RESUMEN
Several studies have demonstrated the role of Wnt and Notch signaling in the pathogenesis of pituitary adenomas, but data are scarce regarding the role of Hedgehog signaling. In this study we investigated the differential expression of gene targets of the Hedgehog signaling pathway. Formalin-fixed, paraffin-embedded specimens from adult patients who underwent transphenoidal resection and normal human pituitary tissues that were obtained from autopsies were used. Clinical information and data from pre-operative MRI scan (extracellular tumor extension, tumor size, displacement of the optic chiasm) were retrieved from the Hospital's database. We used a customized RT(2) Profiler PCR Array, to investigate the expression of genes related to Notch and Hedgehog signaling pathways (PTCH1, PTCH2, GLI1, GLI3, NOTCH3, JAG1, HES1, and HIP). A total of 52 pituitary adenomas (32 non-functioning adenomas, 15 somatotropinomas and 5 prolactinomas) were used in the final analysis. In non-functioning pituitary adenomas there was a significant decrease (approximately 75%) in expression of all Hedgehog related genes that were tested, while Notch3 and Jagged-1 expression was found significantly increased, compared with normal pituitary tissue controls. In contrast, somatotropinomas demonstrated a significant increase in expression of all Hedgehog related genes and a decrease in the expression of Notch3 and Jagged-1. There was no significant difference in the expression of Hedgehog and Notch related genes between prolactinomas and healthy pituitary tissues. Hedgehog signalling appears to be activated in somatotropinomas but not in non-functioning pituitary adenomas in contrast to the expression pattern of Notch signalling pathway.
Asunto(s)
Adenoma/metabolismo , Proteínas Hedgehog/metabolismo , Neoplasias Hipofisarias/metabolismo , Adulto , Anciano , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Proteínas Hedgehog/genética , Humanos , Masculino , Persona de Mediana Edad , Prolactinoma/metabolismo , ARN Mensajero/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal , Adulto JovenRESUMEN
Simvastatin (SIM), which is widely used in hyperlipidemia treatment, has also attracted attention due to its anabolic effects on bones. This study is designed to investigate the effectiveness of 2 mg SIM combined with 3 different carriers as delivery systems. Bone defects were surgically created in the femoral bones of 14 New Zealand white rabbits. The carriers used were the inorganic bovine bone graft (BOS), the hydroxyapatite combined with calcium sulfate (HACS), and the collagen sponge (COS). The bone defects were divided for each time period into 7 groups, as follows: passive control group (CONT), active control groups (BOS), (HACS) and (COS) (no simvastatin), and groups (BOS + SIM), (HACS + SIM) (carrier and simvastatin combination). Animal were sacrificed at 4 and 8 weeks postoperatively, and bone defects areas were prepared for histological examination and histomorphometric evaluation. Analysis of variance demonstrated statistically significant differences between groups depending on the carrier used. At 4 weeks, the BOS + SIM group presented higher rates of new bone formation, whereas at 8 weeks more new bone formation was noted for the HACS + SIM group. This study suggests that local application of simvastatin, combined with an appropriate carrier, can promote new bone formation.
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Enfermedades Óseas/tratamiento farmacológico , Fémur/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Simvastatina/uso terapéutico , Animales , Materiales Biocompatibles/química , Enfermedades Óseas/patología , Regeneración Ósea/efectos de los fármacos , Trasplante Óseo/métodos , Sulfato de Calcio/química , Bovinos , Colágeno/química , Portadores de Fármacos , Durapatita/química , Fémur/patología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Masculino , Membranas Artificiales , Minerales/uso terapéutico , Osteoblastos/efectos de los fármacos , Osteoblastos/patología , Osteocitos/efectos de los fármacos , Osteocitos/patología , Osteogénesis/efectos de los fármacos , Conejos , Simvastatina/administración & dosificación , Factores de TiempoRESUMEN
BACKGROUND: Activation of histamine H1 receptor (H1R) is a well-known hallmark of allergic and inflammatory pathology. Both types of bradykinin receptors (B1R and B2R) are also known to contribute significantly to the latter and some sort of functional interaction between them and H1R has been alluded to in the past. Here we use an experimental model of rat paw oedema formation to examine the effect of exogenously added histamine on the gene expression of H1R and bradykinin receptors B1R and B2R, alone or in combination to rupatadine, a second generation antihistamine agent. METHODS: Histamine-induced oedema formation was monitored with a plethysmometer. The gene expression of H1R, B1R and B2R was analyzed with both conventional and real-time PCR. Rupatadine fumarate was used in pure form and administered intraperitoneally, prior to histamine injection into the paw. Microscopy of haematoxylin and eosin-stained sections of paw tissue was used to examine effects on tissue architecture. RESULTS: Histamine injection into the paw resulted in significant up regulation of H1R and B2R without inducing significant cellular infiltration, but appears to affect less the expression of B1R. Rupatadine was, under the conditions used in this study, very effective in preventing this effect and in suppressing oedema formation through its antihistamine action. CONCLUSION: Rupatadine has a suppressing effect on H1R and B2R gene expression which could add to its efficacy towards allergy and allergy-like conditions.
Asunto(s)
Ciproheptadina/análogos & derivados , Histamina/metabolismo , Receptor de Bradiquinina B2/genética , Receptores Histamínicos H1/genética , Animales , Ciproheptadina/farmacología , Edema/prevención & control , Regulación de la Expresión Génica/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H1/farmacología , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor de Bradiquinina B1/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Pilocytic astrocytoma can be challenging to diagnose. METHODS: Its clinical presentations can differ, directly related to its size and location, and are relatively unreliable. Similarly, imaging findings also vary with the location of the pilocytic astrocytoma. RESULTS: This review provides an overview of the different imaging findings regarding pilocytic astrocytomas using both conventional and advanced magnetic resonance imaging sequences according to tumour location; the findings are strongly related to the tumour's tendency to infiltrate surrounding structures, being able to carry out gross total resection, and finally the prognosis. CONCLUSIONS: Knowledge of these imaging manifestations of pilocytic astrocytoma may be helpful to arrive at an accurate diagnosis. TEACHING POINTS: ⢠To recognise the various imaging findings of pilocytic astrocytoma on both conventional and advanced magnetic resonance imaging sequences. ⢠To identify the characteristic imaging findings according to tumour location. ⢠To discuss the relevant differential diagnoses of pilocytic astrocytoma in each tumour location.
RESUMEN
The purpose of this prospective experimental and clinical study is to evaluate the effectiveness of the intralesional injection of platelet-rich plasma (PRP), in the management of non-healing chronic wounds. Skin defects were created in the ears of 20 white New Zealand rabbits. In the study group, autologous PRP was injected intralesionally. The control group was treated conservatively. Nineteen out of 20 cases of the study group healed within a mean time of 24·9 days. In the control group, seven defects healed within a mean period of 26·7 days, seven ulcers did not heal at day 28 and in six cases a full thickness ear defect was recorded. For a 3-year period, 26 patients with chronic ulcers underwent surgical debridement and intralesional injection of PRP. A histological study was performed before and 7 days after PRP injection. Ten patients healed within a mean period of 7 weeks. In 16 cases, PRP prepared the wound bed for the final and simpler reconstructive procedure. Intralesional injection is a newly described method for application of PRP and represents an effective therapeutic option when dealing with non-healing wounds.
Asunto(s)
Úlcera de la Pierna/terapia , Plasma Rico en Plaquetas , Úlcera Cutánea/terapia , Cicatrización de Heridas/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Biopsia con Aguja , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Estudios de Seguimiento , Úlcera del Pie/patología , Úlcera del Pie/terapia , Humanos , Inmunohistoquímica , Inyecciones Intralesiones , Úlcera de la Pierna/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Conejos , Índice de Severidad de la Enfermedad , Úlcera Cutánea/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
Based on recent developments in glioblastoma subtyping, we examined DARPP32 (PPP1R1B), a neuronal marker against STAT5 and STAT3 that are pro-oncogenic in glioblastoma. mRNA ratios of DARPP32, STAT1, STAT3, STAT5A and STAT5B were assessed in routinely diagnosed gliomas s including a series of glioblastomas from patients (n = 67) treated with chemoradiotherapy (temozolomide), out of which 88 % had sequencing validated IDH-negative disease. DARPP32/STAT1 (p = 0.0007), DARPP32/STAT3 (p = 0.0004) and DARPP32/STAT5B (p = 0.0039) ratios were significantly higher in grade II and III as compared to grade IV tumours. The same high ratios were also associated with absence of immunohistochemically assessed AKT/PKB phosphorylation and survivin protein expression. High DARPP32/STAT3, DARPP32/STAT5B, and STAT5B/STAT3 ratios were associated with longer patient progression free (PFS) and overall survival (OS). Upon multivariate analysis, total/subtotal removal of the tumour (HR:0.431; 95%CI:0.241-0.771, Wald p = 0.005), high DARPP32/STAT5B (HR:0.341; 95%CI:0.169-0.690; Wald p = 0.003) and STAT5B/STAT3 mRNA ratios (HR:0.480; 95%CI:0.280-0.824; Wald p = 0.008) were independent favorable parameters for prolonged PFS. Extent of surgery (HR:0.198; 95%CI:0.101-0.390; p < 0.001) and high DARPP32/STAT5A ratios (HR:0.320; 95%CI:0.160-0.638, p = 0.001) were independently predictive for longer OS. The presented approach is applicable for prospective validation and appears promising towards an effective glioblastoma patient stratification in addition to IDH mutations. These data may contribute to understanding the biology of gliomas with respect to their potential neuronal characteristics and justify STAT-inhibiting therapeutic interventions in the same tumour system.
Asunto(s)
Neoplasias Encefálicas/genética , Fosfoproteína 32 Regulada por Dopamina y AMPc/genética , Glioblastoma/genética , ARN Mensajero/biosíntesis , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT5/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Masculino , Persona de Mediana Edad , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/metabolismo , Survivin , TemozolomidaRESUMEN
BACKGROUND: Diaphragmatic muscular remodeling is caused by various conditions and was mainly studied in pulmonary pathologies and chronic alterations of intra-thoracic pressure. We investigate the effect of the chronically increased intra-abdominal pressure (IAP) on the diaphragm by morphological and biochemical analysis. METHODS: Thirty rabbits were divided into control and study groups. IAP was increased in group B to 12 mmHg for 2 months. The left hemidiaphragm underwent morphological, while the right underwent biochemical analysis. RESULTS: In H&E, all fibers were normal. ATPase analysis demonstrated that type I fibers show no differences between groups. Type ΙΙ(Α) were decreased (p = 0.016) while type ΙΙ(Β/X) fibers were increased (p = 0.025) in group B. Fibers with resistance to fatigue were decreased in group B (p = 0.024). In group B, biochemical activity for glutathione reductase (p = 0.004), glutathione peroxidase (p = 0.021), protein carbonylation (0.029), lipid peroxidation (p = 0.005), and balance of preoxidative-antioxidative factors (p = 0.006) was increased. CONCLUSIONS: Chronically increased IAP induces alterations to the rabbit diaphragm. Adaptation, equivalent to strenuous contraction, transforms the diaphragm to be functionally more efficient toward workload but makes it vulnerable against oxidative stress.
Asunto(s)
Músculos Abdominales/metabolismo , Músculos Abdominales/patología , Adenosina Trifosfatasas/metabolismo , Diafragma/patología , Hipertensión Intraabdominal/metabolismo , Hipertensión Intraabdominal/patología , Músculos Abdominales/enzimología , Animales , Diafragma/metabolismo , Modelos Animales de Enfermedad , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Hipertensión Intraabdominal/enzimología , Peroxidación de Lípido , Masculino , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares de Contracción Lenta/patología , Estrés Oxidativo , Presión , Carbonilación Proteica , ConejosRESUMEN
Antioxidant supplementation has been suggested to prevent exercise-induced muscle injury, but the findings are inconsistent. The objective of this study was to investigate the potential protective role of vitamin E treatment against eccentric exercise-induced muscle injury by examining morphological and functional alterations in rat soleus muscle after downhill running as well as muscle injury markers in the blood. Sixty adult male Wistar rats were randomly assigned to vitamin E-treated or placebo-treated groups studied at rest, immediately post-exercise or 48 h post-exercise (n = 10 per group). Vitamin E was administered by daily intraperitoneal injections of 100 mg/kg body mass of DL: -α-tocopheryl acetate for five consecutive days prior to exercise, resulting in the doubling of its plasma concentration. Downhill running resulted in significant (P < 0.05) changes in all injury markers for the placebo-treated rats at 0 and 48 h post-exercise. However, significantly smaller soleus muscle single-twitch tension (P (t)) and unfused (40 Hz) tetanic force, and greater plasma creatine kinase (CK) and lactate dehydrogenase (LD) activities compared with the control were found only immediately post-exercise for the vitamin E-treated rats (P < 0.05). Maximal tetanic force (P (o)) did not decline significantly compared to sedentary controls at neither time points measured. The vitamin E-treated rats had significantly (P < 0.05) higher soleus muscle P (t) immediately post-exercise than the placebo-treated rats as well as lower plasma CK and LD activity 48 h post-exercise. However, there was no difference in P (o) decline between groups at either time points measured. Vitamin E-treated rats had less pronounced morphological alterations in muscle in the immediate and 48-h post-exercise period. In conclusion, the effect of short-term vitamin E supplementation against eccentric exercise-induced muscle injury did not appear to be physiologically significant, because vitamin E failed to prevent the decline in the functional measure of P (o) compared to the placebo conditions.
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Suplementos Dietéticos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/lesiones , Carrera/lesiones , Vitamina E/farmacología , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Esquema de Medicación , Masculino , Enfermedades Musculares/dietoterapia , Enfermedades Musculares/etiología , Postura/fisiología , Distribución Aleatoria , Ratas , Ratas Wistar , Carrera/fisiología , Factores de Tiempo , Vitamina E/administración & dosificaciónRESUMEN
BACKGROUND: The aim of this study was to specify the histologic response of the rectus abdominis muscle of the rabbit, to the chronically increased intra-abdominal pressure. MATERIALS AND METHODS: Forty-five New Zealand white rabbits were divided into three groups. In all groups, a rubber bag was implanted into the peritoneal cavity. In group A (n=15) the bags were kept empty. In group B (n=15) the bags were filled with normal saline in order to achieve an intra-abdominal pressure of over 12 mmHg. This pressure was kept at this level for 8 wk. In group C (n=15) the intra-abdominal rubber bags were filled with lead covered by silicone, equiponderant to the mean weight of the normal saline insufflated in group B. After 8 wk we took biopsies of the rectus abdominis muscle and counted the proportion of the different types of muscular fibers (type I, IIA, and IIB/X). RESULTS: Significant difference was found in the proportion of the three types of muscle fibers. Intra-abdominal hypertension led to an increase in type I fibers (P=0.008). No difference was noticed between groups A and C. CONCLUSIONS: The histologic response to the increased intra-abdominal pressure was an increase in type I muscle fibers. Charging with lead did not cause any significant change in the proportion of muscular fibers.
Asunto(s)
Hipertensión Intraabdominal/patología , Fibras Musculares de Contracción Rápida/citología , Fibras Musculares de Contracción Lenta/citología , Cavidad Peritoneal/patología , Recto del Abdomen/citología , Animales , Biopsia , Cateterismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Masculino , Obesidad , Presión , ConejosRESUMEN
BACKGROUND: The diaphragm, the major respiratory muscle, contains three types of muscular fibers in dynamic balance between them. The fiber ratios vary in time in function of conditions, such as aging, hypoproteinemia, exercise, and chronic respiratory load. The diaphragmatic adaptation following abdominal conditions remains an unexplored field. This experimental study aims to identify the changes of the diaphragm due to chronic abdominal weight load. This may find application in conditions such as pregnancy, ascites, visceromegaly, large masses, and morbid obesity. METHODS: Thirty rabbits were divided into control (A) and study (B) groups. Group B was loaded with weight for 2 months. The left costal hemidiaphragm were stained with H&E and ATPase (fiber typing), while the right underwent biochemical analysis (prooxidative-antioxidative balance, lipid peroxidation, superoxide dismutase, glutathione reductase and peroxidase activities, total glutathione, and protein carbonylation). RESULTS: In H&E, all fibers were within normal range. ATPase analysis demonstrated reduction of type I (p = 0.019) and an increase of the type ΙΙ(Α) fibers ratio (p < 0.001) in group B, while the type ΙΙ(Β/X) fibers ratio remained stable. The above suggest remodeling of type I fibers into type II(A). Concerning biochemical analysis, difference was observed in glutathione peroxidase activity (p < 0.001). CONCLUSIONS: Chronically loaded abdomen leads to morphological adaptations of the costal diaphragm, but with minor oxidative stress. These diaphragmatic morphological changes are equivalent to heart failure or severe COPD, showing that this remodeling makes the muscle more efficient towards work load, but more vulnerable to fatigue.
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Diafragma/patología , Obesidad Abdominal/fisiopatología , Adaptación Fisiológica , Animales , Diafragma/química , Modelos Animales de Enfermedad , Masculino , Estrés Oxidativo , Conejos , Aumento de Peso/fisiologíaRESUMEN
BACKGROUND: Testing for tumor specific mutations on routine formalin-fixed paraffin-embedded (FFPE) tissues may predict response to treatment in Medical Oncology and has already entered diagnostics, with KRAS mutation assessment as a paradigm. The highly sensitive real time PCR (Q-PCR) methods developed for this purpose are usually standardized under optimal template conditions. In routine diagnostics, however, suboptimal templates pose the challenge. Herein, we addressed the applicability of sequencing and two Q-PCR methods on prospectively assessed diagnostic cases for KRAS mutations. METHODOLOGY/PRINCIPAL FINDINGS: Tumor FFPE-DNA from 135 diagnostic and 75 low-quality control samples was obtained upon macrodissection, tested for fragmentation and assessed for KRAS mutations with dideoxy-sequencing and with two Q-PCR methods (Taqman-minor-groove-binder [TMGB] probes and DxS-KRAS-IVD). Samples with relatively well preserved DNA could be accurately analyzed with sequencing, while Q-PCR methods yielded informative results even in cases with very fragmented DNA (p<0.0001) with 100% sensitivity and specificity vs each other. However, Q-PCR efficiency (Ct values) also depended on DNA-fragmentation (p<0.0001). Q-PCR methods were sensitive to detect
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Genes ras , Mutación , Neoplasias/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Proteínas ras/genética , ADN de Neoplasias/metabolismo , Técnicas de Apoyo para la Decisión , Exones , Genotipo , Humanos , Metástasis de la Neoplasia , Neoplasias/metabolismo , Estudios Prospectivos , Control de Calidad , Análisis de Secuencia de ADN , Programas InformáticosRESUMEN
PURPOSE: Phase I-II studies indicate that imatinib is active in glioblastoma multiforme. To better understand the molecular and clinical effects of imatinib in glioblastoma multiforme, we conducted a neoadjuvant study of imatinib with pretreatment and posttreatment biopsies. EXPERIMENTAL DESIGN: Patients underwent a computerized tomography-guided biopsy of their brain tumors. If diagnosed with glioblastoma multiforme, they were immediately treated with 7 days of imatinib 400 mg orally twice daily followed by either definitive surgery or re-biopsy. Pretreatment and posttreatment tissue specimens were tested by immunohistochemistry for Ki67 and microvessel destiny, and posttreatment specimens were analyzed for the presence of intact imatinib in tissue. Furthermore, pretreatment and posttreatment pairs were analyzed by Western blotting for activation of platelet-derived growth factor receptor, epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase signaling pathways. Pharmacokinetic studies were also done. RESULTS: Twenty patients were enrolled. Median survival was 6.2 months. Intact imatinib was detected in the posttreatment tissue specimens using mass spectrometry. There was no evidence of a drug effect on proliferation, as evidenced by a change in Ki67 expression. Biochemical evidence of response, as shown by decreased activation of AKT and mitogen-activated protein kinase or increased p27 level, was detected in 4 of 11 patients with evaluable, matched pre- and post-imatinib biopsies. Two patients showed high-level EGFR activation and homozygous EGFR mutations, whereas one patient had high-level platelet-derived growth factor receptor-B activation. CONCLUSIONS: Intact imatinib was detected in glioblastoma multiforme tissue. However, the histologic and immunoblotting evaluations suggest that glioblastoma multiforme proliferation and survival mechanisms are not substantially reduced by imatinib therapy in most patients.
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Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Piperazinas/farmacología , Piperazinas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Benzamidas , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Mesilato de Imatinib , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Proteína Oncogénica v-akt/metabolismo , Piperazinas/farmacocinética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Pirimidinas/farmacocinética , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/efectos de los fármacos , Adulto JovenRESUMEN
AIM: The aim of the current study is to evaluate the role of povidone iodine (PVI) in the management of experimental bacterial endophthalmitis in young rabbits. METHOD: Twenty white rabbits were used. Colony-forming units (CFU) of Staphylococcus epidermidis were injected intravitreally into the right eye of each animal. Injected eyes were evaluated clinically daily (anterior and posterior segment examination), and when clinical signs of endophthalmitis appeared, an injection of 0.1 ml PVI was made intravitreally. In group 1 (n = 10), the injected concentration of PVI was 0.1%, and in group 2 (n = 10) the concentration was 0.2%. At the end of the observation period, vitreous sample culture was made, and vitreous and retina specimens were taken for light histology examination as well. results: Group 1 eyes did not show any signs of clinical improvement. Vitreous culture showed the presence of 10(8) CFU/ml of S. epidermidis. Histological examination indicated acute inflammation. Group 2 animals presented a clear gradual regression of the inflammation. Vitreous culture for S. epidermidis proved to be sterile. Histological examination indicated chronic inflammation. CONCLUSIONS: Intravitreal injection of 0.2% PVI is likely to inhibit bacterial endophthalmitis of rabbit eyes due to S. epidermidis.
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Endoftalmitis/tratamiento farmacológico , Povidona Yodada/administración & dosificación , Staphylococcus epidermidis/efectos de los fármacos , Animales , Antiinfecciosos Locales/administración & dosificación , Humor Acuoso/microbiología , Recuento de Colonia Microbiana , Endoftalmitis/etiología , Endoftalmitis/fisiopatología , Ojo/citología , Ojo/fisiopatología , Inflamación , Conejos , Infecciones Estafilocócicas/complicaciones , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Resultado del TratamientoRESUMEN
Perinatal asphyxia (PA) is a major determinant for long-term sensorimotor and locomotor deficits. The model of neonatal hypoxia-ischemia (HI) in 7-day-old rats produces sensorimotor cortex, thalamus and striatum injury, which are all critical for the maintenance of sensory motor function. The aim of this study was to evaluate the long-term neurodevelopmental disturbances in the above experimental model and to assess the neuroprotective effect of MgSO(4) in terms of long-term behavioral and morphological changes. Seven-day-old rats were separated into three groups: A (control), neither ligated nor exposed to hypoxia; B (HI/MgSO(4)) ligated, exposed to hypoxia and treated with MgSO(4) (2 g/kg b.w., i.p.), and C (HI) ligated and exposed to hypoxia. At the age of 42 days, the behavior of the rats was evaluated using 5 sensorimotor tests. Muscle power, motor coordination, reflexes, and limb placing were tested to different sensory stimuli. The study was completed with the histopathological evaluation of brain tissue damage. In all individual tests the HI-treated rats performed significantly worse than the control and MgSO(4)-treated rats and this difference was more pronounced in the limb placing tests. Additionally, neonatal HI resulted in extensive neuronal damage that was limited after MgSO(4) administration. Behavioral alterations represent a useful endpoint for studying the consequences of a perinatal HI insult and the efficacy of potential neuroprotective treatments. MgSO(4) administration resulted in prevention of HI-induced sensorimotor deficits and brain injury.
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Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Sulfato de Magnesio/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/fisiopatología , Hipoxia-Isquemia Encefálica/fisiopatología , Hipoxia-Isquemia Encefálica/prevención & control , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/fisiopatología , Fuerza Muscular/efectos de los fármacos , Fuerza Muscular/fisiología , Propiocepción/efectos de los fármacos , Propiocepción/fisiología , Ratas , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Previous studies have shown contradictory results regarding magnesium-mediated neuroprotection in animal models of perinatal asphyxia. The aim of this study is to investigate the effects of MgSO(4) postasphyxial treatment on hypoxia-ischemia (HI)-induced brain injury in neonatal rats and the possibility that this effect is related to the severity of brain damage. Seven-day-old rats underwent unilateral carotid artery ligation followed by 1 or 2 hours of hypoxia (8% O(2)) and MgSO(4) administration. Adenosine triphosphate/phosphocreatine and glutamate/glutamine measurements and neuropathological evaluation of the hippocampus were used to assess the effects of HI and MgSO(4). HI caused time-dependent changes in energy stores, amino acid concentrations, and brain damage. Administration of MgSO(4) after 1 hour but not after 2 hours of hypoxia resulted in significant prevention of HI-induced brain injury. MgSO(4) administration results in a significant protection against moderate HI-induced brain damage, whereas it fails to offer a similar effect against severe brain damage.
Asunto(s)
Hipoxia Encefálica/prevención & control , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Sulfato de Magnesio/farmacología , Fármacos Neuroprotectores/farmacología , Adenosina Trifosfato/metabolismo , Factores de Edad , Aminoácidos/metabolismo , Animales , Animales Recién Nacidos , Femenino , Hipocampo/patología , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/patología , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia-Isquemia Encefálica/patología , Masculino , Fosfocreatina/metabolismo , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Accumulating data about the impact of hTERT in astrocytic tumor carcinogenesis and recent evidence about its association with disease outcome prompt the evaluation of this molecule with methods applicable in routine pathology practice. In this study, we investigated hTERT protein expression with immunohistochemistry (IHC) and the NCL-hTERT antibody in 49 astrocytic tumors. Results were validated with the assessment of hTERT mRNA (relative quantification, identification of splice variants, in situ hybridization). Specific nuclear hTERT immunostaining patterns (IPs) were characterized as patterns As (single large dot) and Am (multiple dots) without nucleoplasm staining and pattern B (nucleoplasm staining with or without dots), corresponding to low and high relative hTERT expression values (P<0.0001). Low- and high-grade astrocytic tumors were found positive for hTERT in 74 and 85% of cases, respectively. Heterogeneity in the distribution of hTERT-positive cells was observed in all tumors. The prevailing nuclear IPs differed significantly between pilocytic astrocytomas (pattern As) and the rest of histologic types up to glioblastoma (patterns Am and B) (P<0.0001). The described nuclear IPs were also observed in non-neoplastic cells. Positive endothelial cells were found in astrocytic tumors of all grades, even when tumor cells showed no hTERT immunoreactivity. A subset of mature normal neurons was positive for hTERT (pattern As), suggesting a role for this molecule in neuronal maintenance in the adult brain. The nuclear hTERT IPs described here may reflect the functional status of non-neoplastic brain and neoplastic astrocytic cells and support the model of a continuum in the development of glioblastomas from diffuse fibrillary astrocytomas.
Asunto(s)
Astrocitos/metabolismo , Astrocitoma/metabolismo , Química Encefálica/fisiología , Neoplasias Encefálicas/metabolismo , Telomerasa/genética , Telomerasa/metabolismo , Adulto , Anciano , Astrocitos/patología , Astrocitoma/patología , Neoplasias Encefálicas/patología , Niño , Células Endoteliales/patología , Femenino , Fijadores , Formaldehído , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Persona de Mediana Edad , Adhesión en Parafina , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Clinical studies have shown that temozolomide (TMZ) and irinotecan demonstrate activity in high grade astrocytic tumors (HGAT). However, the optimal schedule of administration is unknown. PATIENTS AND METHODS: In the present study, a total of 45 HGAT patients, 38 with glioblastoma multiforme (GBM) and 7 with anaplastic astrocytoma (AA), were treated with TMZ, 150 mg/m(2) on days 1-5, followed by irinotecan, 150 mg/m(2) on days 6 and 17, every 4 weeks for 6 cycles or until the occurrence of unacceptable toxicity or disease progression. Radiation therapy (60 Gy) was initiated on the first day of treatment. RESULTS: Twenty-two patients completed six cycles of treatment. Most frequently recorded side-effects included neutropenia (37%), nausea/vomiting (66%), diarrhea (31%) and infection (44%). Five episodes of vaso-occlusive disease, all of them fatal, were observed. After a median follow-up of 49.8 months, median progression-free survival for patients with GBM was 7.7 months, while median overall survival was 12.8 months. There were six long-term survivors, three of them with GBM. Two out of the five biomarkers studied, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor-C (VEGF-C), were found to be overexpressed in 74% of the tumors, however they had no predictive value for progression-free or overall survival. CONCLUSION: The combination of TMZ and irinotecan, as administered in this study, was accompanied by high rates of toxicity, especially myelotoxicity and infection. Further development of this regimen in the treatment of HGAT is not recommended.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/metabolismo , Astrocitoma/terapia , Biomarcadores de Tumor/biosíntesis , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Glioblastoma/metabolismo , Glioblastoma/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Astrocitoma/tratamiento farmacológico , Astrocitoma/radioterapia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Terapia Combinada , Ciclooxigenasa 2/biosíntesis , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/análogos & derivados , Estudios de Factibilidad , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Humanos , Irinotecán , Antígeno Ki-67/biosíntesis , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTEN/biosíntesis , Cooperación del Paciente , Cuidados Posoperatorios , Temozolomida , Factor C de Crecimiento Endotelial Vascular/biosíntesisRESUMEN
BACKGROUND: Erythropoietin (EPO), originally identified for its critical role in promoting erythrocyte survival and differentiation, has been shown to exert multiple paracrine/autocrine functions. Protective effects of EPO have been demonstrated in various tissues and experimental models of ischaemia-induced injury. In the present study, we investigated the effect of EPO on an in vivo rat model of renal ischaemia/reperfusion (I/R) injury and the possible mechanisms implicated in the EPO-mediated anti-apoptotic action. METHODS: Male Wistar rats, subjected to renal ischaemia for 45 min, were administered either saline or EPO (500 U/kg, i.p.) 20 min prior to I/R. A sham-operated group served as the control. At 48 h of reperfusion, the renal dysfunction and injury was assessed by measurement of serum biochemical markers (urea, creatinine) and histological grading. Apoptosis was assessed by the TUNEL method and morphological criteria. Expression of Bax and NF-kappaB (p65) was also evaluated. RESULTS: High levels of serum urea and creatinine were identified at 48 h after ischaemia. The EPO-treated group had significantly lower serum and creatinine levels. Semi-quantitative assessment of the histological lesions showed that rats subjected to I/R developed marked structural damage, whereas significantly less tubular damage was observed in the EPO-treated group. I/R caused an increase in TUNEL-positive cells that was accompanied by morphological evidence of apoptosis. In the EPO-treated rats only a few scattered TUNEL-positive cells were observed. Up-regulation of Bax in the tubular epithelial cells and increased expression of NF-kappaB was observed in the I/R-treated rats, while diminished expression of Bax and positive immunostaining of NF-kappaB was observed in the EPO-treated rats. CONCLUSION: Administration of EPO as a single dose before the onset of ischaemia produced a significant reduction in tubular injury, which was accompanied by a marked amelioration of renal functional impairment. The cytoprotective action of EPO against I/R injury seems to be associated with its anti-apoptotic action. Moreover, transcription factor NF-kappaB is likely to play a pivotal role in the pathophysiology of I/R renal injury and might have a key role in EPO-mediated protective effects.
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Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Modelos Animales de Enfermedad , Eritropoyetina/uso terapéutico , Daño por Reperfusión/complicaciones , Daño por Reperfusión/tratamiento farmacológico , Lesión Renal Aguda/patología , Animales , Apoptosis , Masculino , FN-kappa B/fisiología , Ratas , Ratas Wistar , Daño por Reperfusión/patologíaRESUMEN
Perinatal asphyxia accounts for behavioral dysfunctions that often manifest as sensorimotor, learning or memory disabilities throughout development and into maturity. Erythropoietin (Epo) has been shown to exert neuroprotective effects in different models of brain injury including experimental models of perinatal asphyxia. However, the effect of Epo on functional abilities following cerebral hypoxia-ischemia (HI) in neonatal rats is not known. The aim of the present study is to investigate the effect of Epo on sensorimotor deficits and brain injury induced by hypoxia-ischemia. Seven-day-old rats underwent unilateral, permanent carotid artery ligation followed by 1 h of hypoxia. Epo was administered as a single dose immediately after the hypoxic insult (2000 U/kg). The neuroprotective effect of Epo was evaluated at postnatal day 42 by using a battery of behavioral tests and histological analysis. The results of the present study suggest that Epo treatment immediately after HI insult significantly facilitated recovery of sensorimotor function. Consistently, histopathological evaluation demonstrated that Epo significantly attenuated brain injury and preserved the integrity of cerebral cortex. These findings indicate that long-term neuroprotective effect of Epo on neonatal HI-induced brain injury might be associated with the preservation of sensorimotor functions.