. Achieving balance between herbal remedies and medical therapy.

The case patient was taking multiple herbal preparations as well as the prescription hypnotic zolpidem. The combination was probably increasing the patient's confusion, agitation, and aggression. The treatment team reached a compromise with the daughter after providing her with education and support. They continued the wheat germ oil and a multivitamin supplement, which appeared safe, even if of limited value. The patient continued taking valproate, 125 mg bid, which reduced her physical aggression and improved resistance to care. All other herbal remedies and zolpidem were discontinued. Balancing traditional therapies with requests for herbal remedies is a common challenge for physicians. The most successful intervention occurs when doctors familiarize themselves with herbal preparations and educate patients and families about the treatments.