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1.
Ann Nucl Med ; 34(4): 244-253, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32114682

RESUMO

BACKGROUND: Patients with advanced neuroendocrine tumors (NETs) of the midgut are suitable candidates for 177Lu-DOTATOC therapy. Integrated SPECT/CT systems have the potential to help improve the accuracy of patient-specific tumor dosimetry. Dose estimations to target organs are generally performed using the Medical Internal Radiation Dose scheme. We present a novel Monte Carlo-based voxel-wise dosimetry approach to determine organ- and tumor-specific total tumor doses (TTD). METHODS: A cohort of 14 patients with histologically confirmed metastasized NETs of the midgut (11 men, 3 women, 62.3 ± 11.0 years of age) underwent a total of 39 cycles of 177Lu-DOTATOC therapy (mean 2.8 cycles, SD ± 1 cycle). After the first cycle of therapy, regions of interest were defined manually on the SPECT/CT images for the kidneys, the spleen, and all 198 tracer-positive tumor lesions in the field of view. Four SPECT images, taken at 4 h, 24 h, 48 h and 72 h after injection of the radiopharmaceutical, were used to determine their effective half-lives in the structures of interest. The absorbed doses were calculated by a three-dimensional dosimetry method based on Monte Carlo simulations. TTD was calculated as the sum of all products of single tumor doses with single tumor volumes divided by the sum of all tumor volumes. RESULTS: The average dose values per cycle were 3.41 ± 1.28 Gy (1.91-6.22 Gy) for the kidneys, 4.40 ± 2.90 Gy (1.14-11.22 Gy) for the spleen, and 9.70 ± 8.96 Gy (1.47-39.49 Gy) for all 177Lu-DOTATOC-positive tumor lesions. Low- and intermediate-grade tumors (G 1-2) absorbed a higher TTD compared to high-grade tumors (G 3) (signed-rank test, p = < 0.05). The pre-therapeutic chromogranin A (CgA) value and the TTD correlated significantly (Pearson correlation: = 0.67, p = 0.01). Higher TTD resulted in a significant decrease of CgA after therapy. CONCLUSION: These results suggest that Monte Carlo-based voxel-wise dosimetry is a very promising tool for predicting the absorbed TTD based on histological and clinical parameters.


Assuntos
Antineoplásicos/farmacocinética , Lutécio/farmacocinética , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Compostos Organometálicos/farmacologia , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Idoso , Antineoplásicos/administração & dosagem , Cromogranina A/efeitos da radiação , Feminino , Humanos , Lutécio/administração & dosagem , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Octreotida/administração & dosagem , Octreotida/química , Octreotida/farmacocinética , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Radioisótopos/administração & dosagem , Radiometria , Compostos Radiofarmacêuticos/administração & dosagem , Dosagem Radioterapêutica , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento
2.
Horm Metab Res ; 49(2): 142-146, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27926951

RESUMO

Familial hypocalciuric hypercalcemia (FHH) belongs to the disorders of a disturbed calcium homeostasis. Genetically, the disorder is inherited in an autosomal-dominant trait and represents an inactivating mutation of the calcium sensing receptor (CaSR) gene. We identified a Franconian kindred in which 6 individuals could be tested by molecular genetic means. In 5 individuals of 3 generations, the mutation could be classified as c.1697_1698delTG. This novel germline mutation creates a premature stop codon leading to a loss of 510 amino acids of the protein. The detection of CaSR gene mutations is suitable to differentiate states of hypercalcemia and may help to avoid invasive procedures such as parathyroidectomies.


Assuntos
Éxons/genética , Mutação/genética , Receptores de Detecção de Cálcio/genética , Idoso , Análise Mutacional de DNA , Feminino , Alemanha , Heterozigoto , Humanos , Masculino , Linhagem , Sítios de Splice de RNA/genética
3.
Neuroscience ; 301: 289-97, 2015 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-26079111

RESUMO

Converging data in songbirds support a central role for the medial preoptic nucleus (POM) in motivational aspects of vocal production. Recent data suggest that dopamine in the POM plays a complex modulatory role in the production of sexually-motivated song and that an optimal level of dopamine D1 receptor stimulation is required to facilitate singing behavior. To further explore this possibility, we used quantitative real-time PCR to examine relationships between mRNA expression of D1 as well as D2 receptors in the POM (and also the lateral septum and Area X) and sexually-motivated singing behavior in male European starlings. Results showed that both males with the highest and lowest D1 expression in the POM sang significantly less than males with intermediate levels of expression. Furthermore, singing behavior rose linearly in association with increasing levels of D1 expression in POM but dropped abruptly, such that individuals with D1 expression values higher than the mean sang very little. Analysis of birds with low and intermediate levels of D1 expression in POM revealed strong positive correlations between D1 expression and song but negative relationships between D2 receptor expression and song. These findings support prior work suggesting an optimal level of POM D1 receptor stimulation best facilitates sexually-motivated singing behavior. Results also suggest that D2 receptors may work in opposition to D1 receptors in POM to modify vocal production.


Assuntos
Motivação/fisiologia , Área Pré-Óptica/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Comportamento Sexual Animal/fisiologia , Vocalização Animal/fisiologia , Análise de Variância , Animais , Regulação da Expressão Gênica , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Masculino , Música , RNA Mensageiro/genética , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Estorninhos , Testosterona/metabolismo
4.
Behav Brain Res ; 278: 12-20, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25264575

RESUMO

Across vertebrates, communication conveys information about an individual's motivational state, yet little is known about the neuroendocrine regulation of motivational aspects of communication. For seasonally breeding songbirds, increases in testosterone in spring stimulate high rates of sexually-motivated courtship song, though not all birds sing at high rates. It is generally assumed that testosterone or its metabolites act within the medial preoptic nucleus (POM) to stimulate the motivation to sing. In addition to androgen receptors (ARs) and testosterone, opioid neuropeptides in the POM influence sexually-motivated song production, and it has been proposed that testosterone may in part regulate song by modifying opioid systems. To gain insight into a possible role for androgen-opioid interactions in the regulation of communication we examined associations between sexually-motivated song and relative expression of ARs, mu opioid receptors (muORs), and preproenkephalin (PENK) in the POM (and other regions) of male European starlings using qPCR. Both AR and PENK expression in POM correlated positively with singing behavior, whereas muOR in POM correlated negatively with song. Furthermore, the ratio of PENK/muOR expression correlated negatively with AR expression in POM. Finally, in the ventral tegmental area (VTA), PENK expression correlated negatively with singing behavior. Results support the hypothesis that ARs may alter opioid gene expression in POM to fine-tune singing to reflect a male's motivational state. Data also suggest that bidirectional relationships may exist between opioids and ARs in POM and song, and additionally support a role for opioids in the VTA, independent of AR activity in this region.


Assuntos
Androgênios/metabolismo , Área Pré-Óptica/metabolismo , Receptores Opioides mu/metabolismo , Comportamento Sexual Animal/fisiologia , Androgênios/genética , Animais , Feminino , Expressão Gênica , Modelos Lineares , Masculino , Motivação , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores Opioides mu/genética , Estorninhos , Testosterona/genética , Testosterona/metabolismo
5.
Exp Clin Endocrinol Diabetes ; 122(5): 273-6, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24839221

RESUMO

OBJECTIVE: Metastases of non-thyroidal tumors to the thyroid gland are infrequently diagnosed in the clinical environment. In autopsy studies, however, metastases to the thyroid gland have a frequency of 1.25-24%. The aim of this investigation was to explore the primary tumor and latency of diagnosis in patients who were diagnosed with metastases to the thyroid gland in 70 institutions associated to a scientific board in Middle Franconia during a 12 year period. DESIGN: Retrospective cross-sectional study. PATIENTS: After a clinical data base research, 35 patients (21 male, 14 female) with a histological diagnosis of a secondary thyroid malignancy were identified between 2002 and 2013. The mean age of the patients at diagnosis of the metastasis was x=68.2 years (median: 70, standard deviation SD=± 8.4, range 46-85 years). The majority of the patients had metastases from renal cell carcinomas (n=19). In the other patients metastases from gastrointestinal carcinomas (n=2), bronchial carcinomas (n=3), malignant melanomas (n=3), sarcomas (n=2), and other tumors (n=6) were diagnosed. The time interval between the diagnosis of the primary tumor and the metastasis to the thyroid gland was different for patients with metastases from renal cell carcinomas and non-renal cell carcinomas (p<0.001, chi-test). CONCLUSIONS: In agreement with previous studies, the majority of metastases to the thyroid gland derive from renal cell carcinomas. In patients with non-renal malignancies, metastases to the thyroid gland are diagnosed simultaneously with the primary tumor to a higher proportion compared with metastasis from renal malignancies.


Assuntos
Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/secundário , Idoso , Neoplasias Brônquicas/epidemiologia , Neoplasias Brônquicas/patologia , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/patologia , Feminino , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/patologia , Alemanha/epidemiologia , Humanos , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Polônia/epidemiologia , Estudos Retrospectivos , Sarcoma/epidemiologia , Sarcoma/patologia , Neoplasias da Glândula Tireoide/patologia
6.
Rofo ; 186(5): 489-95, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24718869

RESUMO

PURPOSE: The purpose of the study was to test the hypothesis that papillary thyroid carcinomas (PTCs) and follicular thyroid carcinomas (FTCs) appear with different ultrasound characteristics. MATERIAL AND METHODS: 90 patients (70 females, 20 males) were included in the study in whom after thyroidectomy the diagnoses of PTCs or FTCs were established. 33 patients (25 females, 8 males) with the diagnosis of follicular adenoma were included in the study as controls (KONs). All patients had ultrasound examinations of the thyroid preoperatively. These ultrasound examinations were evaluated retrospectively with respect to the ultrasound characteristics: "size", "shape", "contour", "structure", "echogenicity" and "calcifications". RESULTS: In PTCs, FTCs and KONs "size" was significantly different (PTCs: MW = 12.5 mm, SD = 8.  mm - FTCs: MW = 35.4 mm, SD = 19.6  mm - KONs: MW = 22.7 mm, SD = 14.5  mm; p <  0.001 for PTCs vs. FTCs, p < 0.001 for PTCs vs. KONs, p = 0.013 for FTCs vs. KONs). Differences were also found with respect to "contour" and "echogenicity" among PTCs, FTCs and KONs (p ≤ 0.035). The parameters "size", "contour", "echogenicity" and "calcifications" correlated for PTCs, FTCs and KONs with a correlation coefficient r = 0.57 (p < 0.05, multivariate regressionanalysis). CONCLUSIONS: PTCs and FTCs appear with different sonographic characteristics. Although there is some overlapping of the sonographic appearances of PTCs and FTCs, the knowledge of these differences should have some impact of the risk adapted further work up.


Assuntos
Adenocarcinoma Folicular/diagnóstico por imagem , Carcinoma Papilar/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Adenocarcinoma Folicular/patologia , Adenocarcinoma Folicular/cirurgia , Adenoma/diagnóstico por imagem , Adenoma/patologia , Adenoma/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/patologia , Carcinoma Papilar/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Sensibilidade e Especificidade , Estatística como Assunto , Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Ultrassonografia , Adulto Jovem
7.
Horm Behav ; 65(4): 329-39, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24594286

RESUMO

Vocalizations convey information about an individual's motivational, internal, and social status. As circumstances change, individuals respond by adjusting vocal behavior accordingly. In European starlings, a male that acquires a nest site socially dominates other males and dramatically increases courtship song. Although circulating testosterone is associated with social status and vocal production it is possible that steroid receptors fine-tune status-appropriate changes in behavior. Here we explored a possible role for androgen receptors. Male starlings that acquired nest sites produced high rates of courtship song. For a subset of males this occurred even in the absence of elevated circulating testosterone. Immunolabeling for androgen receptors (ARir) was highest in the medial preoptic nucleus (POM) in males with both a nest site and elevated testosterone. For HVC, ARir was higher in dominant males with high testosterone (males that sang longer songs) than dominant males with low testosterone (males that sang shorter songs). ARir in the dorsal medial portion of the nucleus intercollicularis (DM) was elevated in males with high testosterone irrespective of dominance status. Song bout length related positively to ARir in POM, HVC and DM, and testosterone concentrations related positively to ARir in POM and DM. Results suggest that the role of testosterone in vocal behavior differs across brain regions and support the hypothesis that testosterone in POM underlies motivation, testosterone in HVC relates to song quality, and testosterone in DM stimulates vocalizations. Our data also suggest that singing may influence AR independent of testosterone and that alternative androgen-independent pathways regulate status-appropriate singing behavior.


Assuntos
Prosencéfalo/fisiologia , Receptores Androgênicos/fisiologia , Predomínio Social , Estorninhos/fisiologia , Testosterona/fisiologia , Vocalização Animal/fisiologia , Animais , Imuno-Histoquímica , Masculino , Estorninhos/metabolismo
8.
Radiat Res ; 178(3): 234-43, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22769026

RESUMO

We examined the benefit of gene expression analysis on peripheral blood cellular subsets of different radiosensitivity to elucidate their utility as biodosimeters for estimation of dose in irradiated individuals. Peripheral mononucleated cells were isolated from 18 healthy volunteers employing density separation in a CPT-NH tube. Peripheral mononucleated cells were cultured in RPMI 1640 medium containing 10% autologous serum and were irradiated with 0.1-1 Gy (240 kV, 13 mA, X rays at 1 Gy/min). A low-dose study was performed with isolated peripheral mononucleated cells from one healthy donor in three independent experiments. Peripheral mononucleated cells were irradiated at 0 (sham), 1, 2.5 and 5 cGy (70 kV, 13 mA X rays at 1 cGy/min) and gene expression was measured 24 and 48 h after irradiation. After irradiation, CD4(+) or CD8(+) cells were isolated by magnetic beads in independent experiments. RNA from lymphocyte subsets and peripheral mononucleated cells was isolated after 24 and 48 h and converted into cDNA. Gene expression of GADD45, CDKN1A, DDB2, PCNA, BAX and ATF3 were determined using RTQ-PCR. Data were analyzed employing linear and logistic regression analysis. The same examinations were performed in 5 individuals either diagnosed using CT scans (up to 4.3 cGy) or by administering (F-18)-fluoro-2-deoxy-d-glucose (F-18 FDG, 0.6 cGy). Methodological, intra- and inter-individual variability in 90-95% of measurements did not exceed the introduced twofold change over sham-irradiated control values in peripheral mononucleated cells and CD4(+) cells, and therefore no false positive results were observed. Dose reconstruction in peripheral mononucleated cells in opposite to CD4(+) lymphocytes required fewer genes and appeared more efficient (R-square = 84.8% compared to 51.8%). In vitro samples exposed to 10 cGy could be completely discriminated from sham-irradiated samples without individual pre-exposure controls, which coincided with our preliminary in vivo results. However, in vitro differential gene expression was measured relative to control values and did not differ significantly at 24 and 48 h after irradiation in contrast to our preliminary in vivo data. In addition, below 5 cGy in vitro data did not show reproducible significant changes in gene expression, which was opposite to our preliminary in vivo data. Therefore a twofold change in gene expression over control sufficiently controls for different sources of variance, and measuring gene expression in peripheral mononucleated cell for biological dosimetry purposes appears superior over measurements in lymphocyte subsets. The increased gene expression measured after low absorbed doses in vivo and in vitro might indicate a particular applicability of this method for a low-level radiation scenario in the absence of individual pre-exposure controls. However, the constant gene expression values measured up to 48 h in our in vitro model at doses >10 cGy, and the absence of reproducible and statistically significant gene expression changes below 5 cGy contrast to the preliminary in vivo results performed at similar doses. Therefore, measurements with our in vitro models should be interpreted cautiously.


Assuntos
Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/efeitos da radiação , Transcriptoma/efeitos da radiação , Adulto , Técnicas de Cultura de Células , Relação Dose-Resposta à Radiação , Feminino , Humanos , Subpopulações de Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Tolerância a Radiação/genética , Radiometria , Fatores de Tempo , Adulto Jovem
9.
Radiologe ; 45(7): 597-607, 2005 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-16059656

RESUMO

PURPOSE: This review shows the diagnostic potential of computed tomography (CT) in the diagnosis and differential diagnosis of acute left-sided colonic diverticulitis. METHODS: Using a single detector spiral CT, standard examination of the entire abdomen is performed after oral and rectal administration of diluted iodinated contrast medium with collimation of 8 mm, pitch of 1.5, and reconstruction increment of 8 mm before and after intravenous contrast injection. Intravenous administration of spasmolytic agents, various patient positions, and the thin-section technique with 3-5 mm slices are beneficial in difficult cases. RESULTS: The differential diagnosis of acute left-sided colonic diverticulitis includes tumorous, inflammatory, and ischemic diseases of the colon as well as infarctions of epiploic appendages and the omentum majus. The knowledge of the various CT criteria of acute colonic diverticulitis and their differential diagnoses helps to establish a correct diagnosis in a wide majority of cases. CONCLUSION: At present, CT is the diagnostic procedure of choice for assessing acute diverticulitis. Distinct knowledge of the CT features helps to differentiate the various entities accurately.


Assuntos
Meios de Contraste , Doença Diverticular do Colo/diagnóstico por imagem , Intensificação de Imagem Radiográfica/métodos , Tomografia Computadorizada por Raios X/métodos , Doença Aguda , Colite/diagnóstico por imagem , Neoplasias do Colo/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Guias de Prática Clínica como Assunto , Padrões de Prática Médica
10.
Nat Struct Biol ; 7(12): 1129-32, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11101895

RESUMO

Arc repressor bearing the N11L substitution (Arc-N11L) is an evolutionary intermediate between the wild type protein, in which the region surrounding position 11 forms a beta-sheet, and a double mutant 'switch Arc', in which this region is helical. Here, Arc-N11L is shown to be able to adopt either the wild type or mutant conformations. Exchange between these structures occurs on the millisecond time scale in a dynamic equilibrium in which the relative populations of each fold depend on temperature, solvent conditions and ligand binding. The N11L mutation serves as an evolutionary bridge from the beta-sheet to the helical fold because in the mutant, Leu is an integral part of the hydrophobic core of the new structure but can also occupy a surface position in the wild type structure. Conversely, the polar Asn 11 side chain serves as a negative design element in wild type Arc because it cannot be incorporated into the core of the mutant fold.


Assuntos
Evolução Molecular , Dobramento de Proteína , Proteínas Repressoras/química , Proteínas Virais/química , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Dicroísmo Circular , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dimerização , Cinética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Regiões Operadoras Genéticas/genética , Ligação Proteica , Estrutura Secundária de Proteína , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Solventes , Espectrometria de Fluorescência , Temperatura , Termodinâmica , Proteínas Virais/genética , Proteínas Virais/metabolismo , Proteínas Virais Reguladoras e Acessórias
11.
Clin Cardiol ; 23(12): 902-8, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11129676

RESUMO

BACKGROUND: Considerable derangements of energy metabolism are to be expected during ischemia and reperfusion. In ischemic myocardium, the oxidative degradation of carbohydrates is shifted toward the anaerobic production of lactate and the oxidation of fatty acids is suppressed. HYPOTHESIS: The aim of this study was to examine the uptake and metabolism of iodine-123 (123I) iodophenylpentadecanoic acid (IPPA) in stunned myocardium. METHODS: In 15 patients, SPECT with 201Tl and 123I IPPA as well as echocardiography with low-dose dobutamine stimulation were performed 12 +/- 5 days after myocardial infarction with reperfusion. Follow-up echocardiography was carried out 24 +/- 8 days later for documentation of functional improvement. Uptake of 201Tl and 123I IPPA were obtained in five left ventricular segments, and dynamic SPECT imaging was used for calculation of the fast and the slow components of the biexponential myocardial 123I IPPA clearance. RESULTS: Wall motion improved in 14 of 26 dysfunctional segments (54%). Stunned segments were characterized by a reduced 123I IPPA extraction, a shorter half-life of the fast, and a longer half-life of the slow clearance component. All parameters of the combined 201Tl/123I IPPA study predicted functional recovery with similar accuracies (area under the receiver operator characteristic curves between 0.68 and 0.76; p = NS). Analysis of 201Tl uptake alone could not predict functional recovery in this study. CONCLUSIONS: Stunned myocardium is characterized by a disturbance of fatty acid metabolism. For prediction of functional improvement, 123I IPPA imaging added significant diagnostic information.


Assuntos
Radioisótopos do Iodo , Iodobenzenos , Miocárdio Atordoado/diagnóstico por imagem , Miocárdio Atordoado/metabolismo , Radioisótopos de Tálio , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Idoso , Metabolismo Energético , Feminino , Humanos , Radioisótopos do Iodo/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Radioisótopos de Tálio/metabolismo , Ultrassonografia
12.
Nature ; 408(6814): 823-6, 2000 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-11130714

RESUMO

The genome of the model plant Arabidopsis thaliana has been sequenced by an international collaboration, The Arabidopsis Genome Initiative. Here we report the complete sequence of chromosome 5. This chromosome is 26 megabases long; it is the second largest Arabidopsis chromosome and represents 21% of the sequenced regions of the genome. The sequence of chromosomes 2 and 4 have been reported previously and that of chromosomes 1 and 3, together with an analysis of the complete genome sequence, are reported in this issue. Analysis of the sequence of chromosome 5 yields further insights into centromere structure and the sequence determinants of heterochromatin condensation. The 5,874 genes encoded on chromosome 5 reveal several new functions in plants, and the patterns of gene organization provide insights into the mechanisms and extent of genome evolution in plants.


Assuntos
Arabidopsis/genética , Genoma de Planta , Animais , Mapeamento Cromossômico , DNA de Plantas , Humanos , Proteínas de Plantas/genética , Análise de Sequência de DNA
13.
Science ; 284(5412): 325-8, 1999 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-10195898

RESUMO

A "switch" mutant of the Arc repressor homodimer was constructed by interchanging the sequence positions of a hydrophobic core residue, leucine 12, and an adjacent surface polar residue, asparagine 11, in each strand of an intersubunit beta sheet. The mutant protein adopts a fold in which each beta strand is replaced by a right-handed helix and side chains in this region undergo significant repacking. The observed structural changes allow the protein to maintain solvent exposure of polar side chains and optimal burial of hydrophobic side chains. These results suggest that new protein folds can evolve from existing folds without drastic or large-scale mutagenesis.


Assuntos
Dobramento de Proteína , Estrutura Secundária de Proteína , Proteínas Repressoras/química , Proteínas Virais/química , Sequência de Aminoácidos , Substituição de Aminoácidos , Asparagina/química , Dicroísmo Circular , Ligação de Hidrogênio , Leucina/química , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Insercional , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Estrutura Terciária de Proteína , Proteínas Virais Reguladoras e Acessórias
14.
Protein Sci ; 8(2): 318-25, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10048325

RESUMO

Hydrophobic substitutions at solvent-exposed positions in two alpha-helical regions of the bacteriophage P22 Arc repressor were introduced by combinatorial mutagenesis. In helix A, hydrophobic residues were tolerated individually at each of the five positions examined, but multiple substitutions were poorly tolerated as shown by the finding that mutants with more than two additional hydrophobic residues were biologically inactive. Several inactive helix A variants were purified and found to have reduced thermal stability relative to wild-type Arc, with a rough correlation between the number of polar-to-hydrophobic substitutions and the magnitude of the stability defect. Quite different results were obtained in helix B, where variants with as many as five polar-to-hydrophobic substitutions were found to be biologically active and one variant with three hydrophobic substitutions had a t(m) 6 degrees C higher than wild-type. By contrast, a helix A mutant with three similar polar-to-hydrophobic substitutions was 23 degrees C less stable than wild-type. Also, one set of three polar-to-hydrophobic substitutions in helix B was tolerated when introduced into the wild-type background but not when introduced into an equally active mutant having a nearly identical structure. Context effects occur both when comparing different regions of the same protein and when comparing the same region in two different homologues.


Assuntos
Bacteriófago P22/química , Proteínas Repressoras/química , Proteínas Virais/química , Aminoácidos/análise , Dicroísmo Circular , Mutagênese Insercional , Conformação Proteica , Desnaturação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Espectrometria de Fluorescência , Temperatura , Proteínas Virais Reguladoras e Acessórias
15.
J Nucl Med ; 39(6): 954-60, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9627325

RESUMO

UNLABELLED: This study analyzed temporal changes of striatal dopamine-D2 receptor binding during the course of different extrapyramidal movement disorders using 123I-iodobenzamide (IBZM) SPECT. METHODS: Eighteen patients (9 with Parkinson's disease, 9 with parkinsonian plus syndrome) were followed for 11-53 mo. Dopamine-D2 receptor binding was assessed using 123I-IBZM SPECT at the beginning and at the end of the follow-up period. SPECT data were acquired 120 min postinjection of 3-5 mCi 123I-IBZM. A semiautomated algorithm was applied to the raw data for semiquantitative evaluation of regional cerebral receptor binding. RESULTS: Intraobserver (r = 0.992) and interobserver (r = 0.930) variance was low for the semiautomated interpretation of the SPECT examination of the dopaminergic D2 receptor binding, reflecting a highly reproducible SPECT algorithm. Mean specific dopamine-D2 receptor binding was lower in patients with parkinsonian plus syndrome compared to patients with Parkinson's disease on the initial (p < 0.001) as well as the follow-up study (p < 0.001). In patients with Parkinson's disease, we observed an unaffected receptor binding compared to a reduced binding of radiotracer in patients with parkinsonian plus syndrome during the course of the disease (p < 0.001). CONCLUSION: During the follow-up, patients with Parkinson's disease showed a constant dopamine-D2 receptor binding. In contrast, patients with parkinsonian plus syndrome revealed a decline of the binding of dopamine-D2 receptor. These findings are in agreement with histopathological data that demonstrated a preserved dopamine-D2 receptor status in patients with Parkinson's disease and a decline of the dopamine-D2 receptors in patients with parkinsonian plus syndrome. SPECT examinations using 123I-IBZM are useful for assessing dynamic changes of dopamine-D2 receptors in extrapyramidal movement disorders. Semiquantitative SPECT evaluations may provide valuable information for clinical management and prognosis of the patient with extrapyramidal movement disorders.


Assuntos
Corpo Estriado/metabolismo , Doença de Parkinson/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Idoso , Benzamidas , Sítios de Ligação , Meios de Contraste , Corpo Estriado/diagnóstico por imagem , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/metabolismo , Variações Dependentes do Observador , Atrofias Olivopontocerebelares/metabolismo , Doença de Parkinson/diagnóstico por imagem , Pirrolidinas , Reprodutibilidade dos Testes , Paralisia Supranuclear Progressiva/metabolismo , Síndrome , Fatores de Tempo , Tomografia Computadorizada de Emissão de Fóton Único
16.
Nuklearmedizin ; 37(2): 49-56, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9547750

RESUMO

AIM: To compare published fractional rate constants of I-123-Iomazenil (IMZ) and C-11-Flumazenil (three-compartment/four-parameter model) with a I-123-Iomazenil receptor index calculated from two SPECT acquisitions and to compare the receptor index of the epileptogenic area with the contralateral side in patients with unilateral temporal lobe epilepsies. METHODS: 28 patients were studied. 13/28 patients had a drug-resistant unilateral temporal lobe epilepsy with a successful focus localisation performed by an extensive video/EEG monitoring. 15 other patients with clinically suspected focal epilepsy and a normal MRI and IMZ SPECT scanning were used as controls. SPECT scanning was performed in all patients 15 and 100 min after intravenous injection of 111 MBq IMZ and 10 min after application of 740 MBq Tc-99m-HMPAO. Quantification of the regional uptake was performed using ROI-technique and the specific and non-specific binding of IMZ was calculated. The receptor index was calculated by the difference of the specific binding from 15 to 100 min p.i. divided by the time interval. RESULTS: The receptor index showed a linear correlation with recently published fractional rate constants k3 (r = 0.69 and 0.67; p = 0.15) and a moderate correlation with the k4 constant (-0.53 and -0.43; p = 0.28) by the means of C-11-Flumazenil PET and I-123-Iomazenil SPECT studies, respectively. However, statistical significance was not reached due to the few data points available from the published reports. Furthermore, the IMZ receptor index was lower in the epileptogenic area of patients with unilateral temporal lobe epilepsies compared with their contralateral side (p = 0.02; Wilcoxon-test). The IMZ receptor index showed a weak correlation with the regional cerebral blood flow independent of the evaluated region (r < 0.4; p < 0.05). CONCLUSION: The IMZ receptor index indicated to be a simple routine approach to estimate the fractional rate constant k3 (r = 0.67). The lower value of the receptor index within the epileptogenic area might be due to a lower receptor density. However in further studies, IMZ might be a helpful tool to find out subtle changes of the receptor affinity due to its approximately 30-fold higher ligand-receptor affinity compared to C-11-Flumazenil.


Assuntos
Encéfalo/diagnóstico por imagem , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/metabolismo , Flumazenil/análogos & derivados , Radioisótopos do Iodo , Receptores de GABA-A/análise , Lobo Temporal/diagnóstico por imagem , Adulto , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular , Eletroencefalografia , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Flumazenil/farmacocinética , Humanos , Radioisótopos do Iodo/farmacocinética , Imageamento por Ressonância Magnética , Masculino , Modelos Neurológicos , Compostos Radiofarmacêuticos/farmacocinética , Análise de Regressão , Tecnécio Tc 99m Exametazima/farmacocinética , Lobo Temporal/irrigação sanguínea , Lobo Temporal/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Gravação em Vídeo
18.
Rofo ; 165(1): 43-51, 1996 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-8765362

RESUMO

PURPOSE: To define characteristic MR-findings in patients with clinically typical extrapyramidal movement disorders. METHODS: 15 patients with Parkinson's disease (PD), 9 with multisystem atrophy (MSA), and 6 with progressive supranuclear palsy (PSP) underwent MRI using a 1.5 T. Magnetom unit. Two investigators analysed the images with special regard to global and/or focal atrophy and to changes in signal intensity of the CNS in the consensus mode. Normal images of 10 subjects served as controls to patient's images. RESULTS: In all patients with PSP and MSA characteristic pathological findings on MRI were observed including regional changes within the extrapyramidal nuclei. In contrast all patients with PD had an unremarkable MRI study of the CNS. CONCLUSION: MRI enables us to define characteristic morphological changes of the brain in patients with extrapyramidal movement disorders. Early recognition of these findings avoids misdiagnoses in patients who are difficult to diagnose.


Assuntos
Imageamento por Ressonância Magnética , Doença de Parkinson Secundária/diagnóstico , Doença de Parkinson/diagnóstico , Adulto , Idoso , Atrofia/diagnóstico , Encéfalo/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Paralisia Supranuclear Progressiva/diagnóstico
19.
Radiol Med ; 91(3): 207-10, 1996 Mar.
Artigo em Italiano | MEDLINE | ID: mdl-8628932

RESUMO

The functional integrity of striatal post-synaptic dopamine D2 receptors is requested for an effective pharmacologic treatment in patients with extrapyramidal movement disorders. Iodine-123 IBZM Single Photon Emission Computed Tomography (SPECT) is a noninvasive radionuclide technique for the morpho-functional imaging of post-synaptic dopamine D2 receptors. In this study, the results of iodine-123 IBZM SPECT and those of apomorphine tests were compared in 32 patients with extrapyramidal movement disorders--22 patients with idiopathic Parkinson's disease (IPD) and 10 with Parkinson's plus syndrome (PPS). Iodine-123 IBZM uptake was measured as the ratio between striatum and frontal cortex activities. Twenty of 22 IPD patients (91%) responded to apomorphine administration, while in 8 of 10 PPS patients (80%) the apomorphine test was negative. Iodine-123 IBZM uptake was significantly higher (p < 0.01) in IPD patients (1.39 +/- 0.114) than in PPS patients (1.27 +/- 0.078). Similarly, iodine-123 IBZM uptake was significantly higher (p < 0.01) in the patients with positive than in those with negative apomorphine test (1.38 +/- 0.113 vs. 1.26 +/- 0.078). In conclusion, the results of this study demonstrate that iodine-123 IBZM SPECT is a radionuclide technique capable of characterizing the patients with extrapyramidal movement disorders and of selecting the subjects who may respond to pharmacological dopamine treatment.


Assuntos
Doenças dos Gânglios da Base/diagnóstico por imagem , Benzamidas , Encéfalo/diagnóstico por imagem , Meios de Contraste , Agonistas de Dopamina/uso terapêutico , Radioisótopos do Iodo , Pirrolidinas , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Apomorfina , Doenças dos Gânglios da Base/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Tomografia Computadorizada de Emissão de Fóton Único/instrumentação , Tomografia Computadorizada de Emissão de Fóton Único/estatística & dados numéricos
20.
Rofo ; 164(2): 114-8, 1996 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-8679972

RESUMO

PURPOSE: Assessment of the functional diagnostic value of Doppler sonographic or sonographic parameters, especially of the peak flow velocity in the inferior thyroid artery in patients with newly manifest autoimmunothyroiditis. MATERIAL AND METHOD: Morphological and Doppler sonographic measurements were done at the inferior thyroid artery on 69 patients suffering from newly manifest Graves' disease or Hashimoto's thyroiditis, as well as on a control group of 18 subjects. The measured data were correlated with thyroid hormone levels and with quantitative scintiscanning. RESULTS: A linear functional correlation was found between the peak flow velocities in the inferior thyroid artery and the fT3 or fT4 level. If the peak flow velocities were greater than 1.2 m/s, hyperthyroid metabolism prevailed, whereas at velocities below 0.3 m/s latent hypothyroidism was present. CONCLUSION: These results show that Doppler sonography of the inferior thyroid artery can supply pointers (capable of being recorded) to the state of functioning of the thyroid even before knowing the laboratory parameters.


Assuntos
Glândula Tireoide/diagnóstico por imagem , Adulto , Idoso , Artérias/diagnóstico por imagem , Velocidade do Fluxo Sanguíneo , Doença de Graves/diagnóstico por imagem , Doença de Graves/fisiopatologia , Humanos , Pessoa de Meia-Idade , Testes de Função Tireóidea/métodos , Glândula Tireoide/irrigação sanguínea , Glândula Tireoide/fisiopatologia , Tireoidite Autoimune/diagnóstico por imagem , Tireoidite Autoimune/fisiopatologia , Ultrassonografia Doppler Dupla/instrumentação , Ultrassonografia Doppler Dupla/métodos
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