RESUMEN
Introduction: IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. Decreased glomerular filtration rate is a known risk factor for disease progression. Aim: We aimed to examine factors that may contribute to disease progression in children that present with impaired eGFR at the onset of IgAN. Materials and methods: Of the 175 patients with IgAN from the Polish Registry of Children with IgAN and IgAVN, 54 (31%) patients with IgAN who had an onset of renal function impairment (GFR < 90 mL/min) were eligible for the study. All of them were analyzed for initial symptoms (GFR according to Schwartz formula, creatinine, proteinuria, IgA, C3), renal biopsy result with assessment by Oxford classification, treatment used (R-renoprotection, P-prednisone+R, Aza-azathioprine+P+R, Cyc-cyclophosphamide+P+R, CsA-cyclosporine+P+R, MMF-mycophenolate mofetil+P+R), and distant follow-up. Based on the GFR score obtained at the end, patients were divided into two groups: A-GFR > 90 mL/min and B-GFR < 90 mL/min. Results: In the study group, the mean age of onset was 12.87 ± 3.57 years, GFR was 66.1 ± 17.3 mL/min, and proteinuria was 18.1 (0-967) mg/kg/d. Renal biopsy was performed 0.2 (0-7) years after the onset of the disease, and MESTC score averaged 2.57 ± 1.6. Treatment was R only in 39% of children, P+R in 20%, Aza+P+R in 28%, Cyc+P+R in 9%, CsA+P+R in 7%, and MMF+P+R in 3%. The length of the observation period was 2.16 (0.05-11) years. At the follow-up, Group A had 30 patients (56%) and Group B had 24 patients (44%). There were no significant differences in any of the other biochemical parameters (except creatinine) or proteinuria values between the groups and the frequency of the MESTC score ≥ 2 and <2 was not significantly different between Groups A and B. Patients with normal GFR at the follow-up (Group A) were significantly more likely to have received prednisone and/or immunosuppressive treatment than those in Group B (p < 0.05) Conclusions: In a population of Polish children with IgAN and decreased renal function at the onset of the disease, 56% had normal GFR in remote observation. The use of immunosuppressive/corticosteroids treatment in children with IgAN and impaired glomerular filtration rate at the beginning of the disease may contribute to the normalization of GFR in the outcome, although this requires confirmation in a larger group of pediatric patients.
RESUMEN
In cat breeding, an important step is reproduction and obtaining healthy offspring. The main factor determining the survival of newborn kittens is the normal course and length of pregnancy. The purpose of this study was to determine the effect of gestation length on the early development of kittens. It was shown that kittens (premature kittens) later double their body weight (p < .01), have lower daily gains (p < .01) and higher body weight during eye-opening (p < .01), which occurs later than in kittens born on time. In addition, due to a shorter period of prenatal development, they require more time until the day of eye-opening, which, together with the length of pregnancy, was defined as development age.
Asunto(s)
Parto , Reproducción , Embarazo , Animales , Femenino , Gatos , Peso CorporalRESUMEN
Imbalance between production and scavenging of free radicals and other reactive oxygen species (ROS) is a component of many diseases, but it is especially important in aging-related diseases of the central nervous system. Oxidative stress-induced neuronal dysfunction plays an important role in the pathomechanism of neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Experimental data showed that free radical scavengers may protect the brain against oxidative modifications. The need for efficient and safe antioxidants with therapeutic potential stimulated the rise of interest in the medicinal plant products, which are a rich source of phytochemicals possessing biological activity. In our studies we focused on alkaloid fractions (AFs) isolated from club moss, Huperzia selago and Diphasiastrum complanatum, due to their beneficial activity and exclusive chemical structure. Our previous study demonstrated that selected alkaloids from Huperzia selago effectively protect macromolecules from oxidative damage. Therefore, in the present study we investigated the effects and mechanisms of action of AFs isolated from Huperzia selago and Diphasiastrum complanatum against sodium nitroprusside (SNP)-induced oxidative injury in PC12 cells. The results demonstrated that the selected AFs via reduction of nitric oxide (NO) liberation protected cells against oxidative stress, DNA and mitochondrial damage, as well as apoptosis caused by SNP. Selected AF notably decreased SNP-evoked mitochondrial polymerase γ (Polg) up-regulation. Furthermore, AF which contains Lycopodine, Serratidine, Lycoposerramine-G and (probably) Cermizine B completely inhibited the SNP-induced expression of interferon-γ (Ifng) and cyclooxygenase 2 (Ptgs2) as well as significantly down-regulated the expression of 12/15-lipoxygenase (Alox12) and tended to decrease the mRNA level of interleukin-6 gene (Il6). In conclusion, these results suggest that the AFs from Huperzia selago effectively protect PC12 cells against SNP-induced oxidative damage by adjusting the level of reactive nitrogen species, suppression of apoptosis and down-regulation of proinflammatory genes. The compounds present in these AFs could be potential candidates to develop successful drugs preventing oxidative damage and apoptosis in age-related neurodegenerative disorders.
Asunto(s)
Alcaloides/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Huperzia/química , Nitroprusiato/farmacología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Células Cultivadas , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/fisiología , Células PC12 , Ratas , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
IgA nephropathy (IgAN) is the most common form of glomerulonephritis in pediatric population. The clinical presentation of the disease in children ranges from microscopic hematuria to end-stage kidney disease. The aim of the study was to retrospectively assess clinical and kidney biopsy features in children with IgAN. We assessed a cohort of 140 children, 88 boys, 52 girls with the diagnosis of IgAN in the period of 2000-2015, entered into the national Polish pediatric IgAN registry. The assessment included the following: proteinuria, hematuria, glomerular filtration rate (GFR), arterial blood pressure, and the renal pathological changes according to the Oxford classification and crescents formation, as modifiable and unmodifiable risk factors. The incidence of IgAN in Poland was set at 9.3 new cases per year. The mean age at onset of IgAN was 11.9 ± 4.3 years, and the most common presentation of the disease was the nephritic syndrome, recognized in 52 % of patients. Kidney biopsy was performed, on average, 1.3 ± 2.0 years after onset of disease. Based on the ROC analysis, a cut-off age at onset of disease for GFR <90 mL/min/1.73 m2 (risk factor of progression) was calculated as 13.9 years. Unmodifiable lesions: segmental sclerosis, tubular atrophy/interstitial fibrosis (S1, T1-2) in the Oxford classification and crescents in kidney biopsy were significantly more common in Gr 1 (>13.9 years) compared with Gr 2 (<13.9 years), despite a significantly shorter time to kidney biopsy in the former. We conclude that IgAN in children may be an insidious disease. A regular urine analysis, especially after respiratory tract infections, seems the best way for an early detection of the disease.
Asunto(s)
Glomerulonefritis por IGA/epidemiología , Glomerulonefritis por IGA/patología , Riñón/patología , Sistema de Registros/estadística & datos numéricos , Adolescente , Análisis de Varianza , Biopsia , Presión Sanguínea , Niño , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/diagnóstico , Hematuria/diagnóstico , Humanos , Incidencia , Masculino , Polonia/epidemiología , Proteinuria/diagnóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Inflammatory bowel disease (IBD) is characterized by chronic, uncontrolled inflammation in the intestinal mucosa. Although the etiology is poorly understood, it is widely accepted that loss of tolerance is involved in the development of IBD. Therefore, re-establishing tolerance or gut homeostasis is one of the key features in the development of new therapeutic strategies. Here we show that antigen targeting to DEC-205 on dendritic cells leads to an interleukin (IL)-10-dependent downregulation of C-X-C chemokine receptor 3 (CXCR3) expression on differentiated antigen-specific T helper type 1 (Th1) cells in vivo. This downregulation interferes with the migration of Th1 cells into the gut and protects mice against severe acute and relapsing intestinal inflammation. Moreover, CD4(+)CXCR3(+) T cells are highly enriched in the inflamed mucosa of IBD patients. Interference with this pathway may therefore be a promising approach for the treatment of IBD. In conclusion, we propose a hitherto undescribed mechanism by which IL-10 can act on effector T cells and orchestrate intestinal immune responses.
Asunto(s)
Antígenos CD/inmunología , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Interleucina-10/inmunología , Lectinas Tipo C/inmunología , Antígenos de Histocompatibilidad Menor/inmunología , Receptores CXCR3/inmunología , Receptores de Superficie Celular/inmunología , Células TH1/inmunología , Animales , Antígenos CD/genética , Antígenos CD4/genética , Antígenos CD4/inmunología , Movimiento Celular , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Enfermedad de Crohn/genética , Enfermedad de Crohn/patología , Células Dendríticas/inmunología , Células Dendríticas/patología , Regulación de la Expresión Génica , Humanos , Tolerancia Inmunológica , Interleucina-10/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Lectinas Tipo C/genética , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Antígenos de Histocompatibilidad Menor/genética , Receptores CXCR3/genética , Receptores de Superficie Celular/genética , Transducción de Señal , Células TH1/patologíaRESUMEN
The aim of the study was to determine whether an elevated IgA level at the time of the diagnosis of IgA nephropathy has an effect on the severity of kidney biopsy findings and long-term outcomes in children. We retrospectively studied 89 children with IgA nephropathy who were stratified into Group 1- elevated serum IgA and Group 2 - normal serum IgA at baseline. The level of IgA, proteinuria, hematuria, glomerular filtration rate (GFR) and hypertension (HTN) were compared at baseline and after the end of the follow-up period of 4.0 ± 3.1 years. Kidney biopsy findings were evaluated using the Oxford classification. The evaluation of treatment included immunosuppressive therapy and renoprotection with angiotensin converting-enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), or no treatment. The elevated serum IgA was found in 46 (52 %) patients and normal serum IgA level was found in 43 (48 %) patients. No differences were found between the two groups regarding the mean age of patients, proteinuria, and the number of patients with reduced GFR or HTN at baseline. In kidney biopsy, mesangial proliferation and segmental sclerosis were significantly more common in Group 1 compared with Group 2 (p < 0.05). Immunosuppressive therapy was used in 67 % children in Group 1 and 75 % children in Group 2. The Kaplan-Meier survival curves for renal function (with normal GFR) and persistent proteinuria did not differ significantly depending on the serum IgA level at baseline. We conclude that in IgA nephropathy the elevated serum IgA at baseline may be associated with mesangial proliferation and segmental sclerosis contribute to glomerulosclerosis, but has no effect on the presence of proteinuria or on the worsening of kidney function during several years of disease course.
Asunto(s)
Glomerulonefritis por IGA/sangre , Glomerulonefritis por IGA/patología , Inmunoglobulina A/sangre , Adolescente , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Biopsia , Niño , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/terapia , Humanos , Hipertensión Renal/complicaciones , Hipertensión Renal/patología , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Riñón/patología , Pruebas de Función Renal , Masculino , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The 90Sr and 137Cs contamination in Polish surface waters has been monitoring since 1994. Surface water samples from six lakes and the Vistula and Oder Rivers were collected in spring and autumn 2012 and 2013. The mean 90Sr and 137Cs concentrations were 3.92 ± 0.40 and 4.49 ± 2.00 mBq L-1, respectively. Correlations were identified between the radionuclide concentrations and meteorological conditions and the original fallout distribution from the Chernobyl disaster. The annual average radionuclide concentrations were not significantly different from the concentrations found between 1994 and 2011. The 137Cs and 90Sr concentrations have been decreasing only slowly.
RESUMEN
BACKGROUND: Patients with psoriasis suffer from chronic skin disease and impaired quality of life. With a prevalence of 1-3% of the population, psoriasis is one of the most common chronic inflammatory autoimmune diseases. Fumaric acid esters (Fumaderm(®)) are approved for the treatment of psoriasis in Germany, but regular Fumaderm therapy with six tablets per day is often limited due to adverse events. OBJECTIVES: This observational study recorded data on quality of life, treatment efficacy and drug dosing in patients suffering from psoriasis treated with Fumaderm under conditions of daily practice in 78 dermatological centres. PATIENTS AND METHODS: In this prospective, multicentre, noninterventional trial we included adult patients with severe plaque psoriasis under outpatient conditions receiving Fumaderm according to the current summary of product characteristics for systemic treatment of psoriasis. At baseline and after 3, 6 and 12 months the dosing regimen under daily conditions, Dermatology Life Quality Index (DLQI) and clinical efficacy with the Psoriasis Area and Severity Index (PASI) were documented. RESULTS: A total of 249 patients were included. The mean DLQI score at study entry was 9·95; the mean PASI was 16·8. The average treatment dose of Fumaderm was 2·8 tablets daily. More than 70% of patients were treated with one to three tablets daily and < 30% were treated with a dose ranging from four to six tablets daily. DLQI and PASI improved in the entire study population by 67·2% and 66·6%, respectively. Specifically, when analysing patients who started Fumaderm within 4 weeks before baseline the mean DLQI score decreased from 11·8 to 2·9 (75% reduction) and the mean PASI score from 19·84 to 7·35 after 12 months (63% improvement). CONCLUSIONS: This is the first field study analysing the use of Fumaderm and the improvement of quality of life in patients with psoriasis under daily outpatient conditions. The improvement of DLQI obtained with Fumaderm was comparable with the improvement observed in patients with psoriasis treated with modern biologics. Importantly, in most patients with good clinical response, the treatment dose was one to three tablets daily.
Asunto(s)
Fármacos Dermatológicos/administración & dosificación , Fumaratos/administración & dosificación , Psoriasis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dimetilfumarato , Relación Dosis-Respuesta a Droga , Sustitución de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Comprimidos , Resultado del Tratamiento , Adulto JovenRESUMEN
Male breast cancer is a rare form of carcinoma with an incidence rate of approximately 0.5-1% compared with cases of breast carcinoma as a whole. Male breast cancer reacts effectively to endocrine therapy because of a high frequency of hormone receptor expression.The aim of the present study was the assessment of correlations between stage, grade, expression of steroid receptors, basal/mesenchymal markers and proliferation index, as well as analysis of the impact of the above-mentioned parameters on overall (OS) and disease-free survival (DFS) in the group of 32 male breast cancer patients, treated at the Centre of Oncology in Cracow.We showed the significant positive correlation between MIB-1 LI and tumor stage, and hormone receptors (ER or PgR) immunonegativity, and expression of EGFR, vimentin (p<0.05) and P-cadherin (the last at statistical border). The presence of any of basal or masenchymal markers correlated with a more advanced tumor stage. Moreover tumors without vimentin expression were characterised by lower MIB-1 LI and were more frequently EGFR immunonegative.We found that hormone receptor negativity, vimentin immunopositivity and high MIB-1 LI are significant independent indicators of poor OS and DFS for male breast cancer patients (p<0.05).
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama Masculina/terapia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama Masculina/química , Neoplasias de la Mama Masculina/mortalidad , Neoplasias de la Mama Masculina/patología , Receptores ErbB/análisis , Humanos , Antígeno Ki-67/análisis , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Vimentina/análisisAsunto(s)
Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/efectos adversos , Educación , Fumaratos/administración & dosificación , Fumaratos/efectos adversos , Psoriasis/tratamiento farmacológico , Administración Oral , Alopecia Areata/tratamiento farmacológico , Alopecia Areata/epidemiología , Alopecia Areata/psicología , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/psicología , Disponibilidad Biológica , Ensayos Clínicos como Asunto , Comorbilidad , Fármacos Dermatológicos/farmacocinética , Dimetilfumarato , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Etanercept , Estudios de Seguimiento , Fumaratos/farmacocinética , Humanos , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/efectos adversos , Tasa de Depuración Metabólica/fisiología , Terapia PUVA/métodos , Proyectos Piloto , Estudios Prospectivos , Psoriasis/epidemiología , Psoriasis/psicología , Calidad de Vida , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Sistema de Registros , Rol del EnfermoRESUMEN
SLC1A1, which encodes the neuronal and epithelial glutamate transporter, is a promising candidate gene for obsessive-compulsive disorder (OCD). In this study, we conducted capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) screen for all 12 identified exons, including all coding regions and approximately 50 bp of flanking introns of the human SLC1A1 in 378 OCD-affected individuals. Full sequencing was completed on samples that showed an aberrant SSCP tracing for identification of the underlying sequence variants. Our aim was to determine if there are differences in the frequencies of relatively common alleles, or rare functional alleles, in 378 OCD cases and 281 ethnically matched controls. We identified one nonsynonymous coding SNP (c.490A > G, T164A) and three synonymous coding SNP (c.81G > C, A27A; c.414A > G, T138T; c.1110T > C, T370T) in case samples. We found no statistical differences in genotype and allele frequencies of common cSNPs in SLC1A1 between the OCD cases and controls. The rare variant T164A was found only in one family. Further investigation of this variant is necessary to determine whether and how it is related to OCD. There was no other evidence of significant accumulation of deleterious coding mutations in SLC1A1 in the OCD cases.
Asunto(s)
Alelos , Transportador 3 de Aminoácidos Excitadores/genética , Trastorno Obsesivo Compulsivo/genética , Polimorfismo Genético , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Variación Genética , Genotipo , Humanos , Masculino , Mutación , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADN , Factores SexualesRESUMEN
AIMS: To determine the prognostic value of proliferative potential and DNA ploidy in 72 brain tumours (36 grade III and 36 grade IV astrocytomas) using bromodeoxyuridine (BrdUrd) incorporation and flow cytometry. MATERIAL AND METHODS: All 72 patients underwent excision, mostly incomplete of the tumour. After surgery, eight patients received conventionally fractionated radiotherapy, 11 patients received accelerated radiotherapy, and 53 patients received hypofractionated radiotherapy. Tumour samples taken during surgery from each patient were incubated in vitro for 1 h at 37 degrees C with BrdUrd using the high pressure oxygen method. The percentage of BrdUrd-labelled cells (BrdUrd labelling index [BrdUrd LI]), and the total DNA content were evaluated: RESULTS: The tumours showed variability in the BrdUrd LI values, which ranged from 0.3 to 19.1%. No difference was observed in mean BrdUrd LI between grade III and grade IV sub-groups. A significantly higher percentage of DNA aneuploidy was observed in grade III gliomas (69.4%) than in grade IV gliomas (52.8%). Univariate analysis showed that younger patients (< or = 51 years) (P = 0.021) with grade III gliomas (P = 0.030) and low tumour proliferation rate (BrdUrd LI < or = 2.7%, P = 0.028) had significantly higher 5-year survival rates. Tumour ploidy had no influence on patients' survival (P = 0.591). However, Cox multi-variate analysis showed that only age over 51 years, and high tumour proliferation rate (BrdUrd LI > 2.7%), were significant unfavourable prognostic factors in patient survival. CONCLUSION: In this study, independent prognostic factors for patients with high-grade gliomas treated with surgery and post-operative radiotherapy are age and tumour proliferation rate assessed according to the BrdUrd LI.
Asunto(s)
Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirugía , Bromodesoxiuridina , Glioma/radioterapia , Glioma/cirugía , Adulto , Factores de Edad , Anciano , Neoplasias Encefálicas/diagnóstico , Proliferación Celular/efectos de los fármacos , Terapia Combinada , ADN de Neoplasias/análisis , ADN de Neoplasias/efectos de los fármacos , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Estudios de Seguimiento , Glioma/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Oxígeno/farmacología , Ploidias , Pronóstico , Sensibilidad y Especificidad , Coloración y Etiquetado , Tasa de Supervivencia , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
In this paper a quantitative explanation for a diamagnetic ortho/para H2 conversion is given. The description is based on the quantum-mechanical density matrix formalism originally developed by Alexander and Binsch for studies of exchange processes in NMR spectra. Only the nuclear spin system is treated quantum-mechanically. Employing the model of a three spin system, the reactions of the hydrogen gas with the catalysts are treated as a phenomenological rate process, described by a rate constant. Numerical calculations reveal that for nearly all possible geometrical arrangements of the three spin system an efficient spin conversion is obtained. Only in the chemically improbable case of a linear group H-X-H no spin conversion is obtained. The efficiency of the spin conversion depends strongly on the lifetime of the H-X-H complex and on the presence of exchange interactions between the two hydrogens. Even moderate exchange couplings cause a quench of the spin conversion. Thus a sufficiently strong binding of the dihydrogen to the S spin is necessary to render the quenching by the exchange interaction ineffective.
Asunto(s)
Espectroscopía de Resonancia por Spin del Electrón , Hidrógeno/química , Catálisis , Cinética , Espectroscopía de Resonancia Magnética , Matemática , Modelos QuímicosRESUMEN
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair and transcription regulation. The aim of this study was to investigate the role of PARP-1 in muscarinic cholinergic receptor signaling. Our data indicate that activation of muscarinic cholinergic receptors by carbachol (1mM) in the presence of GTP gamma S evoked a significant enhancement of PARP activity in the adult rat hippocampus. Moreover, TMB-8 (10 microM), an antagonist of inositol 1, 4, 5 trisphosphate (IP(3)) receptor prevented the activation of PARP-1, which indicates that IP(3) /Ca(2+) signaling is involved in this pathway. The diacylglycerol (DAG)-regulated protein kinase C (PKC) inhibitor (GF109203X) (1 microM) only slightly enhanced PARP activity in hippocampal nuclear fractions, which suggests that DAG/ PKC is not involved in PARP activation.
Asunto(s)
Hipocampo/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Receptores Muscarínicos/metabolismo , Transducción de Señal , Animales , Señalización del Calcio , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Diglicéridos/metabolismo , Ácido Gálico/análogos & derivados , Ácido Gálico/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Técnicas In Vitro , Indoles/farmacología , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inhibidores , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Maleimidas/farmacología , Poli(ADP-Ribosa) Polimerasa-1 , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
Amyloid beta peptide (A beta) and non-A beta component of Alzheimer's disease amyloid (NAC) are involved in pathomechanism of Alzheimer's Disease (AD) and are deposited in the AD brain in the form of senile plaques. However, the mechanism of their neurotoxicity is not fully understood. In this study the sequence of events involved in NAC and A beta peptides evoked toxicity was investigated in brain slices, synaptosomes and in subcellular fractions. Radio-, immunochemical, spectrophotometrical methods and DNA electrophoresis were used in this study. Our data indicated that A beta 1-40 (25 microM) and NAC (10 microM) peptides induced liberation of free radicals and massive DNA damage that lead to activation of DNA bound enzyme poly(ADP-ribose) polymerase-1 (PARP-1). In consequence of these processes apoptosis-inducing factor (AIF) was released from mitochondria and was translocated to nucleus. The inhibitor of PARP, 3-aminobenzamide significantly decreased AIF release from mitochondria and its translocation. Both peptides under the investigational conditions had no effect on caspase-3 activity. Our data indicated that A beta and NAC peptides stimulate AIF-dependent apoptotic pathway that seems to be caspase independent process. The inhibition of PARP-1 may protect the brain against A beta and NAC toxicity.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Factor Inductor de la Apoptosis/metabolismo , Encéfalo/metabolismo , Mitocondrias/metabolismo , Fragmentos de Péptidos/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , alfa-Sinucleína/metabolismo , Animales , Benzamidas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Caspasa 3/metabolismo , Núcleo Celular/metabolismo , Daño del ADN , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Transporte de Proteínas , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Sinaptosomas/metabolismoRESUMEN
The synucleins are a family of presynaptic proteins that are abundant in neurons and include alpha-, beta, and gamma-synuclein. Alpha-synuclein (ASN) is involved in several neurodegenerative age-related disorders but its relevance in physiological aging is unknown. In the present study we investigated the expression of ASN mRNA and protein in the different brain parts of the adult (4-month-old) and aged (24-month-old) rats by using RT-PCR technique and Western blot, respectively. Our results indicated that mRNA expression and immunoreactivity of ASN is similar in brain cortex, hippocampus and striatum but markedly lower in cerebellum comparing to the other brain parts. Aging lowers ASN mRNA expression in striatum and cerebellum by about 40%. The immunoreactivity of ASN in synaptic plasma membranes (SPM) from aged brain cortex, hippocampus and cerebellum is significantly lower comparing to adult by 39%, 24% and 65%, respectively. Beta-synuclein (BSN) was not changed in aged brain comparing to adult. Age-related alteration of ASN may affect the nerve terminals structure and function.
Asunto(s)
Envejecimiento/metabolismo , Encéfalo/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Envejecimiento/genética , Animales , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Regulación de la Expresión Génica/fisiología , Hipocampo/metabolismo , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Terminales Presinápticos/fisiología , Ratas , Ratas Wistar , Sinucleínas , alfa-Sinucleína , Sinucleína beta , gamma-SinucleínaRESUMEN
We examined the effect of gamma-irradiation (4 Gy) alone or combined with estrogen (17beta-estradiol 15 microM) treatment on the radiation response of stromal fibroblasts from cervical tumors. The fibroblasts were derived from tumors of 9 younger (<50 years) and 9 older (>50 years) cervical cancer patients. A normal fibroblast GSH+/+ cell strain was used as a reference cell. The end-points examined 2 days after irradiation were cell cycle distribution and apoptosis as measured of the cellular response to gamma-radiation. The response of examined fibroblast groups to gamma-rays alone was comparable but apoptotic death was more marked in fibroblasts derived from the younger patients with TNM 1+2 tumors than from the older ones. There was a considerable estrogen effect on the response to gamma-rays that differed between stromal fibroblasts from the examined age groups and was dependent on the tumor stage. In particular, we found a marked decrease in the number of apoptotic cells and debris after estrogen + irradiation, as compared to irradiation alone, only in younger patients and TNM 1+2 tumors. These results indicate that the response of stromal fibroblasts to gamma-rays to a considerable extent depends on donors age and tumor stage. Since stromal fibroblasts have been used for prediction of normal tissue late effects in patients treated with radiotherapy, we conclude that they may not be an adequate model for this purpose.
Asunto(s)
Fibroblastos/patología , Fibroblastos/efectos de la radiación , Neoplasias del Cuello Uterino/radioterapia , Factores de Edad , Anciano , Apoptosis , Bromodesoxiuridina/farmacología , Ciclo Celular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Estradiol/farmacología , Estrógenos/metabolismo , Femenino , Citometría de Flujo , Fase G2 , Rayos gamma , Humanos , Persona de Mediana Edad , Mitosis , Tolerancia a Radiación , Fase S , Factores de Tiempo , Neoplasias del Cuello Uterino/metabolismoRESUMEN
Current knowledge about an incidence of bone metastases, use of bisphosphonates and assessment of response to the treatment are surveyed. The bone metastases are quite frequent in patients with breast and prostate cancers. High doses of intravenous pamidronate are particularly useful in the treatment of these patients. Prior to therapy with bisphosphonate special score elaborated by RE Coleman should be calculated. The new biochemical bone resorption markers especially Ntx i Crosslaps seems to be the most efficient for evaluation metastases response.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Difosfonatos/uso terapéutico , Neoplasias Primarias Secundarias , Humanos , Inyecciones Intravenosas , Pamidronato , Resultado del TratamientoRESUMEN
DNA ploidy and the proliferative potential in 75 gliomas were investigated using bromodeoxyuridine labelling index (BrdUrd LI), S-phase fraction (SPF) and argyrophilic nucleolar organizer regions (AgNOR) technique. There were 53 highly malignant (AIII-AIV), and 22 low-grade (AI-AII) gliomas. One fragment of the tumour was fixed in Carnoy's solution for AgNOR test, while the other fragments were used for flow cytometric determination of the labelling index, SPF and DNA ploidy. For the BrdUrdLI, tumour samples from each patient were incubated in vitro for one hour at 37 degrees C with BrdUrd using the high pressure oxygen method. The tumours showed variability in the BrdUrdLI values, SPF and AgNOR counts/cell nucleus. The same percentage of DNA aneuploidy (55%) was found in high-grade as well as in low-grade gliomas. Univariate analysis showed that patients with grade I & II gliomas had significantly higher 3-year survival rate (p = 0.0193) than those with grade III and grade IV gliomas. Also patients with lower proliferation rate of tumours (BrdUrdLI < or =2.3% and AgNOR counts < or =2.6%/cell) had higher 3-year survival rate (p<0.03), which can be helpful in prognosis. Tumour ploidy or SPF had no influence on patients' survival (p = 0.7908). Cox multivariate analysis showed that only patients' age > 45 years and high tumour grade (III and IV) were significant unfavourable prognostic factors in terms of patients' survival.
Asunto(s)
Astrocitoma/patología , Neoplasias Encefálicas/patología , División Celular , Ploidias , Adulto , Aneuploidia , Astrocitoma/genética , Astrocitoma/mortalidad , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Bromodesoxiuridina/metabolismo , ADN de Neoplasias/análisis , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Región Organizadora del Nucléolo/ultraestructura , Pronóstico , Fase S , Tinción con Nitrato de Plata , Tasa de SupervivenciaRESUMEN
In 1996-1998, a total of 2285 Ixodes ricinus ticks (1063 nymphs, 637 males, 585 females) were collected from vegetation from 25 different localities in the 8 Polish provinces throughout the country. Ticks inhabited all 25 collection sites. The average number of ticks per collection site was 91.4 +/- 13.7. All 2285 ticks were examined for Borrelia burgdorferi sensu lato (s.l.) presence, of which 1333 specimens from 3 provinces were tested by routine indirect immunofluorescence assay (IFA) using polyclonal antibody PAB 1B29. The remaining 952 specimens from 5 provinces were examined by polymerase chain reaction (PCR), using FL6 and FL7 primers. The overall infection rate in ticks estimated by these 2 methods was 10. 2%. Nymphs showed lower positivity rate (6.2%) as compared to adult ticks (14.9% in females and 12.4% in males). The highest percentage of infected I. ricinus ticks (37.5%) was noted in the Katowice province while the lowest (4.1%) in the Bia ystok province. In particular collection sites, infection rates varied from 0-37.5%. The obtained results confirmed that B. burgdorferi s.l. is present throughout the distributional areas of I. ricinus in Poland and that a prevalence of spirochete-infected ticks may be high in some locations.