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1.
Pediatr Nephrol ; 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39320552

RESUMO

BACKGROUND: Anti-GBM disease is a rare vasculitis mediated by pathogenic antibodies against collagen IV. Anti-GBM disease presents with rapid progressive glomerulonephritis and leads to kidney failure if untreated. KDIGO recommends plasma exchanges (PEX) for antibody elimination and steroids plus cyclophosphamide (CTX) to suppress antibody production. CTX is associated with severe side effects including gonadal toxicity. Rituximab (RTX) and mycophenolate mofetil (MMF) might be a less toxic but equally efficient alternative to CTX. Studies in pediatric anti-GBM disease patients receiving RTX and MMF instead of CTX are lacking. METHODS: A retrospective survey in 8 tertiary German centers was performed. The clinical data of patients diagnosed between 2014 and 2022 were collected and analyzed. RESULTS: Five adolescent patients treated with PEX and RTX and/or MMF due to anti-GBM disease were analyzed. All patients had anti-GBM antibodies, hematuria, glomerular proteinuria, and pulmonary hemorrhage. eGFR was 124 ml/min/1.73 m2 (range 47-162), and all patients were non-dialysis-dependent but with relevant histological kidney affection (mean crescents on kidney biopsy 77%). Antibody clearance was achieved after 13 PEX cycles (range 6-31). Four out of 5 patients received methylprednisolone pulses. All patients received oral prednisolone and MMF, and four patients received a median of 4 RTX doses (range 2-4). After a mean follow-up of 27 months, 4/5 patients had conserved or improved kidney function, while one patient (20%) developed kidney failure. CONCLUSIONS: In this small series of pediatric non-dialysis-dependent anti-GBM disease patients, first-line treatment with RTX and MMF showed a favorable kidney outcome in 4/5 cases and had an acceptable side effect profile.

2.
Pediatr Nephrol ; 38(7): 2093-2100, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36538056

RESUMO

BACKGROUND: Impaired kidney concentration capacity is present in half of the patients with autosomal dominant polycystic kidney disease (ADPKD). The kidney concentrating capacity was further impaired within the animal model of autosomal recessive polycystic kidney disease (ARPKD). To date, only one small study has investigated it in children having ARPKD. Therefore, we aimed to study the kidney concentrating ability in a larger cohort of children with ARPKD. METHODS: Eighteen children (median age 8.5 years, range 1.3-16.8) were retrospectively investigated. A standardized kidney concentrating capacity test was performed after the application of a nasal drop of desmopressin (urine osmolality > 900 mOsmol/kg). The glomerular filtration rate was estimated using the Schwartz formula (eGFR) and blood pressure (BP) was measured as office BP. RESULTS: Kidney concentrating capacity was decreased (urine osmolality < 900 mOsmol/kg) in 100% of children with ARPKD. The median urine osmolality after desmopressin application was 389 (range 235-601) mOsmol/kg. Sixteen patients (89%) were defined as hypertensive based on their actual BP level or their use of antihypertensive drugs. The maximum amounts of urinary concentration correlated significantly with eGFR (r = 0.72, p < 0.0001) and hypertensive scores (r = 0.50, p < 0.05), but not with kidney size. Twelve patients (67%) were defined as having CKD stages 2-4. The median concentrating capacity was significantly lower in children within this group, when compared to children with CKD stage 1 possessing a normal eGFR (544 mOsmol/kg, range 413-600 mOsmol/kg vs. 327 mOsmol/kg, range 235-417 mOsmol/l, p < 0.001). CONCLUSIONS: Impaired kidney concentrating capacity is present in most children with ARPKD and is associated with decreased eGFR and hypertension. A higher resolution version of the Graphical abstract is available as Supplementary information.


Assuntos
Hipertensão , Rim Policístico Autossômico Dominante , Rim Policístico Autossômico Recessivo , Insuficiência Renal Crônica , Criança , Humanos , Rim Policístico Autossômico Recessivo/complicações , Desamino Arginina Vasopressina , Estudos Retrospectivos , Rim , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/complicações
3.
Eur J Pediatr ; 180(12): 3599-3603, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34176013

RESUMO

Cystic kidney diseases such as autosomal recessive or dominant polycystic kidney disease (ARPKD and ADPKD) are associated with high prevalence of arterial hypertension. On the contrary, studies on hypertension in children with renal cysts and diabetes (RCAD) syndrome caused by abnormalities in the HNF1B gene are rare. Therefore, the primary aim of our study was to investigate the prevalence of high blood pressure in children with RCAD syndrome due to HNF1B gene abnormalities and secondary to search for possible risk factors for development of high blood pressure. Data on all children with genetically proven RCAD syndrome from three pediatric nephrology tertiary centers were retrospectively reviewed (office blood pressure (BP), ambulatory blood pressure monitoring (ABPM), creatinine clearance, renal ultrasound, echocardiography, albuminuria/proteinuria). High blood pressure was defined as BP ≥ 95th percentile of the current ESH 2016 guidelines and/or by the use of antihypertensive drugs. Thirty-two children with RCAD syndrome were investigated. Three children received ACE inhibitors for hypertension and/or proteinuria. High blood pressure was diagnosed using office BP in 22% of the children (n = 7). In the 7 performed ABPM, 1 child (14%) was diagnosed with hypertension and one child with white-coat hypertension. Creatinine clearance, proteinuria, albuminuria, body mass index, enlargement, or hypodysplasia of the kidneys and prevalence of HNF1B-gene deletion or mutation were not significantly different between hypertensive and normotensive children.Conclusion: High blood pressure is present in 22% of children with RCAD syndrome. What is Known: • Arterial hypertension is a common complication in children with polycystic kidney diseases. What is New: • High office blood pressure is present in 22% and ambulatory hypertension in 14% of children with renal cyst and diabetes (RCAD) syndrome.


Assuntos
Diabetes Mellitus , Hipertensão , Rim Policístico Autossômico Dominante , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Doenças do Sistema Nervoso Central , Criança , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2 , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Doenças Renais Císticas , Estudos Retrospectivos
4.
J Neurosci ; 38(14): 3441-3452, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29618546

RESUMO

Selective attention allows focusing on only part of the incoming sensory information. Neurons in the extrastriate visual cortex reflect such selective processing when different stimuli are simultaneously present in their large receptive fields. Their spiking response then resembles the response to the attended stimulus when presented in isolation. Unclear is where in the neuronal pathway attention intervenes to achieve such selective signal routing and processing. To investigate this question, we tagged two equivalent visual stimuli by independent broadband luminance noise and used the spectral coherence of these behaviorally irrelevant signals with the field potential of a local neuronal population in male macaque monkeys' area V4 as a measure for their respective causal influences. This new experimental paradigm revealed that signal transmission was considerably weaker for the not-attended stimulus. Furthermore, our results show that attention does not need to modulate responses in the input populations sending signals to V4 to selectively represent a stimulus, nor do they suggest a change of the V4 neurons' output gain depending on their feature similarity with the stimuli. Our results rather imply that selective attention uses a gating mechanism comprising the synaptic "inputs" that transmit signals from upstream areas into the V4 neurons. A minimal model implementing attention-dependent routing by gamma-band synchrony replicated the attentional gating effect and the signals' spectral transfer characteristics. It supports the proposal that selective interareal gamma-band synchrony subserves signal routing and explains our experimental finding that attention selectively gates signals already at the level of afferent synaptic input.SIGNIFICANCE STATEMENT Depending on the behavioral context, the brain needs to channel the flow of information through its networks of massively interconnected neurons. We designed an experiment that allows to causally assess routing of information originating from an attended object. We found that attention "gates" signals at the interplay between afferent fibers and the local neurons. A minimal model demonstrated that coherent gamma-rhythmic activity (∼60 Hz) between local neurons and their afferent-providing input neurons can realize the gating. Importantly, the attended signals did not need to be amplified already in an earlier processing stage, nor did they get amplified by a simple output response modulation. The method provides a useful tool to study mechanisms of dynamic network configuration underlying cognitive processes.


Assuntos
Atenção , Filtro Sensorial , Córtex Visual/fisiologia , Animais , Macaca mulatta , Masculino , Percepção Visual
5.
Phys Rev Lett ; 119(9): 098301, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28949567

RESUMO

Determination of causal relations among observables is of fundamental interest in many fields dealing with complex systems. Since nonlinear systems generically behave as wholes, classical notions of causality assuming separability of subsystems often turn out inadequate. Still lacking is a mathematically transparent measure of the magnitude of effective causal influences in cyclic systems. For deterministic systems we found that the expansions of mappings among time-delay state space reconstructions from different observables not only reflect the directed coupling strengths, but also the dependency of effective influences on the system's temporally varying state. Estimation of the expansions from pairs of time series is straightforward and used to define novel causality indices. Mathematical and numerical analysis demonstrate that they reveal the asymmetry of causal influences including their time dependence, as well as provide measures for the effective strengths of causal links in complex systems.

6.
Inorg Chem ; 56(11): 6712-6724, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28497971

RESUMO

As part of a comprehensive study of N-unsubstituted bispidines, the novel 9,9-difluorobispidine (D) has been synthesized. The compound crystallizes from pentane below 0 °C in the ordered-crystalline phase D-II and undergoes at 0-30 °C a stepwise endothermic phase transition to a dynamically disordered crystalline phase D-I; melting occurs at 227 °C. Single crystalline D-II has been subjected to X-ray structure analysis, revealing association of the molecules to form chains. Reaction of (1,5-hexadiene)PtCl2 with D affords {C7H10F2(NH)2}PtCl2 (D1), which can be converted by conventional routes to {C7H10F2(NH)2}Pt(cbdca)·5H2O (D2) and {C7H10F2(NH)2}Pt(C2O4) (D3). Compound D1 crystallizes solvent-free from water and is isomorphous to the solvent-free parent bispidine analogue (A1). The pentahydrate D2 is isomorphous to the bispidine and 9-oxabispidine homologues (A2 and C2), as shown by X-ray structure analyses. An increased polarity of the bispidine skeleton as a consequence of the high electronegativity of fluorine is seen as the reason for low cytotoxic potency of D1-D3.


Assuntos
Carboplatina/química , Cisplatino/química , Compostos Organoplatínicos/química , Carboplatina/análogos & derivados , Carboplatina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/análogos & derivados , Cisplatino/farmacologia , Humanos , Conformação Molecular , Compostos Organoplatínicos/farmacologia , Oxaliplatina
7.
Sensors (Basel) ; 17(4)2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28375161

RESUMO

Implantable neuronal interfaces to the brain are an important keystone for future medical applications. However, entering this field of research is difficult since such an implant requires components from many different areas of technology. Since the complete avoidance of wires is important due to the risk of infections and other long-term problems, means for wirelessly transmitting data and energy are a necessity which adds to the requirements. In recent literature, many high-tech components for such implants are presented with remarkable properties. However, these components are typically not freely available for such a system. Every group needs to re-develop their own solution. This raises the question if it is possible to create a reusable design for an implant and its external base-station, such that it allows other groups to use it as a starting point. In this article, we try to answer this question by presenting a design based exclusively on commercial off-the-shelf components and studying the properties of the resulting system. Following this idea, we present a fully wireless neuronal implant for simultaneously measuring electrocorticography signals at 128 locations from the surface of the brain. All design files are available as open source.


Assuntos
Eletrocorticografia , Encéfalo , Interfaces Cérebro-Computador , Próteses e Implantes , Tecnologia sem Fio
8.
J Am Chem Soc ; 138(30): 9444-51, 2016 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-27267866

RESUMO

Cesium bis(perfluoro-triphenylborane)amide, Cs[H2NB2(C6F5)6] (1), has been prepared by the reaction of sodium salt and CsF in dichloromethane and water. The compound is exceptional for a [H2NB2(C6F5)6](-) salt in that it contains a monatomic solute-free cation. Determination of the molecular structure revealed a novel C2 symmetrical conformation of the weakly coordinating [H2NB2(C6F5)6](-) anion, which gives rise to an unprecedented 16-coordinate (CN 16) Cs(+) cation in a likewise unprecedented tetracosahedral arrangement of F atoms. The poor solubility of 1 allows nearly quantitative separation of Cs(+) from water, which suggests potential applications as an effective (134/137)Cs remover from nuclear waste solutions, administration as an antidote for (134/137)Cs poisoning, and use for (131/137)Cs radiotherapy (brachytherapy). Rb[H2NB2(C6F5)6]·CH2Cl2 (2) has also been characterized, featuring two inequivalent Rb(+) cations having CN 10, one of which involves Rb(+)(η(2)-Cl2CH2)2 coordination.

9.
Inorg Chem ; 55(18): 9424-35, 2016 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-27603202

RESUMO

The literature synthesis of 9-oxabispidine [OC6H10(NH)2, C] has been revisited and optimized, which includes determination of the crystal structures of C, the secondary component trans-(PhSO2)NC4H6O(CH2I)2 (trans-III), and the unexpected solute intermediate OC6H10(NSO2Ph)2·(1)/2py (V·(1)/2py). The reaction of (1,5-hexadiene)platinum dichloride with C yields {OC6H10(NH)2}PtCl2 (C1), which is converted to {OC6H10(NH)2}Pt(cbdca)·5H2O (C2) and {OC6H10(NH)2}Pt(C2O4) (C3). In the crystal, C1 forms a planar 2D network by N-H··Cl and N-H··O hydrogen bonding. In the crystal structure of C2, which is isomorphous to the parent bispidine compound (A2), all complex molecules are encapsulated by a water shell. While complexes C1 and C3 are virtually insoluble in water, C2 dissolves quite well. The low cytotoxicity of compounds C1-C3 is explained by an increased polarity of the bonds in the C skeleton as a consequence of the electronegative O atom.


Assuntos
Antineoplásicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Carboplatina/análogos & derivados , Cisplatino/análogos & derivados , Compostos Organoplatínicos/química , Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Carboplatina/síntese química , Técnicas de Química Sintética , Cisplatino/síntese química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Compostos Organoplatínicos/síntese química , Oxaliplatina
10.
Inorg Chem ; 55(6): 2986-97, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-26918619

RESUMO

3,7-Diallyl-bispidin-9-one (6) (bispidin-9-one = 3,7-diazabicyclo[3.3.1]nonan-9-one) is converted to N-unsubstituted spiro[bispidin-9,2'-[1,3]dioxolane] (12; 35%). The ketal crystallizes in the forms of anhydrous 12a and the dihydrate 12b. The molecules in anhydrous 12a are linked to each other, forming N1-H1···N2-H2···N1* hydrogen-bond chiral helices of alternating chirality. In the dihydrate 12b, the ketal molecules are connected to a central string of water molecules by O3-H···O1 and O4-H···N1 hydrogen bonds, but not to themselves. Reaction of 12 with (1,5-hexadiene)PtCl2 affords almost quantitatively spiro[bispidin-9,2'-[1,3]dioxolane]PtCl2 (13). Cleavage of the ketal to retrieve the ketone produces the geminal diol (bispidin-9,9-diol)PtCl2 (14; 85%). Compound 14 reacts with Ag2cbdca (cbdca = 1,1-cyclobutanedicarboxylate) to give the dihydrate (bispidin-9,9-diol)Pt(cbdca)·2H2O (15b), which can be dehydrated to obtain anhydrous (bispidin-9,9-diol)Pt(cbdca) (15a). Similarly, anhydrous (bispidin-9,9-diol)Pt(oxalate) (16) is obtained. Crystal structures of 14 and 15b reveal association by various forms of O-H···O, O-H···Cl, N-H···Cl, and N-H···O hydrogen bonds. Biological studies showed a moderate cytotoxic activity of the bispidin-9,9-diol complexes 14-16, compared to the 9,9-unsubstituted bispidine complexes. No unspecific cytotoxicity of 14-16 up to 316 µM was found against the noncancer cell line HEK293.


Assuntos
Antineoplásicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Carboplatina/química , Cisplatino/química , Compostos Organoplatínicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Estrutura Molecular , Oxaliplatina
11.
J Neurophysiol ; 114(3): 1593-605, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26108958

RESUMO

Selective attention allows to focus on relevant information and to ignore distracting features of a visual scene. These principles of information processing are reflected in response properties of neurons in visual area V4: if a neuron is presented with two stimuli in its receptive field, and one is attended, it responds as if the nonattended stimulus was absent (biased competition). In addition, when the luminance of the two stimuli is temporally and independently varied, local field potentials are correlated with the modulation of the attended stimulus and not, or much less, correlated with the nonattended stimulus (information routing). To explain these results in one coherent framework, we present a two-layer spiking cortical network model with distance-dependent lateral connectivity and converging feed-forward connections. With oscillations arising inherently from the network structure, our model reproduces both experimental observations. Hereby, lateral interactions and shifts of relative phases between sending and receiving layers (communication through coherence) are identified as the main mechanisms underlying both biased competition as well as selective routing. Exploring the parameter space, we show that the effects are robust and prevalent over a broad range of parameters. In addition, we identify the strength of lateral inhibition in the first model layer as crucial for determining the working regime of the system: increasing lateral inhibition allows a transition from a network configuration with mixed representations to one with bistable representations of the competing stimuli. The latter is discussed as a possible neural correlate of multistable perception phenomena such as binocular rivalry.


Assuntos
Atenção , Modelos Neurológicos , Neurônios/fisiologia , Córtex Visual/fisiologia , Percepção Visual , Animais , Retroalimentação Fisiológica , Humanos , Córtex Visual/citologia
12.
Angew Chem Int Ed Engl ; 54(26): 7488-90, 2015 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-26031741

RESUMO

With scorpionate ligands finding their way into organonickel chemistry, the state of the art of present-day nickel(IV) chemistry is highlighted. Will rapid CX coupling reactions emerge as a domain of higher-oxidation-state nickel chemistry?

13.
Angew Chem Int Ed Engl ; 54(15): 4482-7, 2015 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-25712229

RESUMO

The pairing of ions of opposite charge is a fundamental principle in chemistry, and is widely applied in synthesis and catalysis. In contrast, cation-cation association remains an elusive concept, lacking in supporting experimental evidence. While studying the structure and properties of 4-oxopiperidinium salts [OC5 H8 NH2 ]X for a series of anions X(-) of decreasing basicity, we observed a gradual self-association of the cations, concluding in the formation of an isolated dicationic pair. In 4-oxopiperidinium bis(trifluoromethylsulfonyl)amide, the cations are linked by NH⋅⋅⋅OC hydrogen bonds to form chains, flanked by hydrogen bonds to the anions. In the tetra(perfluoro-tert-butoxy)aluminate salt, the anions are fully separated from the cations, and the cations associate pairwise by NCH⋅⋅⋅OC hydrogen bonds. The compounds represent the first genuine examples of self-association of simple organic cations based merely on hydrogen bonding as evidenced by X-ray structure analysis, and provide a paradigm for an extension of this class of compounds.

14.
Inorg Chem ; 53(7): 3371-84, 2014 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-24665859

RESUMO

Bispidine (3,7-diazabicyclo[3.3.1]nonane, C7H14N2) analogues of cisplatin, carboplatin, and oxaliplatin have been prepared. (C7H14N2)PtCl2·DMF (1b), obtained from (1,5-hexadiene)PtCl2 and bispidine in DMF, is dimeric in the solid state. Dissolving 1b in hot N-methylformamide allows crystallization of the solvent-free polymeric (C7H14N2)PtCl2 (1a). Recrystallization of 1a,b from hot water yields the trihydrate (C7H14N2)PtCl2·3H2O (1c). Reaction of 1 with Ag2(cbdca) (cbdca = 1,1-cyclobutanedicarboxylate) in water affords the pentahydrate (C7H14N2)Pt{C4H6(CO2)2}·5H2O (2b), which loses water in vacuo to give (C7H14N2)Pt{C4H6(CO2)2} (2a). Reaction of 1 with AgNO3 in water, followed by addition of Na2C2O4, affords the water-free polymeric (C7H14N2)Pt(C2O4) (3). All complexes have been structurally characterized, revealing various patterns of N-H···Cl and N-H···O hydrogen bonds. In the hydrates 1c and 2b the complexes are embedded in intricate three-dimensional water networks. Complexes 1a, 2a, and 3 have been tested for their cytotoxicity against human cancer cell lines K562 (chronic myeloid leukemia), A2780 (ovarian cancer), and its platinum-resistant subline A2780 CisR and are compared to their parent analogues. The new complexes show significant cytotoxic activity along with a low platinum resistance factor.


Assuntos
Antineoplásicos/toxicidade , Compostos Bicíclicos Heterocíclicos com Pontes/química , Carboplatina/análogos & derivados , Carboplatina/toxicidade , Cisplatino/análogos & derivados , Cisplatino/toxicidade , Compostos Organoplatínicos/toxicidade , Antineoplásicos/síntese química , Carboplatina/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/síntese química , Corantes , Humanos , Modelos Moleculares , Conformação Molecular , Compostos Organoplatínicos/síntese química , Oxaliplatina , Relação Estrutura-Atividade , Sais de Tetrazólio , Tiazóis
15.
Sci Rep ; 14(1): 5495, 2024 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448513

RESUMO

Urinary tract obstruction during renal development leads to inflammation, leukocyte infiltration, tubular cell death, and interstitial fibrosis. Interleukin-10 (IL-10) is an anti-inflammatory cytokine, produced mainly by monocytes/macrophages and regulatory T-cells. IL-10 inhibits innate and adaptive immune responses. IL-10 has a protective role in the adult model of obstructive uropathy. However, its role in neonatal obstructive uropathy is still unclear which led us to study the role of IL-10 in neonatal mice with unilateral ureteral obstruction (UUO). UUO serves as a model for congenital obstructive nephropathies, a leading cause of kidney failure in children. Newborn Il-10-/- and C57BL/6 wildtype-mice (WT) were subjected to complete UUO or sham-operation on the 2nd day of life. Neonatal kidneys were harvested at day 3, 7, and 14 of life and analyzed for different leukocyte subpopulations by FACS, for cytokines and chemokines by Luminex assay and ELISA, and for inflammation, programmed cell death, and fibrosis by immunohistochemistry and western blot. Compared to WT mice, Il-10-/- mice showed reduced infiltration of neutrophils, CD11bhi cells, conventional type 1 dendritic cells, and T-cells following UUO. Il-10-/- mice with UUO also showed a reduction in pro-inflammatory cytokine and chemokine release compared to WT with UUO, mainly of IP-10, IL-1α, MIP-2α and IL-17A. In addition, Il-10-/- mice showed less necroptosis after UUO while the rate of apoptosis was not different. Finally, α-SMA and collagen abundance as readout for fibrosis were similar in Il-10-/- and WT with UUO. Surprisingly and in contrast to adult Il-10-/- mice undergoing UUO, neonatal Il-10-/- mice with UUO showed a reduced inflammatory response compared to respective WT control mice with UUO. Notably, long term changes such as renal fibrosis were not different between neonatal Il-10-/- and neonatal WT mice with UUO suggesting that IL-10 signaling is different in neonates and adults with UUO.


Assuntos
Nefropatias , Obstrução Ureteral , Adulto , Animais , Criança , Humanos , Camundongos , Animais Recém-Nascidos , Citocinas , Fibrose , Inflamação , Interleucina-10/genética , Camundongos Endogâmicos C57BL
16.
Heliyon ; 9(4): e15158, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37089358

RESUMO

Management of cardiac arrhythmias often requires direct current cardioversion (DCC) to restore sinus rhythm. This intervention varies greatly between countries and hospitals, mostly regarding the organization of an elective DCC, and the choice of the sedation. The aim of this study is to assess the safety and efficacy of an elective DCC performed in a cardiology day hospital, led by trained nurses, and using intravenous Etomidate as sedation. We performed a retrospective cohort study at a single tertiary hospital in Belgium. Data were collected from January 2017 to October 2020. A total of 788 electrical cardioversions were performed on 574 patients from 2017 to 2020. Age was 70.9 ± 10 years. Restoration of sinus rhythm was obtained in 89.5% of the patients. One (0.1%) patient experienced ischemic stroke within 24 h, despite adequate anticoagulation. There were 4 (0.5%) cases of transient sinus arrest requiring atropine. Three patients (0.4%) experienced respiratory depression, requiring bag-mask ventilation but not oro-tracheal intubation. There were no cases of hypotension. No periprocedural death was reported. In conclusion, an elective electrical cardioversion performed and led by trained nurses, using Etomidate as sedation, appears to be both safe and effective.

17.
J Immunother Cancer ; 11(5)2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37208128

RESUMO

BACKGROUND: Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens. METHODS: Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo. RESULTS: MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model. CONCLUSION: The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients.


Assuntos
Anticorpos Biespecíficos , Melanoma , Humanos , Camundongos , Animais , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Linfócitos T , Recidiva Local de Neoplasia , Antígenos de Neoplasias
18.
Biomedicines ; 10(8)2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-36009441

RESUMO

Posterior urethral valves (PUV) are the most common form of lower urinary tract obstructions (LUTO). The valves can be surgically corrected postnatally; however, the impairment of kidney and bladder development is irreversible and has lifelong implications. Chronic kidney disease (CKD) and bladder dysfunction are frequent problems. Approximately 20% of PUV patients will reach end-stage kidney disease (ESKD). The subvesical obstruction in PUV leads to muscular hypertrophy and fibrotic remodelling in the bladder, which both impair its function. Kidney development is disturbed and results in dysplasia, hypoplasia, inflammation and renal fibrosis, which are hallmarks of CKD. The prognoses of PUV patients are based on prenatal and postnatal parameters. Prenatal parameters include signs of renal hypodysplasia in the analysis of fetal urine. Postnatally, the most robust predictor of PUV is the nadir serum creatinine after valve ablation. A value that is below 0.4 mg/dl implies a very low risk for ESKD, whereas a value above 0.85 mg/dl indicates a high risk for ESKD. In addition, bladder dysfunction and renal dysplasia point towards an unbeneficial kidney outcome. Experimental urinary markers such as MCP-1 and TGF-ß, as well as microalbuminuria, indicate progression to CKD. Until now, prenatal intervention may improve survival but yields no renal benefit. The management of PUV patients includes control of bladder dysfunction and CKD treatment to slow down progression by controlling hypertension, proteinuria and infections. In kidney transplantation, aggressive bladder management is essential to ensure optimal graft survival.

19.
JACC Case Rep ; 4(12): 734-737, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35734532

RESUMO

Coronary angiography is a routinely performed intervention, with radial catheterization the recommended approach. We report a unique case of perforation of the right vertebral artery following coronary angiography that was successfully treated by endovascular management. (Level of Difficulty: Advanced.).

20.
Radiat Oncol ; 16(1): 43, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632272

RESUMO

Radiation nephropathy (RN) is a kidney injury induced by ionizing radiation. In a clinical setting, ionizing radiation is used in radiotherapy (RT). The use and the intensity of radiation therapy is limited by normal-tissue damage including kidney toxicity. Different thresholds for kidney toxicity exist for different entities of RT. Histopathologic features of RN include vascular, glomerular and tubulointerstitial damage. The different molecular and cellular pathomechanisms involved in RN are not fully understood. Ionizing radiation causes double-stranded breaks in the DNA, followed by cell death including apoptosis and necrosis of renal endothelial, tubular and glomerular cells. Especially in the latent phase of RN oxidative stress and inflammation have been proposed as putative pathomechanisms, but so far no clear evidence was found. Cellular senescence, activation of the renin-angiotensin-aldosterone-system and vascular dysfunction might contribute to RN, but only limited data is available. Several signalling pathways have been identified in animal models of RN and different approaches to mitigate RN have been investigated. Drugs that attenuate cell death and inflammation or reduce oxidative stress and renal fibrosis were tested. Renin-angiotensin-aldosterone-system blockade, anti-apoptotic drugs, statins, and antioxidants have been shown to reduce the severity of RN. These results provide a rationale for the development of new strategies to prevent or reduce radiation-induced kidney toxicity.


Assuntos
Rim/patologia , Rim/efeitos da radiação , Lesões por Radiação/patologia , Animais , Senescência Celular/efeitos da radiação , Dano ao DNA/efeitos da radiação , Fibrose , Humanos , Hipertensão Renovascular/diagnóstico , Hipertensão Renovascular/etiologia , Hipertensão Renovascular/patologia , Hipertensão Renovascular/terapia , Inflamação , Rim/lesões , Estresse Oxidativo/efeitos da radiação , Lesões por Radiação/diagnóstico , Lesões por Radiação/etiologia , Lesões por Radiação/terapia , Radioterapia/efeitos adversos , Sistema Renina-Angiotensina/efeitos da radiação
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