RESUMO
BACKGROUND: The combination of high blood pressure and hyperglycemia contributes to the development of diabetic complications. Ambulatory monitoring of blood pressure (ABPM) is seen as standard to assess blood pressure (BP) regulation. OBJECTIVE: We evaluated 24-hour BP regulation in 3529 children with type 1 diabetes, representing 5.6% of the patients <20 years of age documented in the DPV registry, and studied the influence of BP parameters including pulse pressure (PP) and blood pressure variability (BPV) on microalbuminuria (MA) and diabetic retinopathy (DR). RESULTS: BP was increased in this selected cohort of children with diabetes compared to healthy German controls (standard deviation score (SDS) day: systolic BP (SBP) +0.06, mean arterial pressure (MAP) +0.08, PP +0.3; night: SBP +0.6, diastolic BP +0.6, MAP +0.8), while daytime diastolic BP (SDS -0.2) and dipping of SBP and MAP were reduced (SBP -1.1 SDS, MAP 12.4% vs 19.4%), PP showed reverse dipping (-0.7 SDS). Children with microvascular complications had by +0.1 to +0.75 SDS higher BP parameters, except of nocturnal PP in MA and diurnal and nocturnal PP in DR. Reverse dipping of PP was more pronounced in the children with MA (-5.1% vs -0.8%) and DR (-2.6% vs -1.0%). BP alteration was stronger in girls and increased with age. CONCLUSION: There is an early and close link between 24-hour blood pressure regulation and the development of diabetic complications not only for systolic, diastolic, and mean arterial BP but also for the derived BP parameter PP and BPV in our selected patients.
Assuntos
Albuminúria/etiologia , Pressão Sanguínea , Ritmo Circadiano , Diabetes Mellitus Tipo 1/fisiopatologia , Retinopatia Diabética/etiologia , Adolescente , Criança , Diabetes Mellitus Tipo 1/complicações , Feminino , Humanos , MasculinoRESUMO
Secreted WNT proteins control cell differentiation and proliferation in many tissues, and NOTUM is a secreted enzyme that modulates WNT morphogens by removing a palmitoleoylate moiety that is essential for their activity. To better understand the role this enzyme in development, the authors produced NOTUM-deficient mice by targeted insertional disruption of the Notum gene. The authors discovered a critical role for NOTUM in dentin morphogenesis suggesting that increased WNT activity can disrupt odontoblast differentiation and orientation in both incisor and molar teeth. Although molars in Notum(-/-) mice had normal-shaped crowns and normal mantle dentin, the defective crown dentin resulted in enamel prone to fracture during mastication and made teeth more susceptible to endodontal inflammation and necrosis. The dentin dysplasia and short roots contributed to tooth hypermobility and to the spread of periodontal inflammation, which often progressed to periapical abscess formation. The additional incidental finding of renal agenesis in some Notum (-/-) mice indicated that NOTUM also has a role in kidney development, with undiagnosed bilateral renal agenesis most likely responsible for the observed decreased perinatal viability of Notum(-/-) mice. The findings support a significant role for NOTUM in modulating WNT signaling pathways that have pleiotropic effects on tooth and kidney development.
Assuntos
Displasia da Dentina/enzimologia , Esterases/metabolismo , Via de Sinalização Wnt , Animais , Diferenciação Celular , Displasia da Dentina/genética , Esterases/genética , Feminino , Humanos , Incisivo/crescimento & desenvolvimento , Rim/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Knockout , Dente Molar/crescimento & desenvolvimento , Mutagênese Insercional , Odontogênese/genéticaRESUMO
GREMLIN 2 (GREM2)--formerly, protein related to Dan and cerberus (PRDC)-is a potent antagonist of the bone morphogenetic proteins 2 and 4, but little else in known about its functions. We found that Grem2(-/-) mice developed small deformed mandibular and maxillary incisors, indicating that GREMLIN2 is required for normal tooth morphogenesis. Although DEXA scans suggested that bone mineral density might be increased in Grem2(-/-) mice, histology did not reveal any evident bone phenotype. Grem2(-/-) mice did not display any other notable phenotypes evaluated in a high-throughput screening process that encompassed a range of immunologic, metabolic, ophthalmic, and behavioral parameters. Our findings indicate that Grem2 can be added to the growing list of genes that affect tooth development in mice.
Assuntos
Transdução de Sinais , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Feminino , Incisivo , Masculino , Camundongos , Camundongos Knockout , OdontogêneseRESUMO
Mice deficient in TMEM218 (Tmem218(-/-) ) were generated as part of an effort to identify and validate pharmaceutically tractable targets for drug development through large-scale phenotypic screening of knockout mice. Routine diagnostics, expression analysis, histopathology, and electroretinogram analyses completed on Tmem218(-/-) mice identified a previously unknown role for TMEM218 in the development and function of the kidney and eye. The major observed phenotypes in Tmem218(-/-) mice were progressive cystic kidney disease and retinal degeneration. The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy and disruption of tubular basement membranes in essentially normal-sized kidneys. The retinal lesions were characterized by slow-onset loss of photoreceptors, which resulted in reduced electroretinogram responses. These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans. At least 10% of NPHP cases present with extrarenal conditions, which most often include retinal degeneration. Senior-Løken syndrome is characterized by the concurrent development of autosomal recessive NPHP and retinitis pigmentosa. Since mutations in the known NPHP genes collectively account for only about 30% of NPHP cases, it is possible that TMEM218 could be involved in the development of similar ciliopathies in humans. In reviewing all other reported mouse models of NPHP, we suggest that Tmem218(-/-) mice could provide a useful model for elucidating the pathogenesis of cilia-associated disease in both the kidney and the retina, as well as in developing and testing novel therapeutic strategies for Senior-Løken syndrome.
Assuntos
Modelos Animais de Doenças , Doenças Renais Císticas/veterinária , Amaurose Congênita de Leber/veterinária , Proteínas de Membrana/genética , Camundongos Knockout/genética , Atrofias Ópticas Hereditárias/veterinária , Degeneração Retiniana/veterinária , Animais , Ciliopatias , Eletrorretinografia/veterinária , Olho/patologia , Feminino , Rim/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Amaurose Congênita de Leber/patologia , Masculino , Proteínas de Membrana/fisiologia , Camundongos , Atrofias Ópticas Hereditárias/patologia , Retina/patologia , Degeneração Retiniana/genéticaRESUMO
We examined the sequence variation of mitochondrial DNA control region and cytochrome b gene of the house mouse (Mus musculus sensu lato) drawn from ca. 200 localities, with 286 new samples drawn primarily from previously unsampled portions of their Eurasian distribution and with the objective of further clarifying evolutionary episodes of this species before and after the onset of human-mediated long-distance dispersals. Phylogenetic analysis of the expanded data detected five equally distinct clades, with geographic ranges of northern Eurasia (musculus, MUS), India and Southeast Asia (castaneus, CAS), Nepal (unspecified, NEP), western Europe (domesticus, DOM) and Yemen (gentilulus). Our results confirm previous suggestions of Southwestern Asia as the likely place of origin of M. musculus and the region of Iran, Afghanistan, Pakistan, and northern India, specifically as the ancestral homeland of CAS. The divergence of the subspecies lineages and of internal sublineage differentiation within CAS were estimated to be 0.37-0.47 and 0.14-0.23 million years ago (mya), respectively, assuming a split of M. musculus and Mus spretus at 1.7 mya. Of the four CAS sublineages detected, only one extends to eastern parts of India, Southeast Asia, Indonesia, Philippines, South China, Northeast China, Primorye, Sakhalin and Japan, implying a dramatic range expansion of CAS out of its homeland during an evolutionary short time, perhaps associated with the spread of agricultural practices. Multiple and non-coincident eastward dispersal events of MUS sublineages to distant geographic areas, such as northern China, Russia and Korea, are inferred, with the possibility of several different routes.
Assuntos
Citocromos b/genética , DNA Mitocondrial/genética , Evolução Molecular , Distribuição Animal , Animais , China , Europa (Continente) , Especiação Genética , Haplótipos , Índia , Camundongos , Dados de Sequência Molecular , Filogenia , Filogeografia , Sequências Reguladoras de Ácido Nucleico , Federação Russa , Análise de Sequência de DNARESUMO
Almost all mitochondrial proteins are encoded in the nuclear DNA and synthesized in the cytosol as pre-proteins. There is a protein translocase located in the mitochondrial outer membrane that transports mitochondrial pre-proteins into mitochondria. The central component of this translocase of the outer mitochondrial membrane (TOMM) complex is TOMM40, and TOMM5 is one of three small subunits associated with TOMM40. Translocase of outer mitochondrial membrane 5 homolog (Tomm5(-/-)) knockout mice demonstrated an unexpected lung-specific phenotype characterized by widespread intra-alveolar fibrosis. Although TOMM5-deficient mice tested normal in a very broad range of phenotyping assays, they displayed histopathological lesions in the lung that were consistent with those reported in humans with cryptogenic organizing pneumonia (COP), which is also known as bronchiolitis obliterans organizing pneumonia (BOOP). The lesions had a patchy distribution in the lung and were characterized by the presence of intraluminal fibrogenic buds consisting of fibroblasts and myofibroblasts embedded in a loose connective tissue matrix that occupied the lumina of alveoli and alveolar ducts, with preservation of underlying alveolar architecture. In addition to macrophages, which were numerous in affected and surrounding alveoli, eosinophils comprised the most common and widespread inflammatory cell. Taken together, the findings in Tomm5(-/-) mice provide yet another example of the value of histopathology as a baseline assay in high-throughput phenotyping systems.
Assuntos
Pneumonia em Organização Criptogênica/patologia , Modelos Animais de Doenças , Proteínas de Membrana Transportadoras/genética , Animais , Pneumonia em Organização Criptogênica/enzimologia , Eosinófilos/patologia , Feminino , Fibroblastos/patologia , Fibrose/patologia , Humanos , Pulmão/patologia , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membranas Mitocondriais/enzimologia , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Fenótipo , Alvéolos Pulmonares/patologia , Timo/patologiaRESUMO
Minimally invasive endovascular interventions have become an important tool for the treatment of cardiovascular diseases such as ischemic heart disease, peripheral artery disease, and stroke. X-ray fluoroscopy and digital subtraction angiography are used to precisely guide these procedures, but they are associated with radiation exposure for patients and clinical staff. Magnetic Particle Imaging (MPI) is an emerging imaging technology using time-varying magnetic fields combined with magnetic nanoparticle tracers for fast and highly sensitive imaging. In recent years, basic experiments have shown that MPI has great potential for cardiovascular applications. However, commercially available MPI scanners were too large and expensive and had a small field of view (FOV) designed for rodents, which limited further translational research. The first human-sized MPI scanner designed specifically for brain imaging showed promising results but had limitations in gradient strength, acquisition time and portability. Here, we present a portable interventional MPI (iMPI) system dedicated for real-time endovascular interventions free of ionizing radiation. It uses a novel field generator approach with a very large FOV and an application-oriented open design enabling hybrid approaches with conventional X-ray-based angiography. The feasibility of a real-time iMPI-guided percutaneous transluminal angioplasty (PTA) is shown in a realistic dynamic human-sized leg model.
Assuntos
Angioplastia , Doença Arterial Periférica , Humanos , Angiografia Digital , Encéfalo , Campos MagnéticosRESUMO
Secondary contact zones have the potential to shed light on the mode and rate at which reproductive isolation accumulates during allopatric speciation. We investigated the population genetics of a contact zone between two highly divergent lineages of field voles (Microtus agrestis) in the Swiss Jura mountains. To shed light on the processes underlying introgression, we used maternally, paternally, and bi-parentally inherited markers. Though the two lineages maintained a strong genetic structure, we found some hybrids and evidence of gene flow. The extent of introgression varied with the mode of inheritance, being highest for mtDNA and absent for the Y chromosome. In addition, introgression was asymmetric, occurring only from the Northern to the Southern lineage. Both patterns seem parsimoniously explained by neutral processes linked to differences in effective sizes and sex-biased dispersal rates. The lineage with lower effective population size was also the more introgressed, and the mode-of-inheritance effect correlated with the male-biased dispersal rate of microtine rodents. We cannot exclude, however, that Haldane's effect contributed to the latter, as we found a marginally significant deficit in males (the heterogametic sex) among hybrids. We propose a possible demographic scenario to account for the patterns documented, and empirical extensions to further investigate this contact zone.
Assuntos
Arvicolinae/genética , Isolamento Reprodutivo , Animais , DNA Mitocondrial/química , Feminino , Fluxo Gênico , Especiação Genética , Haplótipos , Hibridização Genética , Masculino , Repetições de Microssatélites , Densidade Demográfica , Dinâmica Populacional , Análise de Sequência de DNA , Fatores Sexuais , Cromossomo Y/químicaRESUMO
Cardiomyopathy developed in mice deficient for α-kinase 3 (ALPK3), a nuclear kinase previously implicated in the differentiation of cardiomyocytes. Alpk3 (-/-) mice were produced according to normal Mendelian ratios and appeared normal except for a nonprogressive cardiomyopathy that had features of both hypertrophic and dilated forms of cardiomyopathy. Cardiac hypertrophy in Alpk3 (-/-) mice was characterized by increased thickness of both left and right ventricular (LV and RV) walls and by markedly increased heart weight and increased heart weight/body weight and heart weight/tibia length ratios. Magnetic resonance imaging studies confirmed the increased thickness in both septal and LV free walls at end-diastole, although there was no significant change in LV wall thickness at end-systole. Myocardial hypertrophy was the predominant feature in Alpk3 (-/-) mice, but several changes more typically associated with dilated cardiomyopathy included a marked increase in end-diastolic and end-systolic LV volume, as well as reduced cardiac output, stroke volume, and ejection fractions, suggesting LV chamber dilation. Magnetic resonance imaging showed a 50% reduction in both septal and free wall LV contractility in Alpk3 (-/-) mice. Interstitial fibrosis and inflammation were notably absent in Alpk3 (-/-) mice; however, light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils. These lesions could account for the impaired contractility of the myofibrillar apparatus and contribute to the pathogenesis of cardiomyopathy in Alpk3 (-/-) mice.
Assuntos
Cardiomiopatias/patologia , Coração/fisiopatologia , Miocárdio/patologia , Miócitos Cardíacos/patologia , Fosfotransferases/metabolismo , Animais , Diástole , Dobutamina/farmacologia , Feminino , Insuficiência Cardíaca/patologia , Frequência Cardíaca , Ventrículos do Coração/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Contração Miocárdica/efeitos dos fármacos , Fosfotransferases/genética , Deleção de Sequência , Volume Sistólico , SístoleRESUMO
There is evidence that genetic factors play a role in the complex multifactorial pathogenesis of hydrocephalus. Identification of the genes involved in the development of this neurologic disorder in animal models may elucidate factors responsible for the excessive accumulation of cerebrospinal fluid in hydrocephalic humans. The authors report here a brief summary of findings from 12 lines of genetically engineered mice that presented with autosomal recessive congenital hydrocephalus. This study illustrates the value of knockout mice in identifying genetic factors involved in the development of congenital hydrocephalus. Findings suggest that dysfunctional motile cilia represent the underlying pathogenetic mechanism in 8 of the 12 lines (Ulk4, Nme5, Nme7, Kif27, Stk36, Dpcd, Ak7, and Ak8). The likely underlying cause in the remaining 4 lines (RIKEN 4930444A02, Celsr2, Mboat7, and transgenic FZD3) was not determined, but it is possible that some of these could also have ciliary defects. For example, the cerebellar malformations observed in RIKEN 4930444A02 knockout mice show similarities to a number of developmental disorders, such as Joubert, Meckel-Gruber, and Bardet-Biedl syndromes, which involve mutations in cilia-related genes. Even though the direct relevance of mouse models to hydrocephalus in humans remains uncertain, the high prevalence of familial patterns of inheritance for congenital hydrocephalus in humans suggests that identification of genes responsible for development of hydrocephalus in mice may lead to the identification of homologous modifier genes and susceptibility alleles in humans. Also, characterization of mouse models can enhance understanding of important cell signaling and developmental pathways involved in the pathogenesis of hydrocephalus.
Assuntos
Encéfalo/patologia , Deficiências do Desenvolvimento/genética , Hidrocefalia/genética , Doenças do Sistema Nervoso/genética , Animais , Cerebelo/patologia , Deficiências do Desenvolvimento/fisiopatologia , Modelos Animais de Doenças , Engenharia Genética , Humanos , Hidrocefalia/complicações , Hidrocefalia/fisiopatologia , Infertilidade/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mutagênese , Mutação , Doenças do Sistema Nervoso/fisiopatologia , Fenótipo , Rinite/complicações , Transdução de Sinais , Sinusite/complicações , Situs Inversus/genéticaRESUMO
The FAM20 family of secreted proteins consists of three members (FAM20A, FAM20B, and FAM20C) recently linked to developmental disorders suggesting roles for FAM20 proteins in modulating biomineralization processes. The authors report here findings in knockout mice having null mutations affecting each of the three FAM20 proteins. Both Fam20a and Fam20c null mice survived to adulthood and showed biomineralization defects. Fam20b (-/-) embryos showed severe stunting and increased mortality at E13.5, although early lethality precluded detailed investigations. Physiologic calcification or biomineralization of extracellular matrices is a normal process in the development and functioning of various tissues (eg, bones and teeth). The lesions that developed in teeth, bones, or blood vessels after functional deletion of either Fam20a or Fam20c support a significant role for their encoded proteins in modulating biomineralization processes. Severe amelogenesis imperfecta (AI) was present in both Fam20a and Fam20c null mice. In addition, Fam20a (-/-) mice developed disseminated calcifications of muscular arteries and intrapulmonary calcifications, similar to those of fetuin-A deficient mice, although they were normocalcemic and normophosphatemic, with normal dentin and bone. Fam20a gene expression was detected in ameloblasts, odontoblasts, and the parathyroid gland, with local and systemic effects suggesting both local and/or systemic effects for FAM20A. In contrast, Fam20c (-/-) mice lacked ectopic calcifications but were severely hypophosphatemic and developed notable lesions in both dentin and bone to accompany the AI. The bone and dentin lesions, plus the marked hypophosphatemia and elevated serum alkaline phosphatase and FGF23 levels, are indicative of autosomal recessive hypophosphatemic rickets/osteomalacia in Fam20c (-/-) mice.
Assuntos
Amelogênese Imperfeita/veterinária , Proteínas de Ligação ao Cálcio/genética , Proteínas da Matriz Extracelular/genética , Osteomalacia/veterinária , Proteínas/genética , Raquitismo/veterinária , Fosfatase Alcalina/sangue , Amelogênese Imperfeita/metabolismo , Amelogênese Imperfeita/patologia , Animais , Cálcio/sangue , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas do Esmalte Dentário/genética , Proteínas do Esmalte Dentário/metabolismo , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/metabolismo , Feminino , Fator de Crescimento de Fibroblastos 23 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteomalacia/metabolismo , Osteomalacia/patologia , Fenótipo , Fósforo/sangue , Proteínas/metabolismo , Radiografia , Raquitismo/metabolismo , Raquitismo/patologia , Dente/diagnóstico por imagem , Dente/metabolismo , Dente/patologia , Calcificação de DenteRESUMO
Empathy is defined as the ability to vicariously experience others' suffering (vicarious pain) or feeling their joy (vicarious reward). While most neuroimaging studies have focused on vicarious pain and describe similar neural responses during the observed and the personal negative affective involvement, only initial evidence has been reported for the neural responses to others' rewards and positive empathy. Here, we propose a novel approach, based on the simultaneous recording of multi-subject EEG signals and exploiting the wavelet coherence decomposition to measure the temporal alignment between ERPs in a dyad of interacting subjects. We used the Third-Party Punishment (TPP) paradigm to elicit the personal and vicarious experiences. During a positive experience, we observed the simultaneous presence in both agents of the Late Positive Potential (LPP), an ERP component related to emotion processing, as well as the existence of an inter-subject ERPs synchronization in the related time window. Moreover, the amplitude of the LPP synchronization was modulated by the presence of a human-agent. Finally, the localized brain circuits subtending the ERP-synchronization correspond to key-regions of personal and vicarious reward. Our findings suggest that the temporal and spatial ERPs alignment might be a novel and direct proxy measure of empathy.
Assuntos
Encéfalo , Empatia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Emoções/fisiologia , Humanos , Dor/psicologia , RecompensaRESUMO
The ubiquitously expressed chloride channel 7 (CLCN7) is present within the ruffled border of osteoclasts. Mutations in the CLCN7 gene in humans (homologous to murine Clcn7) are responsible for several types of osteopetrosis in humans, and deficiencies in CLCN7 can present with retinal degeneration and a neuronal storage disease. A previously reported Clcn7(-/-) mouse showed diffuse osteopetrosis accompanied by severe retinal and neuronal degeneration. In contrast, the authors produced a novel Clcn7(-/-) mutant where mice did not develop osteopetrosis but still developed lethal neural and retinal degeneration. In these mice, there was a rapid progressive loss of the outer nuclear layer and photoreceptor layers of the retina. Laminar degeneration and necrosis of neurons in layers IV and V of the cerebral cortex and in the CA2/CA3 regions of the hippocampus were associated with intraneuronal accumulations of autofluorescent granules (periodic acid-Schiff positive). The extensive reactive gliosis was always associated with the accumulation of intraneuronal cytoplasmic material. The authors found, through quantitative real time polymerase chain reaction analyses, that an alternate Clcn7 transcript (previously identified only in bone marrow) showed minimal expression in the brain and eye but moderate expression in bone, which correlates with rescue of the osteopetrotic phenotype in the face of continued retinal and neuronal degeneration. Findings in this knockout mouse model prove that osteopetrotic compression of the brain is not responsible for neuronal and retinal degeneration in CLCN7-deficient mice; rather, they suggest that neurotoxicity is most likely due to lysosomal dysfunction as a result of the functional lack of this chloride channel in the central nervous system and eye.
Assuntos
Processamento Alternativo , Canais de Cloreto/metabolismo , Doenças Neurodegenerativas/patologia , Osteopetrose/patologia , Degeneração Retiniana/patologia , Animais , Densidade Óssea/genética , Canais de Cloreto/genética , Variação Genética , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Osteopetrose/complicações , Osteopetrose/genética , Osteopetrose/metabolismo , Degeneração Retiniana/etiologia , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismoRESUMO
This investigation found that genetic inactivation of mouse Atg4b, 1 of the 4 mammalian homologs of the autophagy-related gene Atg4, resulted in amorphous globular bodies in the neuropil of the deep cerebellar nuclei and adjacent vestibular nuclei but nowhere else in the brain or other tissues. The spheroid-like bodies in the deep cerebellar and vestibular nuclei showed heterogeneous composition, reactivity with anti-ubiquitin antibody, and staining characteristics of proteinaceous material. Atg4b-deficient (Atg4b (-/-)) mice also showed a mild but measurable impairment of motor performance on the Rotarod. Atg4b (-/-) mice produced by breeding heterozygous parents were produced at a slightly lower than expected ratio to heterozygous and wild-type siblings but showed no other clear abnormalities in a battery of screening tests. These findings appear to be different than those reported for inactivation of other Atg4 homologs, suggesting that these homologs have tissue-specific functions beyond redundancy.
Assuntos
Cerebelo/patologia , Cisteína Endopeptidases/deficiência , Cisteína Endopeptidases/genética , Atividade Motora/genética , Fenótipo , Animais , Proteínas Relacionadas à Autofagia , Cerebelo/metabolismo , Cruzamentos Genéticos , Inativação Gênica , Técnicas Histológicas , Camundongos , Camundongos Knockout , Teste de Desempenho do Rota-RodRESUMO
Congenital generalized lipodystrophy (CGL) comprises a heterogeneous group of rare diseases associated with partial or total loss of adipose tissue. Of these, autosomal recessive Berardinelli-Seip congenital lipodystrophy (BSCL) is characterized by the absence of metabolically active subcutaneous and visceral adipose tissues. Metabolic abnormalities associated with lipodystrophy include insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. One form of BSCL has been linked to genetic mutations affecting the lipid biosynthetic enzyme 1-acyl-sn-glycerol 3-phosphate O-acyltransferase 2 (AGPAT2), which is highly expressed in adipose tissue. Precisely how AGPAT2 deficiency causes lipodystrophy remains unresolved, but possible mechanisms include impaired lipogenesis (triglyceride synthesis and storage), blocked adipogenesis (differentiation of preadipocytes to adipocytes), or apoptosis/necrosis of adipocytes. Agpat2(-/-) mice share important pathophysiologic features of CGL previously reported in humans. However, the small white adipose tissue (WAT) depots consisting largely of amoeboid adipocytes with microvesiculated basophilic cytoplasm showed that adipogenesis with deficient lipogenesis was present in all usual locations. Although well-defined lobules of brown adipose tissue (BAT) were present, massive necrosis resulted in early ablation of BAT. Although necrotic or apoptotic adipocytes were not detected in WAT of 10-day-old Agpat2(-/-), the absence of adipocytes in aged mice indicates that these cells must undergo necrosis/apoptosis at some point. Another significant finding in aged lipodystrophic mice was massive pancreatic islet hypertrophy in the face of chronic hyperglycemia, which suggests that glucotoxicity is insufficient by itself to cause ß-cell loss and that adipocyte-derived factors help regulate total ß-cell mass.
Assuntos
1-Acilglicerol-3-Fosfato O-Aciltransferase/metabolismo , Lipodistrofia/congênito , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Envelhecimento , Animais , Glicemia/metabolismo , Teste de Tolerância a Glucose , Hepatomegalia/genética , Hepatomegalia/patologia , Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Lipodistrofia/genética , Lipodistrofia/patologia , Camundongos , Camundongos KnockoutRESUMO
UNLABELLED: AIMS OF THE INVESTIGATION: The 6-minute-walk-test (6-MWT) is an effective tool for measuring physical fitness in elderly patients. The increased walking distance is taken as a parameter for improved physical conditions. Frequently an unaltered walking distance is found after participation in a rehabilitation measure, but heart rate is significantly lower in the second challenge, indicating an improved physical fitness. This positive effect is not recognized when only the walking distance is considered. METHODS: We therefore carried out a retrospective analysis of the 6-MWT tests performed by 303 male patients (69.2 ± 8.7 years) before and after 3-4 weeks of clinical rehabilitation. Instrumented by a mobile pulse oximeter for recording oxygen saturation and heart rate, patients were instructed at the outset and at the end of their rehabilitation stay to walk as fast as they could during 6 min. Measurements were performed every 30 s and printed. A new parameter, efficiency (E = S/6/f (C)) was introduced: the ratio of the walking distance, S, divided by 6 min and divided by the mean heart frequency, f (C) (beats/minute). RESULTS: The patients group walked 351 ± 79 m at 106.2 ± 12.7 beats/min in the initial 6-MWT and 362 ± 76.0 m at a heart rate of 104.0 ± 12.2 beats/min in the final test. Along with the increase in walking distance, efficiency E increased from 0.56 ± 0.13 m/beat to 0.59 ± 0.12 m/beat. Efficiency significantly correlates with the walking distance (p < 0.01). 54 patients (18%) had an increased efficiency in the final test at the end of rehabilitation although they walked a shorter distance compared to the initial test value: they walked with a lower heart frequency. CONCLUSIONS: The patient's performance of the second walk test with an unchanged distance at a lower heart frequency reveals an improved physical fitness. This is solely described by an increase of the parameter of efficiency, E. Calculation of this parameter delivers a quantification of the effect of exercise training irrespective of the patient's cooperation. Efficiency, hence, is a meaningful complement to the sole consideration of the distance walked in the assessment of physical fitness as a benefit of rehabilitation.
Assuntos
Teste de Esforço/métodos , Aptidão Física , Pneumoconiose/reabilitação , Doença Pulmonar Obstrutiva Crônica/reabilitação , Caminhada , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia por Exercício , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Resistência Física , Centros de Reabilitação , Treinamento Resistido , Indenização aos TrabalhadoresRESUMO
Determination of the spin echo signal evolution and of transverse relaxation rates is of high importance for microstructural modeling of muscle tissue in magnetic resonance imaging. So far, numerically exact solutions for the NMR signal dynamics in muscle tissue models have been reported only for the gradient echo free induction decay, with spin echo problems usually solved by approximate methods. In this work, we modeled the spin echo signal numerically exact by discretizing the radial dimension of the Bloch-Torrey equation and expanding the angular dependency in terms of even Chebyshev polynomials. This allows us to express the time dependence of the local magnetization as a closed-form matrix expression. Using this method, we were able to accurately capture the spin echo local and total magnetization dynamics. The obtained transverse relaxation rates showed a high concordance with random walker and finite-element simulations. We could demonstrate that in cases of smaller diffusion coefficients, the commonly used strong collision approximation significantly underestimates the true value considerably. Instead, the limiting behavior in this regime is correctly described either by the full solution or by the slow diffusion approximation. Experimentally measured transverse relaxation rates of a mouse limb muscle showed an angular dependence in accordance with the theoretical prediction.
RESUMO
PURPOSE: Magnetic Particle Imaging (MPI) is a new, background- and radiation-free tomographic imaging method that enables near real-time imaging of superparamagnetic iron-oxide nanoparticles (SPIONs) with high temporal and spatial resolution. This phantom study aims to investigate the potential of MPI for visualization of the stent lumen in intracranial flow diverters (FD). METHODS: Nitinol FD of different dimensions (outer diameter: 3.5 mm, 4.0 mm, 5.5 mm; total length: 22-40 mm) were scanned in vascular phantoms in a custom-built MPI scanner (in-plane resolution: ~ 2 mm, field of view: 65 mm length, 29 mm diameter). Phantoms were filled with diluted (1:50) SPION tracer agent Ferucarbotran (10 µmol (Fe)/ml; NaCL). Each phantom was measured in 32 different projections (overall acquisition time per image: 3200 ms, 5averages). After image reconstruction from raw data, two radiologists assessed image quality using a 5-point Likert scale. The signal intensity profile was measured using a semi-automatic evaluation tool. RESULTS: MPI visualized the lumen of all FD without relevant differences between the stented vessel phantom and the reference phantom. At 3.5 mm image quality was slightly inferior to the larger diameters. The FD themselves neither generated an MPI signal nor did they lead to relevant imaging artifacts. Ratings of both radiologists showed no significant difference, interrater reliability was good (ICC 0.84). A quantitative evaluation of the signal intensity profile did not reveal any significant differences (p > 0.05) either. CONCLUSION: MPI visualizes the lumen of nitinol FD stents in vessel phantoms without relevant stent-induced artifacts.
Assuntos
Artefatos , Tomografia , Fenômenos Magnéticos , Imagens de Fantasmas , Reprodutibilidade dos Testes , StentsRESUMO
Previously, we have shown that a multicopy family of related but unique genes encodes the major surface glycoprotein (MSG) of Pneumocystis carinii. To examine whether different members of this gene family are expressed by P. carinii, antisera were prepared against peptides whose sequences were determined from the deduced amino acid sequences of variants of rat-derived MSG. Immunohistochemical staining of serial sections of rat lungs of infected animals showed that at least three variants of MSG were expressed in an individual lobe, that there was a focal expression of these variants within the lung, and that the relative numbers of these foci were different. Indirect immunofluorescent staining of purified P. carinii organisms using these antisera revealed that at least three variants of MSG were present in organisms isolated from an individual rat and that both cysts and trophozoites reacted with each antiserum. A substantial difference in the fraction of organisms reacting with a specific antipeptide antiserum was seen when comparing organisms isolated from rats raised in a single colony over a period of two years as well as organisms isolated at one time point from rats raised in different colonies. This demonstration of antigenic variation in P. carinii supports the hypothesis that P. carinii utilizes such variation for evading host defense mechanisms.
Assuntos
Proteínas Fúngicas/biossíntese , Genes Bacterianos , Variação Genética , Glicoproteínas de Membrana/biossíntese , Família Multigênica , Pneumocystis/metabolismo , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais , Proteínas Fúngicas/análise , Expressão Gênica , Soros Imunes , Pulmão/microbiologia , Masculino , Glicoproteínas de Membrana/análise , Camundongos , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/imunologia , Pneumocystis/isolamento & purificação , Coelhos , Ratos , Ratos Sprague-DawleyRESUMO
Tubulin tyrosine ligase-like 1 (TTLL1) protein is a member of the tubulin tyrosine ligase superfamily of proteins that are involved in the posttranslational polyglutamylation of tubulin in axonemal microtubules within cilia and flagella. To investigate the physiological role of TTLL1, the authors generated mice with a gene trap mutation in the Ttll1 gene that provide confirmation in a mammalian model that polyglutamylation plays an important role in some ciliary and flagellar functions. For the first time, mice homozygous for the Ttll1 mutation exhibited accumulations of exudates in the nasal passages and sinuses, rhinosinusitis, otitis media, and male infertility. In homozygous mutant male mice, abnormal sperm morphology and function were characterized by shortened or absent flagella and immotility. Although homozygous mutant males were infertile, the females were fertile. These findings are consistent with a diagnosis of primary ciliary dyskinesia (PCD) resulting from ciliary dysfunction. They indicate that Ttll1 is essential for normal motility of respiratory cilia and the biogenesis and function of sperm flagella but that the defect does not result in the hydrocephalus or laterality defects often seen in other forms of PCD. The absence of early-onset lethal hydrocephalus in Ttll1-mutant mice may enable studies to evaluate the long-term effects of PCD in the respiratory system of mice. Although no mutations in the orthologous gene have been linked with PCD in humans, investigating the role of TTLL1 and polyglutamylation of tubulin in cilia and flagella should advance an understanding of the biogenesis and function of these organelles in mammals and have potential diagnostic and therapeutic applications.