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1.
Acta Neurochir (Wien) ; 165(12): 4279-4292, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37535206

RESUMO

BACKGROUND: Tumors of the fourth ventricle are frequently treated pathologies in pediatric neurosurgery. Data regarding predictors for permanent neurological deficits, long-term functional outcomes, cerebellar mutism (CM), the extent of resection (EOR), and oncological outcomes are scarce. We attempt to contribute to this topic with an analysis of our institutional cohort. METHODS: A retrospective single-center study of patients aged ≤ 19 years who underwent primary surgical resection of a fourth ventricular tumor over a 15-year period (2006-2021). Predictors analyzed included age, gender, surgical approach, anatomical pattern, tumor grade, EOR, tumor volume, and others as appropriate. RESULTS: One hundred six patients were included (64 males, mean age 7.3 years). The rate of permanent neurological deficit was 24.2%; lateral tumor extension (p = 0.036) and tumor volume greater than 38 cm3 (p = 0.020) were significant predictors. The presence of a deficit was the only significant predictor of reduced (less than 90) Lansky score (p = 0.005). CM occurred in 20.8% of patients and was influenced by medulloblastoma histology (p = 0.011), lateral tumor extension (p = 0.017), and male gender (p = 0.021). No significant difference between the transvermian and telovelar approach in the development of CM was detected (p = 0.478). No significant predictor was found for the EOR. EOR was not found to be a significant predictor of overall survival for both low-grade and high-grade tumors; however, gross total resection (GTR) was protective against tumor recurrence compared to near-total or subtotal resection (p < 0.001). In addition, survival was found to be better in older patients (≥ 7.0 years, p = 0.019). CONCLUSION: The overall rate of postoperative complications remains high due to the eloquent localization. Older patients (> 7 years) have been found to have better outcomes and prognosis. Achieving GTR whenever feasible and safe has been shown to be critical for tumor recurrence. CM was more common in patients with medulloblastoma and in patients with tumors extending through the foramen of Luschka. The telovelar approach uses a safe and anatomically sparing corridor; however, it has not been associated with a lower incidence of CM and neurological sequelae in our series, showing that each case should be assessed on an individual basis.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Humanos , Criança , Masculino , Idoso , Quarto Ventrículo/diagnóstico por imagem , Quarto Ventrículo/cirurgia , Estudos Retrospectivos , Procedimentos Neurocirúrgicos/efeitos adversos , Meduloblastoma/cirurgia , Recidiva Local de Neoplasia/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Neoplasias Cerebelares/cirurgia , Neoplasias Cerebelares/etiologia , Resultado do Tratamento
2.
J Am Chem Soc ; 144(42): 19437-19446, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36245092

RESUMO

A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C-H functionalization of diverse (hetero)aromatics with dibenzothiophene-S-oxide followed by the Negishi cross-cooupling with bis(4,6-dichloropyrimidin-5-yl)zinc. This cross-coupling afforded a series of (het)aryl-pyrimidines that were converted to fused deazapurine heterocycles through azidation and thermal cyclization. The fused heterocycles were glycosylated to the corresponding 2'-deoxy- and ribonucleosides, and a series of derivatives were prepared by nucleophilic substitutions at position 4. Four series of new polycyclic thieno-fused 7-deazapurine nucleosides were synthesized using this strategy. Most of the deoxyribonucleosides showed good cytotoxic activity, especially for the CCRF-CEM cell line. Phenyl- and thienyl-substituted thieno-fused 7-deazapurine nucleosides were fluorescent, and the former one was converted to 2'-deoxyribonucleoside triphosphate for enzymatic synthesis of labeled oligonucleotides.


Assuntos
Nucleosídeos , Ribonucleosídeos , Linhagem Celular Tumoral , Pirimidinas , Óxidos , Zinco , Oligonucleotídeos , Desoxirribonucleosídeos , Nucleosídeos de Purina
3.
Chembiochem ; 23(3): e202100608, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-34821441

RESUMO

All four iodinated 2'-deoxyribonucleoside triphosphates (dNTPs) derived from 5-iodouracil, 5-iodocytosine, 7-iodo-7-deazaadenine and 7-iodo-7-deazaguanine were prepared and studied as substrates for KOD XL DNA polymerase. All of the nucleotides were readily incorporated by primer extension and by PCR amplification to form DNA containing iodinated nucleobases. Systematic study of the Suzuki-Miyaura cross-coupling reactions with two bulkier arylboronic acids revealed that the 5-iodopyrimidines were more reactive and gave cross-coupling products both in the terminal or internal position in single-stranded oligonucleotides (ssONs) and in the terminal position of double-stranded DNA (dsDNA), whereas the 7-iodo-7-deazapurines were less reactive and gave cross-coupling products only in the terminal position. None of the four iodinated bases reacted in an internal position of dsDNA. These findings are useful for the use of the iodinated nucleobases for post-synthetic modification of DNA with functional groups for various applications.


Assuntos
DNA Polimerase Dirigida por DNA/metabolismo , DNA/química , Nucleosídeos/síntese química , Purinas/síntese química , Pirimidinas/síntese química , Halogenação , Conformação Molecular , Nucleosídeos/química , Purinas/química , Pirimidinas/química
4.
Acta Neurochir (Wien) ; 164(6): 1459-1472, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35043265

RESUMO

BACKGROUND: Childhood thalamopeduncular gliomas arise at the interface of the thalamus and cerebral peduncle. The optimal treatment is total resection but not at the cost of neurological function. We present long-term clinical and oncological outcomes of maximal safe resection. METHODS: Retrospective review of prospectively collected data: demography, symptomatology, imaging, extent of resection, surgical complications, histology, functional and oncological outcome. RESULTS: During 16-year period (2005-2020), 21 patients were treated at our institution. These were 13 girls and 8 boys (mean age 7.6 years). Presentation included progressive hemiparesis in 9 patients, raised intracranial pressure in 9 patients and cerebellar symptomatology in 3 patients. The tumour was confined to the thalamus in 6 cases. Extent of resection was judged on postoperative imaging as total (6), near-total (6) and less extensive (9). Surgical complications included progression of baseline neurological status in 6 patients, and 5 of these gradually improved to preoperative status. All tumours were classified as low-grade gliomas. Disease progression was observed in 9 patients (median progression-free survival 7.3 years). At last follow-up (median 6.1 years), all patients were alive, median Lansky score of 90. Seven patients were without evidence of disease, 6 had stable disease, 7 stable following progression and 1 had progressive disease managed expectantly. CONCLUSION: Paediatric patients with low-grade thalamopeduncular gliomas have excellent long-term functional and oncological outcomes when gross total resection is not achievable. Surgery should aim at total resection; however, neurological function should not be endangered due to excellent chance for long-term survival.


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Criança , Feminino , Glioma/complicações , Glioma/diagnóstico por imagem , Glioma/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Procedimentos Neurocirúrgicos/métodos , Estudos Retrospectivos , Tálamo/diagnóstico por imagem , Tálamo/patologia , Tálamo/cirurgia , Resultado do Tratamento
5.
Bioorg Med Chem Lett ; 40: 127957, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33741462

RESUMO

Trypanosoma brucei parasites cause Human African Trypanosomiasis and the current drugs for its treatment are often inefficient and toxic. This urges the need to development of new antitrypanosomal agents. We report the synthesis and biological profiling of 3'-deoxy-3'-fluororibonucleosides derived from 7-deazaadenine nucleosides bearing diverse substituents at position 7. They were synthesized through glycosylation of 6-chloro-7-bromo- or -7-iodo-7-deazapurine with protected 3'-fluororibose followed by cross-coupling reactions at position 7 and/or deprotection. Most of the title nucleosides displayed micromolar or submicromolar activity against Trypanosoma brucei brucei. The most active were the 7-bromo- and 7-iododerivatives which exerted double-digit nanomolar activity against T. b. brucei and T. b. gambiense and no cytotoxicity and thus represent promising candidates for further development.


Assuntos
Ribonucleosídeos/farmacologia , Tripanossomicidas/farmacologia , Linhagem Celular Tumoral , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ribonucleosídeos/síntese química , Ribonucleosídeos/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidade , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei gambiense/efeitos dos fármacos
6.
Chemistry ; 26(57): 13002-13015, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-32275109

RESUMO

All four isomeric series of novel 4-substituted pyrido-fused 7-deazapurine ribonucleosides possessing the pyridine nitrogen atom at different positions were designed and synthesized. The total synthesis of each isomeric fused heterocycle through multistep heterocyclization was followed by glycosylation and derivatization at position 4 by cross-coupling reactions or nucleophilic substitutions. All compounds were tested for cytostatic and antiviral activity. The most active were pyrido[4',3':4,5]pyrimidine nucleosides bearing MeO, NH2 , MeS, or CH3 groups at position 4, which showed submicromolar cytotoxic effects and good selectivity for cancer cells. The mechanism involved activation by phosphorylation and incorporation to DNA where the presence of the modified ribonucleosides causes double-strand breaks and apoptosis.


Assuntos
Ribonucleosídeos/síntese química , Antineoplásicos/farmacologia , Antivirais/farmacologia , Purinas/farmacologia , Ribonucleosídeos/farmacologia , Relação Estrutura-Atividade
7.
J Org Chem ; 85(12): 8085-8101, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32432875

RESUMO

Two isomeric series of benzothieno-fused 7-deazapurine (benzo[4',5']thieno[3',2':4,5]- and benzo[4',5']thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidine) ribonucleosides were designed and synthesized. Key steps of the synthesis included the Negishi coupling of zincated dichloropyrimidine with 2- or 3-iodobenzothiophene followed by azidation, thermal or photochemical cyclization, glycosylation, and final functionalization at position 6 through cross-couplings or nucleophilic substitutions. Deprotection gave the final nucleosides, some of which showed moderate cytotoxic and antiviral activity. Most of the free nucleosides showed moderate to strong fluorescence with emission maxima of 362-554 nm. 2'-Deoxyribonucleoside and its 5'-O-triphosphate were also prepared from benzothieno-fused 7-deazaadenine derivative, and the triphosphate was a good substrate for KOD XL DNA polymerase in primer extension synthesis of modified DNA which exerted a weak fluorescence which was slightly enhanced in double-stranded DNA as compared to single-stranded oligonucleotides.


Assuntos
Ribonucleosídeos , Antivirais , Nucleosídeos , Purinas
8.
J Org Chem ; 85(16): 10539-10551, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32692916

RESUMO

A series of 8-substituted 1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrrolo[2,3-d]pyrimidine (methylpyrazolo-fused 7-deazapurine) ribonucleosides have been designed and synthesized. Two synthetic approaches to the key heterocyclic aglycon 7, (i) a six-step classical heterocyclization starting from 5-chloro-1-methyl-4-nitropyrazole and (ii) a three-step cross-coupling and cyclization approach starting from the zincated 4,6-dichloropyrimidine, gave comparable total yields of 18% vs 13%. The glycosylation of 7 was attempted by three different methods but only the Vorbrüggen silyl-base protocol was efficient and stereoselective to give desired ß-anomeric nucleoside intermediate 17A. Its nucleophilic substitutions or cross-coupling reactions at position 8 and deprotection of the sugar moiety gave eight derivatives of pyrazolo-fused deazapurine ribonucleosides, some of which were weakly fluorescent. Methyl, amino, and methylsulfanyl derivatives exerted submicromolar cytotoxic effects in vitro against a panel of cancer and leukemia cell lines as well as antiviral effects against hepatitis C virus in the replicon assay.


Assuntos
Nucleosídeos , Ribonucleosídeos , Antivirais/farmacologia , Purinas/farmacologia , Ribonucleosídeos/farmacologia
9.
BMC Neurol ; 20(1): 359, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32972372

RESUMO

BACKGROUND: Immune-mediated mechanisms substantially contribute to the Rasmussen encephalitis (RE) pathology, but for unknown reasons, immunotherapy is generally ineffective in patients who have already developed intractable epilepsy; overall laboratory data regarding the effect of immunotherapy on patients with RE are limited. We analyzed multiple samples from seven differently treated children with RE and evaluated the effects of immunotherapies on neuroinflammation. Immunotherapy was introduced to all patients at the time of intractable epilepsy and they all had to undergo hemispherothomy. METHODS: Immunohistochemistry, flow cytometry, Luminex multiplex bead and enzyme-linked immunosorbent assay techniques were combined to determine: 1) inflammatory changes and lymphocyte subpopulations in 45 brain tissues; 2) lymphocyte subpopulations and the levels of 12 chemokines/cytokines in 24 cerebrospinal fluid (CSF) samples and 30 blood samples; and 3) the dynamics of these parameters in four RE patients from whom multiple samples were collected. RESULTS: Sustained T cell-targeted therapy with cyclophosphamide, natalizumab, alemtuzumab, and intrathecal methotrexate (ITMTX), but not with azathioprine, substantially reduced inflammation in brain tissues. Despite the therapy, the distributions of CD8+ T cells and the levels of C-X-C motif ligand (CXCL) 10, CXCL13, and B cell activating factor (BAFF) in patients' CSF remained increased compared to controls. A therapeutic approach combining alemtuzumab and ITMTX was the most effective in producing simultaneous reductions in histopathological inflammatory findings and in the numbers of activated CD8+ T cells in the brain tissue, as well as in the overall CD8+ T cell population and chemokine/cytokine production in the CSF. CONCLUSIONS: We provide evidence that various T cell-targeted immunotherapies reduced inflammation in the brains of RE patients. The observation that intractable epilepsy persisted in all of the patients suggests a relative independence of seizure activity on the presence of T cells in the brain later in the disease course. Thus, new therapeutic targets must be identified. CXCL10, CXCL13 and BAFF levels were substantially increased in CSF from all patients and their significance in RE pathology remains to be addressed.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Encefalite/terapia , Imunoterapia/métodos , Encéfalo/patologia , Criança , Pré-Escolar , Citocinas/imunologia , Encefalite/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Inflamação/terapia , Masculino
10.
Epilepsia ; 60(11): 2263-2276, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31612465

RESUMO

OBJECTIVE: To evaluate the impact of generalized quasiperiodic epileptiform discharges ("hurdles") observed in non-rapid eye movement (NREM) sleep on cognitive function in children with intractable focal epilepsy. "Hurdles" pattern does not meet the criteria of the electrical status epilepticus in slow-wave sleep (ESES). METHODS: In a retrospective analysis, 24 patients with "hurdles" and their 24 peers matched for demographic and epilepsy-related variables were compared in terms of neuropsychological domains and electroencephalography (EEG)-derived quantifiers. Both "hurdles" and controls were children between 2 and 19 years of age who had intractable focal epilepsy evaluated as candidates of resective epilepsy surgery. RESULTS: Full-scale intelligence quotient/developmental quotient (FSIQ/DQ) (P = .002) and visuoconstructional skills (P = .004) were significantly lower in children with "hurdles" compared to controls. Patients with "hurdles" presented with higher interictal spike indexes in sleep (P < .001, median difference -0.9, 95% confidence interval [CI] -1.4, -0.6) and wakefulness (P < .001, median difference -0.3, 95% CI -0.5, -1). Relative time of sleep spindles in NREM sleep was significantly reduced (P < .001, median difference 0.1, 95% CI 0.0, 0.1) in the "hurdles" group. The time proportion of sleep spindles represented a significant positive (P = .008) and spike index of generalized spikes in sleep a significant negative explanatory variable (P = .004) of FSIQ/DQ scores. The proportion of seizure-free patients 2 years after epilepsy surgery did not differ significantly between the two groups (P = .19). SIGNIFICANCE: Although the "hurdles" pattern does not fulfill the criteria of ESES, it is associated with a pronounced cognitive dysfunction. Disturbed sleep structure marked by reduced sleep spindles and generalized spiking in sleep is associated with worse cognitive performance. Despite having a generalized nature, we did not find a lower probability of postsurgical seizure freedom in patients with "hurdles" pattern.


Assuntos
Disfunção Cognitiva/fisiopatologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletroencefalografia/tendências , Epilepsias Parciais/fisiopatologia , Sono/fisiologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/psicologia , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/psicologia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Vigília/fisiologia , Adulto Jovem
11.
J Neurooncol ; 143(1): 15-25, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30827009

RESUMO

PURPOSE: The aim of this study was to test the possibility of using specimens obtained by a cavitron ultrasonic surgical aspirator (CUSA) in flow and mass cytometry investigations of pediatric brain tumors. METHODS: CUSA specimens obtained from 19 pediatric patients with brain tumors were investigated. Flow and mass cytometry methods were applied to analyze the composition of material collected using the CUSA. Cell suspensions were prepared from CUSA aspirates. Then sample viability was assessed by conventional flow cytometry and subsequently stained with a panel of 31 metal-labeled antibodies. RESULTS: Viability assessment was performed using conventional flow cytometry. Viability of cells in the acquired samples was below 50% in 16 of 19 cases. A mass cytometry investigation and subsequent analysis enabled us to discriminate brain tumor cells from contaminating leukocytes, whose proportions varied across the specimens. The addition of the viability marker cisplatin directly into the mass cytometry panel gave the means to selecting viable cells only for subsequent analyses. The proportion of non-viable cells was higher among tumor cells compared leukocytes. CONCLUSIONS: When the analysis of the tumor cell immunophenotype is performed with markers for determining viability, the expression of the investigated markers can be evaluated. Suitable markers can be selected by high-throughput methods, such as mass cytometry, and those that are diagnostically relevant can be investigated using flow cytometry, which is more flexible in terms of time.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirurgia , Sobrevivência Celular , Cisplatino/metabolismo , Citometria de Fluxo , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Procedimentos Neurocirúrgicos/instrumentação , Análise de Célula Única , Terapia por Ultrassom/instrumentação
12.
Tumour Biol ; 37(8): 10723-9, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26873484

RESUMO

The MYB gene codes for the c-Myb transcription factor maintaining proliferation of colon epithelial progenitors, thus controlling colon development and homeostasis. This gene is overexpressed in early phases of colorectal cancer (CRC) tumorigenesis. The aim of this study was to examine the expression of c-Myb in CRC tissue samples both at the messenger RNA (mRNA) and protein levels and to evaluate their associations with clinicopathological characteristics in a group of 108 CRC patients. Statistically significant negative association was found between the frequency of the c-Myb-positive tumor cells assessed by immunohistochemistry and the presence of distant metastases (p < 0.01) but not tumor differentiation, tumor stage, lymph node involvement, vascular invasion, tumor localization, age, and gender of the patients. Although the c-Myb protein level in the tumor tissue correlated with its mRNA level, no significant association between MYB mRNA and any clinicopathological characteristics was observed. We conclude that albeit overexpression of c-Myb is considered as an important factor contributing to early phases of CRC tumorigenesis, it may later have negative effect on tumor cell dissemination as observed recently in breast cancer as well. Further studies are required to explain the role of c-Myb during formation of CRC distant metastases.


Assuntos
Adenocarcinoma/secundário , Neoplasias Colorretais/genética , Genes myb , Proteínas de Neoplasias/biossíntese , Proteínas Proto-Oncogênicas c-myb/biossíntese , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Neoplasias Colorretais/patologia , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-myb/genética , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese
13.
Bioorg Med Chem ; 24(19): 4528-4535, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27498304

RESUMO

Four 6-substituted 4-amino-pyrimido[4,5-b]indole 2'-deoxyribonucleoside triphosphates (dA(BX)TPs) were prepared by glycosylation of 4,6-dichloropyrimidoindole followed by ammonolysis, cross-coupling and triphosphorylation. They were found to be moderate to good substrates for DNA polymerases in primer extension. They also exerted fluorescence with emission maxima 335-378nm. When incorporated to oligonucleotide probes, they did not show significant mismatch discrimination but the 6-benzofuryl 4-amino-pyrimido[4,5-b]indole nucleotide displayed a useful sensitivity to protein binding in experiment with SSB protein.


Assuntos
Nucleotídeos de Desoxiadenina/química , Desoxirribonucleosídeos/química , Corantes Fluorescentes/química , Indóis/química , Sondas de Oligonucleotídeos/química , Pareamento Incorreto de Bases , Sequência de Bases , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Nucleotídeos de Desoxiadenina/síntese química , Nucleotídeos de Desoxiadenina/metabolismo , Desoxirribonucleosídeos/síntese química , Desoxirribonucleosídeos/metabolismo , Escherichia coli/química , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Indóis/síntese química , Indóis/metabolismo , Sondas de Oligonucleotídeos/síntese química , Sondas de Oligonucleotídeos/metabolismo , Espectrometria de Fluorescência
14.
Microsc Microanal ; 21(4): 863-75, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25951852

RESUMO

Mechanical properties of the arterial wall depend largely on orientation and density of collagen fiber bundles. Several methods have been developed for observation of collagen orientation and density; the most frequently applied collagen-specific manual approach is based on polarized light (PL). However, it is very time consuming and the results are operator dependent. We have proposed a new automated method for evaluation of collagen fiber direction from two-dimensional polarized light microscopy images (2D PLM). The algorithm has been verified against artificial images and validated against manual measurements. Finally the collagen content has been estimated. The proposed algorithm was capable of estimating orientation of some 35 k points in 15 min when applied to aortic tissue and over 500 k points in 35 min for Achilles tendon. The average angular disagreement between each operator and the algorithm was -9.3±8.6° and -3.8±8.6° in the case of aortic tissue and -1.6±6.4° and 2.6±7.8° for Achilles tendon. Estimated mean collagen content was 30.3±5.8% and 94.3±2.7% for aortic media and Achilles tendon, respectively. The proposed automated approach is operator independent and several orders faster than manual measurements and therefore has the potential to replace manual measurements of collagen orientation via PLM.


Assuntos
Tendão do Calcâneo/química , Tendão do Calcâneo/ultraestrutura , Aorta/química , Aorta/ultraestrutura , Colágeno/análise , Colágeno/ultraestrutura , Microscopia de Polarização , Animais , Automação Laboratorial , Processamento de Imagem Assistida por Computador , Suínos
15.
Cas Lek Cesk ; 154(4): 161-7, 2015.
Artigo em Tcheco | MEDLINE | ID: mdl-26357857

RESUMO

Type 2 diabetes incidence is growing worldwide. It is in up to 50% cases linked with diabetic foot syndrome. This is associated with peripheral neuropathy and peripheral artery disease which increases risk of defects with impaired healing. Resulting high number of amputations has major influence on the quality of life and constitutes serious clinical issue. In recent years numerous clinical studies have shown positive effect of new treatment modality using regenerative potential of the autologous stem cells transplantation. This review tries to summarize existing results of therapeutic revascularization using stem cell and to outline mechanism of their action.


Assuntos
Pé Diabético/cirurgia , Transplante de Células-Tronco/métodos , Procedimentos Cirúrgicos Vasculares/métodos , Humanos , Síndrome , Cicatrização
16.
Epileptic Disord ; 16(2): 213-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24777063

RESUMO

A 4-year-old girl with intractable epilepsy due to left-side hemispheric cortical dysplasia underwent a hemispherotomy. She was seizure-free after the surgery. EEG showed persistent abundant epileptiform activity over the left (disconnected) hemisphere, including ictal patterns that neither generalised nor had clinical correlates. Antiepileptic medication was completely withdrawn four years following the surgery. One week after the withdrawal, she developed episodes of intense left-sided hemicranias (ipsilateral to the surgery) with vomiting and photophobia that did not resemble her habitual seizures and were unresponsive to non-steroidal anti-inflammatory drugs. Video-EEG showed association of the headache attacks with ictal patterns over the disconnected hemisphere. Brain MRI revealed increased signal changes in the left hemisphere. Attacks responded promptly to i.v. midazolam and carbamazepine at a low dose. Mechanisms underlying peri-ictal headache originating in the disconnected hemisphere are discussed. [Published with video sequences].


Assuntos
Epilepsia/complicações , Cefaleia/complicações , Convulsões/complicações , Anticonvulsivantes/uso terapêutico , Encéfalo/patologia , Carbamazepina/uso terapêutico , Pré-Escolar , Eletroencefalografia , Epilepsia/patologia , Epilepsia/cirurgia , Feminino , Lateralidade Funcional , Cefaleia/patologia , Hemisferectomia , Humanos , Midazolam/uso terapêutico , Procedimentos Neurocirúrgicos , Convulsões/patologia
17.
ACS Omega ; 9(18): 20557-20570, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38737052

RESUMO

A series of quinolino-fused 7-deazapurine (pyrimido[5',4':4,5]pyrrolo[3,2-f]quinoline) ribonucleosides were designed and synthesized. The synthesis of the key 11-chloro-pyrimido[5',4':4,5]pyrrolo[3,2-f]quinoline was based on the Negishi cross-coupling of iodoquinoline with zincated 4,6-dichloropyrimidine followed by azidation and thermal or photochemical cyclization. Vorbrüggen glycosylation of the tetracyclic heterocycle followed by cross-coupling or substitution reactions at position 11 gave the desired set of final nucleosides that showed moderate to weak cytostatic activity and fluorescent properties. The corresponding fused adenosine derivative was converted to the triphosphate and successfully incorporated to RNA using in vitro transcription with T7 RNA polymerase.

18.
Epilepsia Open ; 9(1): 424-431, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37943122

RESUMO

Focal cortical dysplasia (FCD) represents the most common cause of drug-resistant epilepsy in adult and pediatric surgical series. However, genetic factors contributing to severe phenotypes of FCD remain unknown. We present a patient with an exceptionally rapid development of drug-resistant epilepsy evolving in super-refractory status epilepticus. We performed multiple clinical (serial EEG, MRI), biochemical (metabolic and immunological screening), genetic (WES from blood- and brain-derived DNA), and histopathological investigations. The patient presented 1 month after an uncomplicated varicella infection. MRI was negative, as well as other biochemical and immunological examinations. Whole-exome sequencing of blood-derived DNA detected a heterozygous paternally inherited variant NM_006267.4(RANBP2):c.5233A>G p.(Ile1745Val) (Chr2[GRCh37]:g.109382228A>G), a gene associated with a susceptibility to infection-induced acute necrotizing encephalopathy. No combination of anti-seizure medication led to a sustained seizure freedom and the patient warranted induction of propofol anesthesia with high-dose intravenous midazolam and continuous respiratory support that however failed to abort seizure activity. Brain biopsy revealed FCD type IIa; this finding led to the indication of an emergency right-sided hemispherotomy that rendered the patient temporarily seizure-free. Postsurgically, he remains on antiseizure medication and experiences rare nondisabling seizures. This report highlights a uniquely severe clinical course of FCD putatively modified by the RANBP2 variant. PLAIN LANGUAGE SUMMARY: We report a case summary of a patient who came to our attention for epilepsy that could not be controlled with medication. His clinical course progressed rapidly to life-threatening status epilepticus with other unusual neurological findings. Therefore, we decided to surgically remove a piece of brain tissue in order to clarify the diagnosis that showed features of a structural brain abnormality associated with severe epilepsy, the focal cortical dysplasia. Later, a genetic variant in a gene associated with another condition, was found, and we hypothesize that this genetic variant could have contributed to this severe clinical course of our patient.


Assuntos
Encefalopatias , Epilepsia Resistente a Medicamentos , Epilepsia , Displasia Cortical Focal , Chaperonas Moleculares , Complexo de Proteínas Formadoras de Poros Nucleares , Estado Epiléptico , Criança , Pré-Escolar , Humanos , Masculino , Progressão da Doença , DNA , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia/complicações , Midazolam , Estado Epiléptico/genética , Estado Epiléptico/cirurgia
19.
Bioorg Med Chem ; 21(17): 5362-72, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23827234

RESUMO

Two series of new 4-aminopyrimido[4,5-b]indole ribonucleosides bearing phenyl or hetaryl group at position 5 or 6 have been prepared by Suzuki or Stille cross-coupling reactions employing X-Phos ligand with (het)arylboronic acids or stannanes. A series of 4-substituted nucleosides has been also prepared by Pd-catalyzed cross-couplings or nucleophilic substitution. Some of these compounds displayed moderate antiviral activities against HCV and dengue viruses.


Assuntos
Adenosina/análogos & derivados , Antivirais/síntese química , Indóis/química , Ribonucleosídeos/química , Antivirais/farmacologia , Antivirais/toxicidade , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Vírus da Dengue/efeitos dos fármacos , Células HL-60 , Células HeLa , Células Hep G2 , Hepacivirus/efeitos dos fármacos , Humanos , Paládio/química , Ribonucleosídeos/farmacologia , Ribonucleosídeos/toxicidade
20.
Epileptic Disord ; 15(1): 3-13, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23531745

RESUMO

AIMS: To assess the practical localising value of subtraction ictal single-photon emission computed tomography (SISCOM) coregistered with MRI and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with extratemporal epilepsy and normal MRI. METHODS: We retrospectively studied a group of 14 patients who received surgery due to intractable epilepsy and who were shown to have focal cortical dysplasia, undetected by MRI, based on histological investigation. We coregistered preoperative SISCOM and PET images with postoperative MRI and visually determined whether the SISCOM focus, PET hypometabolic area, and cerebral cortex, exhibiting prominent abnormalities on intracranial EEG, were removed completely, incompletely, or not at all. These results and histopathological findings were compared with postoperative seizure outcome. RESULTS: Two patients underwent one-stage multimodal image-guided surgery and the remaining 12 underwent long-term invasive EEG. SISCOM findings were localised for all but 1 patient. FDG-PET was normal in 3 subjects, 2 of whom had favourable postsurgical outcome (Engel class I and II). Complete resection of the SISCOM focus (n=3), the area of PET hypometabolism (n=2), or the cortical regions with intracranial EEG abnormalities (n=7) were predictive of favourable postsurgical outcome. Favourable outcome was also encountered in: 4 of 8 patients with incomplete resection and 1 of 2 with no resection of the SISCOM focus; 4 of 7 patients with incomplete resection and 1 of 2 with no resection of the PET hypometabolic area; and 2 of 7 patients with incomplete resection of the area corresponding to intracranial EEG abnormality. No correlation between histopathological FCD subtype and seizure outcome was observed. CONCLUSION: Complete resection of the dysplastic cortex localised by SISCOM, FDG-PET or intracranial EEG is a reliable predictor of favourable postoperative seizure outcome in patients with non-lesional extratemporal epilepsy.


Assuntos
Encéfalo/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Adolescente , Adulto , Encéfalo/patologia , Encéfalo/cirurgia , Mapeamento Encefálico/métodos , Criança , Eletroencefalografia , Epilepsia/patologia , Epilepsia/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Cintilografia , Estudos Retrospectivos , Cirurgia Assistida por Computador , Resultado do Tratamento
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