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A 55-year-old male patient under permanent testosterone therapy for hypogonadism presented with abdominal pain and increased blood pressure values. In the physical examination a plethora was noted and laboratory examinations revealed polyglobulia. In the subsequent diagnostic process polycythemia vera and cancer could be excluded as the cause. A secondary polyglobulia due to testosterone substitution was diagnosed. Unphysiologically high testosterone levels represent a rare cause of secondary polyglobulia and with an appropriate medical history should be taken into account at an early stage.
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Androgênios/efeitos adversos , Terapia de Reposição Hormonal/efeitos adversos , Policitemia/induzido quimicamente , Testosterona/efeitos adversos , Dor Abdominal/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Hipogonadismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Policitemia Vera/diagnósticoRESUMO
The spin texture of the unoccupied bands of the surface alloy Bi/Ag(111) is investigated with spin- and angle-resolved inverse photoemission and first-principles calculations. Surprisingly, the measured spin character does not always reflect the calculated spin texture of the bands. With the help of photoemission calculations within the one-step model, however, the discrepancy is traced back to the influence of the orbital symmetry of the respective states in combination with the experimental geometry. In particular, the calculations show that the spin texture of a surface band with mixed orbital symmetries may neither be recovered with s- nor p- nor unpolarized light. In general, spin information from direct or inverse photoemission experiments on electronic states with mixed orbital symmetries at spin-orbit-influenced surfaces has to be taken with a pinch of salt, while it remains reliable for states with pure symmetry.
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Islets of patients with type 2 diabetes display the typical features of an inflammatory process characterized by the presence of cytokines, chemokines, immune cell infiltration, impaired function and tissue destruction with fibrotic areas. Functional studies have shown that targeting inflammation may improve insulin secretion and sensitivity. In particular clinical proof of concept studies using modulators of the interleukin-1ß (IL-1ß)-nuclear factor--κB (NF-κB) pathway demonstrated the role of the innate immune system in type 2 diabetes. This programme has now entered the phase 3 of clinical development. Other targets such as tumour necrosis factor α (TNFα) may be equally important but have been neglected based on poorly designed studies. In this article we discuss the mechanisms of islet inflammation in type 2 diabetes and review the opportunity of clinical translation.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Inflamação/prevenção & controle , Terapia de Alvo Molecular , Animais , Diabetes Mellitus Tipo 2/complicações , Humanos , Inflamação/complicações , Ilhotas Pancreáticas/patologiaRESUMO
The surface of W(110) exhibits a Dirac-cone-like state with d character within a spin-orbit-induced symmetry gap. As a function of the wave vector parallel to the surface, it shows a nearly massless energy dispersion and a pronounced spin polarization, which is antisymmetric with respect to the Brillouin zone center. In addition, the observed constant energy contours are strongly anisotropic for all energies. This discovery opens new pathways to the study of surface spin-density waves arising from a strong Fermi surface nesting as well as d-electron-based topological properties.
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Recent studies suggest an inflammatory process, characterized by local cytokine/chemokine production and immune cell infiltration, regulates islet dysfunction and insulin resistance in type 2 diabetes. However, the factor initiating this inflammatory response is not known. Here, we characterized tissue inflammation in the type 2 diabetic GK rat with a focus on the pancreatic islet and investigated a role for IL-1. GK rat islets, previously characterized by increased macrophage infiltration, displayed increased expression of several inflammatory markers including IL-1beta. In the periphery, increased expression of IL-1beta was observed primarily in the liver. Specific blockade of IL-1 activity by the IL-1 receptor antagonist (IL-1Ra) reduced the release of inflammatory cytokines/chemokines from GK islets in vitro and from mouse islets exposed to metabolic stress. Islets from mice deficient in IL-1beta or MyD88 challenged with glucose and palmitate in vitro also produced significantly less IL-6 and chemokines. In vivo, treatment of GK rats with IL-1Ra decreased hyperglycemia, reduced the proinsulin/insulin ratio, and improved insulin sensitivity. In addition, islet-derived proinflammatory cytokines/chemokines (IL-1beta, IL-6, TNFalpha, KC, MCP-1, and MIP-1alpha) and islet CD68(+), MHC II(+), and CD53(+) immune cell infiltration were reduced by IL-1Ra treatment. Treated GK rats also exhibited fewer markers of inflammation in the liver. We conclude that elevated islet IL-1beta activity in the GK rat promotes cytokine and chemokine expression, leading to the recruitment of innate immune cells. Rather than being directly cytotoxic, IL-1beta may drive tissue inflammation that impacts on both beta cell functional mass and insulin sensitivity in type 2 diabetes.
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Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hiperglicemia/patologia , Inflamação/patologia , Interleucina-1/antagonistas & inibidores , Interleucina-1/metabolismo , Ilhotas Pancreáticas/metabolismo , Animais , Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Antígenos de Diferenciação de Linfócitos T/biossíntese , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Ratos , Ratos Wistar , Tetraspanina 25RESUMO
The spin-dependent lifetimes of hot electrons in fcc Co films were studied by spin- and time-resolved two-photon photoemission. Even for excitation energies close to the Fermi level, we find almost identical lifetimes for majority and minority electrons. This result contradicts ab initio theories predicting 5 to 10 times longer lifetimes for the majority electrons in 3d ferromagnets. We provide direct experimental evidence that this discrepancy is caused by the dominance of exchange scattering in inelastic electron decay, in combination with the excitation of secondary electrons. The latter are inherent for all real materials and devices.
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In a combined experimental and theoretical study, we investigated how Fe and Co adlayers on W(110) affect the Dirac-type surface state (DSS). Angle-resolved photoelectron spectroscopy data show an increase in binding energy of 75 meV and 107 meV for Fe and Co, respectively. In order to identify the origin of the energy shift we performed first-principles calculations of the surface electronic structure. The inward surface relaxation of the uncovered W(110) surface is lifted by the adlayers. This structural change is one reason of the energy shift of the DSS. Furthermore, the Fe and Co adlayers change the surface potential, which results in an additional energy shift of the DSS.
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The magnetic exchange splitting of electronic states in a 7 monolayer Fe film on Cu(001) was investigated below and above the Curie temperature T(C), using image-potential surface states as sensor. At T(C), the long-range magnetic order breaks down as reflected by a vanishing spin splitting and vanishing spin polarization. The exchange splitting, in contrast, does not change abruptly at T(C) but persists up to T=1.2T(C). Equally, the spin-integrated linewidth shows no signature of the magnetic phase transition but smoothly decreases with increasing temperature. Our experimental results confirm theoretical expectations that, at T(C), the long-range magnetic order disappears but the local magnetic moments and, in particular, the valence electronic structure are unaffected by the phase transition.
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We report on a combined experimental and theoretical study of the spin-dependent relaxation processes in the electron system of an iron film on Cu(100). Spin-, time-, energy- and angle-resolved two-photon photoemission shows a strong characteristic dependence of the lifetime of photoexcited electrons on their spin and energy. Ab initio calculations as well as a many-body treatment corroborate that the observed properties are determined by relaxation processes involving magnon emission. Thereby we demonstrate that magnon emission by hot electrons occurs on the femtosecond time scale and thus provides a significant source of ultrafast spin-flip processes. Furthermore, engineering of the magnon spectrum paves the way for tuning the dynamic properties of magnetic materials.
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Spin-dependent reflection of low-energy electrons at the W(110) surface caused by spin-orbit interaction was studied experimentally and theoretically. Comprehensive information for a wide range of electron incidence angles and energies was collected via maps for the reflectivity, the spin-dependent reflection asymmetry, and the figure of merit of the spin separation. The experimental results are compared with calculations of the scattering process using a realistic surface potential barrier. The results are discussed in view of possible applications of W(110) as a scattering target in spin-polarization detectors. Possible working points for use in single- as well as multi-channel spin-polarization-detection devices are identified and discussed.
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AIMS/HYPOTHESIS: In vitro studies point to a toxic effect of high glucose and non-esterified fatty acids on beta cells. Whether elevated levels of glucose and lipids induce beta cell loss in vivo is less clear. The domestic cat has recently been proposed as a valuable animal model for human type 2 diabetes because feline diabetes shows several similarities with diabetes in humans, including obesity-induced insulin resistance, impaired beta cell function, decreased number of beta cells and pancreatic amyloid deposition. METHODS: We infused healthy cats with glucose or lipids for 10 days to clamp their blood concentrations at the approximate level found in untreated feline diabetes (glucose: 25-30 mmol/l; triacylglycerols: 3-7 mmol/l). RESULTS: Glucose and lipid levels were adequately targeted. Plasma non-esterified fatty acids were increased by lipid infusion 1.7-fold. A dramatic and progressive decline of plasma insulin levels was observed in glucose-infused cats beginning after 2 days of hyperglycaemic clamp. In contrast, plasma insulin concentration and glucose tolerance test were not affected by hyperlipidaemia. Compared with controls, glucose-infused cats had a 50% decrease in beta cells per pancreatic area. Apoptotic islet cells and cleaved caspase-3-positive beta cells were observed in glucose-infused cats only. CONCLUSIONS/INTERPRETATION: Sustained hyperglycaemia but not hyperlipidaemia induces early and severe beta cell dysfunction in cats, and excess glucose causes beta cell loss via apoptosis in vivo. Hyperglycaemic clamps in cats may provide a good model to study the pathogenesis of glucose toxicity in beta cells.
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Doenças do Gato/fisiopatologia , Hiperglicemia/veterinária , Hiperlipidemias/veterinária , Células Secretoras de Insulina/fisiologia , Animais , Animais Domésticos , Glicemia/metabolismo , Gatos , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/toxicidade , Hiperglicemia/fisiopatologia , Hiperlipidemias/fisiopatologia , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , MasculinoRESUMO
The scientific enthusiasm for ultrathin Fe films on Cu(001) has now lasted for more than 20 years. Is there ferromagnetic iron with a face-centred cubic (fcc) structure? Does ferromagnetism in Fe hinge on the body-centred cubic (bcc) structure? In this contribution, we try to establish that the electron system gives evidence of ferromagnetic behaviour with fcc-like electronic bands. We examine a crystal-induced surface state, which is characteristic of fcc surface order. Furthermore, we compare electronic signatures of fcc and bcc: the d-band exchange splitting, image-potential-state energies and the work function. We conclude that, from the viewpoint of the electronic structure, Fe on Cu(001) is found to be ferromagnetic throughout the fcc-like phase. This result raises a new question: how much deviation from the relaxed fcc order is acceptable without losing the electronic signature of fcc?
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AIM: Prevalence, optimal diagnostic approach and consequences of clinically unsuspected osteomyelitis in diabetic foot ulcers are unclear. Early diagnosis of this infection may be crucial to ensure correct management. METHODS: We conducted a prospective study in 20 diabetic patients with a chronic foot ulcer (>8 weeks) without antibiotic pretreatment and without clinical signs for osteomyelitis to assess the prevalence of clinically unsuspected osteomyelitis and to compare the value of magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and 99mTc-labelled monoclonal antigranulocyte antibody scintigraphy (99mTc-MOAB). Those with suggestive scans underwent bone biopsy for histology (n = 7). RESULTS: Osteomyelitis was confirmed by biopsy in seven of the 20 clinically unsuspected foot ulcers. Presence of osteomyelitis was not related to age, ulcer size, ulcer duration, duration of diabetes or HbA1c. C-reactive protein was slightly elevated in patients with osteomyelitis (35.1 +/- 16.0 mg L(-1) vs. 12.2 +/- 2.6 mg L(-1) in patients with and without osteomyelitis respectively; P = 0.07). MRI was positive in six of the seven patients with proven osteomyelitis, whereas 18F-FDG PET and 99mTc-MOAB were positive only in (the same) two patients. Of the seven patients with osteomyelitis, five had lower limb amputation and in one patient the ulcer was persisting after 24 months of follow-up. In contrast, of the 13 patients without detectable signs of osteomyelitis on imaging modalities only two had lower limb amputation and two persisting ulcers. CONCLUSIONS: Clinically unsuspected osteomyelitis is frequent in persisting foot ulcers and is a high risk factor for adverse outcome. MRI appears superior to 18F-FDG PET and 99mTc-MOAB in detecting foot ulcer-associated osteomyelitis and might be the preferred imaging modality in patients with nonhealing diabetic foot ulcers.
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Pé Diabético/diagnóstico por imagem , Fluordesoxiglucose F18 , Imageamento por Ressonância Magnética , Osteomielite/diagnóstico , Compostos Radiofarmacêuticos , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Pé Diabético/complicações , Pé Diabético/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Tomografia por Emissão de Pósitrons , Radiografia , Staphylococcus aureus/isolamento & purificaçãoRESUMO
Islets of patients with type 2 diabetes have the feature of an inflammatory process reflected by the presence of cytokines, immune cells, beta-cell apoptosis, amyloid deposits and fibrosis. Indeed, beta-cells from patients with type 2 diabetes display inflammatory markers, including increased interleukin (IL)-1 beta expression. Furthermore, increased islet-associated macrophages are observed in human type 2 diabetic patients and in most animal models of diabetes. Importantly, increased numbers of macrophages are detectable very early in high fat-fed mice islets, before the onset of diabetes. These immune cells are most likely attracted by islet-derived chemokines, produced in response to metabolic stress, and under the control of IL-1 beta. It follows that modulation of intra-islet inflammatory mediators, in particular IL-1 beta, may prevent insulitis in type 2 diabetes and therefore presents itself as a possible causal therapy with disease-modifying potential.
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Diabetes Mellitus Tipo 2/imunologia , Insulina/imunologia , Interleucina-1beta/imunologia , Ilhotas Pancreáticas/imunologia , Animais , Apoptose/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucagon/biossíntese , Humanos , Imuno-Histoquímica , Insulina/biossíntese , Interleucina-1beta/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , RatosRESUMO
The C2v surface symmetry of W(110) strongly influences a spin-orbit-induced Dirac-cone-like surface state and its characterization by spin- and angle-resolved photoelectron spectroscopy. In particular, using circular polarized light, a distinctive k-dependent spin texture is observed along the [Formula: see text] direction of the surface Brillouin zone. For all spin components Px, Py, and Pz, non-zero values are detected, while the initial-state spin polarization has only a Py component due to mirror symmetry. The observed complex spin texture of the surface state is controlled by transition matrix element effects, which include orbital symmetries of the involved electron states as well as the geometry of the experimental set-up.
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We present a combined experimental setup for spin- and angle-resolved direct and inverse photoemission in the vacuum ultraviolet energy range for measurements of the electronic structure below and above the Fermi level. Both techniques are installed in one ultrahigh-vacuum chamber and, as a consequence, allow quasisimultaneous measurements on one and the same sample preparation. The photoemission experiment consists of a gas discharge lamp and an electron energy analyzer equipped with a spin polarization detector based on spin-polarized low-energy electron diffraction. Our homemade inverse-photoemission spectrometer comprises a GaAs photocathode as spin-polarized electron source and Geiger-Muller counters for photon detection at a fixed energy of 9.9 eV. The total energy resolution of the experiment is better than 50 meV for photoemission and better than 200 meV for inverse photoemission. The performance of our combined direct and inverse-photoemission experiment with respect to angular and energy resolutions is exemplified by the Fermi-level crossing of the Cu(111) L-gap surface state. Spin-resolved measurements of Co films on Cu(001) are used to characterize the Sherman function of the spin polarization detector as well as the spin polarization of our electron source.
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We present a spectrometer for inverse photoemission in the vacuum ultraviolet range with variable energy resolution between 400 and 165 meV full width at half maximum. The energy distribution of the electron beam used for excitation can be adjusted between 300 and 125 meV by the use of a toroidal 90 degrees electrostatic deflector combined with a slit aperture. The emitted photons are detected by Geiger-Muller counters filled with either acetone or iodine as counting gas. The optical bandpasses of the detectors can be tuned between 100 and 330 meV by varying the temperature of their entrance windows. The overall resolution of the spectrometer is determined by measuring the Fermi-level onset in inverse-photoemission data of polycrystalline gold. Furthermore, the resolution enhancement is demonstrated by spectra of image-potential-induced surface states at Cu(001).
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Espectrofotometria Ultravioleta/instrumentação , Desenho Assistido por Computador , Transferência de Energia , Desenho de Equipamento , Análise de Falha de Equipamento , Fótons , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta/métodosRESUMO
The gerbil Psammomys obesus develops nutrition-dependent diabetes. We studied the interaction between diet and diabetic predisposition for beta-cell function. A 4-day high-energy (HE) diet induced a 3-, 4-, and 1.5-fold increase in serum glucose, insulin, and triglycerides, respectively, in diabetes-prone (DP) but not diabetes-resistant (DR) P. obesus. Hyperglycemia and concurrent 90% depletion of islet immunoreactive insulin stores were partially corrected by an 18-h fast. In vitro early insulin response to glucose was blunted in both DR and DP perifused islets. The HE diet augmented early and late insulin response in DR islets, whereas in DP islets, secretion progressively declined. Dose-response studies showed a species-related increase in islet glucose sensitivity, further augmented in DP P. obesus by a HE diet, concomitant with a decreased threshold for glucose and a 55% reduction in maximal response. These changes were associated with a fourfold increase in glucose phosphorylation capacity in DP islets. There were no differences in islet glucokinase (GK) and hexokinase (HK) Km; however, GK Vmax was 3.7- to 4.6-fold higher in DP islets, and HK Vmax was augmented 3.7-fold by the HE diet in DP islets. We conclude that the insulin-resistant P. obesus has an inherent deficiency in insulin release. In the genetically predisposed P. obesus (DP), augmented islet glucose phosphorylation ability and diet-induced reduction of the glucose threshold for secretion may lead to inadequate insulin secretion and depletion of insulin stores in the presence of caloric abundance. Thus, genetic predisposition and beta-cell maladaptation to nutritional load seem to determine together the progression to overt diabetes in this species. It is hypothesized that similar events may occur in obese type 2 diabetic patients.
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Diabetes Mellitus Tipo 2/fisiopatologia , Dieta , Gerbillinae/genética , Ilhotas Pancreáticas/fisiopatologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Diabetes Mellitus Tipo 2/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Privação de Alimentos/fisiologia , Predisposição Genética para Doença , Glucose/metabolismo , Glucose/farmacologia , Insulina/sangue , FosforilaçãoRESUMO
The gerbil Psammomys obesus develops nutrition-dependent diabetes associated with moderate obesity. The disease is characterized by initial hyperinsulinemia, progressing to hypoinsulinemia associated with depleted pancreatic insulin stores. The contribution of changes in beta-cell turnover to insulin deficiency was investigated in vivo during transition to overt diabetes. Normo glycemic diabetes-prone P. obesus animals who were given a high-calorie diet developed hyperglycemia within 4 days, which was found to be associated with a progressive decline in pancreatic insulin content. This was accompanied by a transient increase in beta-cell proliferative activity and by a prolonged increase in the rate of beta-cell death, culminating in disruption of islet architecture. The hypothesis that "glucotoxicity" was responsible for these in vivo changes was investigated in vitro in primary islet cultures. Exposure of islets from diabetes-prone P. obesus to high glucose levels resulted in a dose-dependent increase in beta-cell DNA fragmentation. In contrast, high glucose levels did not induce DNA fragmentation in rat islets, whereas islets from a diabetes-resistant P. obesus line exhibited a reduced and delayed response. Aminoguanidine did not prevent glucose-induced beta-cell DNA fragmentation in vitro, suggesting that formation of nitric oxide and/or advanced glycation end products plays no major role. Elevated glucose concentrations stimulated beta-cell proliferation in both rat and P. obesus islets. However, unlike the marked long-lasting effect in rat islets, only a transient and reduced proliferative response was observed in P. obesus islets; furthermore, beta-cell proliferation was inhibited after prolonged exposure to elevated glucose levels. These results suggest that hyperglycemia-induced beta-cell death coupled with reduced proliferative capacity may contribute to the insulin deficiency and deterioration of glucose homeostasis in P. obesus. Similar adverse effects of hyperglycemia could play a role in the evolution of type 2 diabetes in genetically susceptible individuals.
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Apoptose/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Hiperglicemia/fisiopatologia , Ilhotas Pancreáticas/fisiopatologia , Animais , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Fragmentação do DNA , Diabetes Mellitus Tipo 2/genética , Feminino , Gerbillinae , Glucose/farmacologia , Ilhotas Pancreáticas/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Glucotoxicity and lipotoxicity contribute to the impaired beta-cell function observed in type 2 diabetes. Here we examine the effect of saturated and unsaturated fatty acids at different glucose concentrations on beta-cell proliferation and apoptosis. Adult rat pancreatic islets were cultured onto plates coated with extracellular matrix derived from bovine corneal endothelial cells. Exposure of islets to saturated fatty acid (0.5 mmol/l palmitic acid) in medium containing 5.5, 11.1, or 33.3 mmol/l glucose for 4 days resulted in a five- to ninefold increase of beta-cell DNA fragmentation. In contrast, monounsaturated palmitoleic acid alone (0.5 mmol/l) or in combination with palmitic acid (0.25 or 0.5 mmol/l each) did not affect DNA fragmentation. Increasing concentrations of glucose promoted beta-cell proliferation that was dramatically reduced by palmitic acid. Palmitoleic acid enhanced the proliferation activity in medium containing 5.5 mmol/l glucose but had no additional effect at higher glucose concentrations (11.1 and 33.3 mmol/l). The cell-permeable ceramide analog C2-ceramide mimicked both the palmitic acid-induced beta-cell apoptosis and decrease in proliferation. Moreover, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on beta-cell viability. Additionally, palmitic acid but not palmitoleic acid decreased the expression of the mitochondrial adenine nucleotide translocator and induced release of cytochrome c from the mitochondria into the cytosol. Finally, palmitoleic acid improved beta-cell-secretory function that was reduced by palmitic acid. Taken together, these results suggest that the lipotoxic effect of the saturated palmitic acid involves an increased apoptosis rate coupled with reduced proliferation capacity of beta-cells and impaired insulin secretion. The deleterious effect of palmitate on beta-cell turnover is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway. In contrast, the monounsaturated palmitoleic acid does not affect beta-cell apoptosis, yet it promotes beta-cell proliferation at low glucose concentrations, counteracting the negative effects of palmitic acid as well as improving beta-cell function.