Low rCBV values in glioblastoma tumor progression under chemoradiotherapy.

PURPOSE: After standard treatment for glioblastoma, perfusion MRI remains challenging for differentiating tumor progression from post-treatment changes. Our objectives were (1) to correlate rCBV values at diagnosis and at first tumor progression and (2) to analyze the relationship of rCBV values at tumor recurrence with enhancing volume, localization of tumor progression, and time elapsed since the end of radiotherapy in tumor recurrence. METHODS: Inclusion criteria were (1) age > 18 years, (2) histologically confirmed glioblastoma treated with STUPP regimen, and (3) tumor progression according to RANO criteria > 12 weeks after radiotherapy. Co-registration of segmented enhancing tumor VOIs with dynamic susceptibility contrast perfusion MRI was performed using Olea Sphere software. For tumor recurrence, we correlated rCBV values with enhancing tumor volume, with recurrence localization, and with time elapsed from the end of radiotherapy to progression. Analyses were performed with SPSS software. RESULTS: Sixty-four patients with glioblastoma were included in the study. Changes in rCBV values between diagnosis and first tumor progression were significant (p < 0.001), with a mean and median decreases of 32% and 46%, respectively. Mean rCBV values were also different (p < 0.01) when tumors progressed distally (radiation field rCBV values of 1.679 versus 3.409 distally). However, changes and, therefore, low rCBV values after radiotherapy in tumor recurrence were independent of time. CONCLUSION: Chemoradiation alters tumor perfusion and rCBV values may be decreased in the setting of tumor progression. Changes in rCBV values with respect to diagnosis, with low rCBV in tumor progression, are independent of time but related to the site of recurrence.

Susceptibility background for type 2 diabetes in eleven Mexican Indigenous populations: HNF4A gene analysis.

The genetic risk of developing type 2 diabetes (T2D) increases in parallel with the proportion of Native American ancestry. Mestizo Mexicans have a 70% Native Amerindian genetic background. The T130I polymorphism in the HNF4A gene has been associated with early-onset T2D in mestizo Mexicans. Thus, the aim of the present study was to evaluate the frequency and relationship of the T130I variant in the HNF4A gene with risk factors for developing T2D in eleven indigenous groups from Mexico. In two groups, all exons of the HNF4A gene were directly sequenced; in the remaining the T130I polymorphism was analyzed by restriction fragment length polymorphism. Ancestry informative markers were assessed to confirm the Amerindian component. An additional analysis of EHH was carried out. Interestingly, HNF4A gene screening revealed only the presence of the T130I polymorphism. The range frequency of the risk allele (T) in the indigenous groups was from 2.7 to 16%. Genotypic frequencies (T130I/I130I) were higher and significantly different from those of all of the populations included in the HapMap Project (P < 0.005). EHH scores suggest a positive selection for T130I polymorphism. Metabolic traits indicate a relationship between the T130I/I130I genotypes with high triglyceride concentrations in the indigenous groups (P < 0.005). These results strongly suggest that the high frequency of the T130I polymorphism and its biological relationship with dysfunction in lipid metabolism in Mexican indigenous groups is a risk factor for the developing of T2D in Mexicans.

Ras signaling is essential for skin development.

Proliferation in the epidermis is a tightly controlled process. During skin development, epidermis formation and hair follicle morphogenesis crucially depend on the regulated balance between proliferation and differentiation. Here we deleted all three Ras loci (H-Ras, N-Ras and K-Ras) from keratinocytes in vitro as well as specifically from the epidermis in mice using a K5Cre strain. Upon Ras elimination, keratinocytes ceased proliferation and entered into senescence without any signs of apoptosis induction. Constitutive activation of the mitogen-activated protein kinase pathway was able to partially rescue the proliferative defects. In mice, Ras signaling was essential for proper development of the epidermis and hair follicles. Deletion of the three Ras loci during epidermis formation in mouse embryos caused a dramatic decrease in proliferation, resulting in a substantially thinner epidermis and delayed appearance of differentiation markers. We could not detect apoptotic or senescent cells in these embryos suggesting that loss of Ras protein expression only leads to severe hypoproliferation. These observations provide genetic evidence for an essential role of Ras proteins in the control of keratinocyte and epidermal proliferation.

Frecuencia de periodontitis en una muestra de diabéticos tipo 2 y no diabéticos de Santiago de Chile / Frequency of periodontitis in a sample of type 2 diabetics and non diabetics

Background: Periodontitis is highly prevalent in the general population and some diseases such as diabetes could favor its development, reaching a prevalence of over 60 percent. Aim: To evaluate the prevalence of periodontitis in a sample of DM2 patients and to compare it with non-diabetic subjects. Patients and Methods: We enrolled patients with DM2 and non-diabetic adult subjects. According to periodontal diagnosis, they were classified as healthy, having mild to moderate periodontitis and having severe periodontitis. Anthropometric assessment was performed and a fasting blood sample was obtained to measure blood glucose and lipid profile. In diabetics, HbA1c, creatinine, microalbuminuria, EKG and fundoscopy were evaluated. Results: We studied 62 patients with DM2, aged 55.2 +/- 9.4 years and with 4.7 +/- 4.6 years of diagnosis of diabetes and 65 non-diabetic subjects, aged 50 +/- 9.6 years. Among diabetics, HbA1c values were 7.85 +/- 2.3 percent. The proportion of periodontitis was significantly higher in DM2 than in non-diabetics (98 and 89 percent, p = 0.02). Mild to moderate and severe periodontitis was observed in 39 and 60 percent of diabetic patients, respectively. Among non-diabetics, 11 percent were healthy, 5 percent had gingivitis, 37 percent mild to moderate periodontitis and 48 percent had severe periodontitis. The frequency of chronic complications of diabetes was low, except for positive microalbuminuria, that was present in 42.6 percent of patients. Conclusions: We found a high prevalence of periodontitis in diabetic and no diabetic patients, but among the former, it was near to 100 percent. Periodontal examination should be considered as part of the evaluation of patients with type 2 diabetes.

Sífilis ocular: Presentación de diez casos y revisión de la literatura / Ocular syphilis: Ten new cases and review of the literature

Introduction: Ocular manifestations in patients with syphilis may involve almost any of the structures of the eye. Objectives: To describe ten new cases of syphilis with eye involvement and to briefly discuss the management and therapy of such condition. Material and Methods: Ten cases were retrospectively studied over 13 years. Demographic factors, ophthalmologic examination, and laboratory tests were assessed. Results: Seven of the 10 cases were male and 3 were female. The mean age of patients was 39,7 years. Disease presentation included: panuveitis (6 patients), optic neuritis (3), retinal vasculitis (1) and Argyll-Robertson pupil (1). Cerebrospinal fluid VDRL test was positive in 6 patients and 3 patients were HIV (+). Conclusions: Syphilis is able to display diverse ophthalmologic manifestations. Not in all the cases the CSF-VDRL test was positive. Antitreponemal therapy generates a fast and effective response in the affected patients.

Introducción: Las manifestaciones oculares de los pacientes con sífilis pueden comprometer cualquiera de las estructuras del ojo. Objetivos: Describir diez nuevos casos de sífilis con compromiso ocular y realizar una breve discusión de su manejo y tratamiento. Pacientes y Métodos: Se estudiaron, de forma retrospectiva, diez casos en un período de 13 años. Se evaluaron factores demográficos, exámenes oftalmológico y de laboratorio. Resultados: De los diez casos, 7 eran hombres y 3 mujeres. El promedio de edad fue de 39,7 años. Las presentaciones fueron: panuveítis (n: 6), neuritis óptica (n: 3), vasculitis retinal (n: 1) y pupila de Argyll-Robertson (n: 1). Se obtuvo VDRL (+) en líquido cefalorraquídeo en 6 pacientes y serología para VIH (+) en 3 pacientes. Conclusiones: La sífilis puede producir variadas manifestaciones oftalmológicas. No en todos los casos el VDRL resultó positivo en el LCR. El tratamiento anti-treponémico produce una rápida y efectiva respuesta en los pacientes afectados.

[Ocular syphilis: ten new cases and review of the literature]. / Sífilis ocular: Presentación de diez casos y revisión de la literatura.

INTRODUCTION: Ocular manifestations in patients with syphilis may involve almost any of the structures of the eye. OBJECTIVES: To describe ten new cases of syphilis with eye involvement and to briefly discuss the management and therapy of such condition. MATERIAL AND METHODS: Ten cases were retrospectively studied over 13 years. Demographic factors, ophthalmologic examination, and laboratory tests were assessed. RESULTS: Seven of the 10 cases were male and 3 were female. The mean age of patients was 39,7 years. Disease presentation included: panuveitis (6 patients), optic neuritis (3), retinal vasculitis (1) and Argyll-Robertson pupil (1). Cerebrospinal fluid VDRL test was positive in 6 patients and 3 patients were HIV (+). CONCLUSIONS: Syphilis is able to display diverse ophthalmologic manifestations. Not in all the cases the CSF-VDRL test was positive. Antitreponemal therapy generates a fast and effective response in the affected patients.

Evaluación prospectiva de la combinación colirio-ungüento de ciprofloxacino-dexametasona y tobramicina-dexametasona en cirugía de catarata / Prospective evaluation of eye drops and ointments of ciprofloxacin/dexamethasone versus tobramycin/dexamethasone combinations in ocular surgery

El uso profiláctico de antibióticos y antiinflamatorios post cirugía oftálmica es una práctica común. La tobramicina es aminoglicósido con espectro de gram negativos y alguns gram positivos. Ciprofloxacino tiene un mayor espectro. Objetivo: Comparar la eficacia y seguridad de la combinación colirio y ungüento de cirpofloxacino/dexametasona versus tobramicina/dexametasona. Pacientes y métodos: Se estudio en forma randomizada y doble ciego, 64 pacientes durante 15 días. Se realizaron 3 controles donde se registró agudeza visual, presión intraocular y una escala subjetiva y objetiva. Resultados: 60 pacientes completaron el estudio. El prurito fue menor en el grupo tratado con ciprofloxacino (0.26 v/s 0.47; p<0,05). Conclusiones: El estudio demostró eficacia y seguridad antibiótica equivalente entre ambas combinaciones. Considerando el mayor espectro antibacteriano de ciprofloxacino y la menor incidencia de prurito se plantea que el uso de esta combinación en pacientes post cirugía de catarata entregaría una protección antibiótica segura y con espectro más amplio.

The prohylactic use of antibiotics and anti-inflammatories drugs is a common practice in ophthalmic surgery. Tobramycin is an aminoglycoside with gram negative spectrum, covering some gram positive bacteria. Ciprofloxacin has a broader spectrum of effectivity. Purpose: To compare effectiveness and safety of eye drops and ointments of ciprofloxacim/dexamethasone versus tobramysin/dexamethasone combinations. Patients and methods: Random and doubled masked study, performed in 64 patients who had cataract surgery. In a 15 days follow up, the effectiveness of both antibiotic combinations were tested. Visual acuity, intraocular pressure, objective and subjective scale were performed. Results: 60 patients (93.4 percent) completed the follow up. Itching presented a significant difference between both groups, being lower in the ciprofloxacin/dexamethasone combination (0.26 vs 0.47. p<0.05). Conclusions: The study shows an equivalent effectiveness and safety of both antibiotic combinations. Considering the broader spectrum of ciprofloxacin and the lower frequency of itchness, ciprofloxacin/dexamethasone combination seems to be a good choice for post operative treatment in cataract surgery.

Decreased responsiveness of gluconeogenesis to the modulation by sulfonylureas in hepatocytes isolated from obese (fa/fa) Zucker rats.

The influence of the hypoglycemic agent glipizide (0-100 microM) on the rate of gluconeogenesis from lactate, as well as on the levels of fructose 2,6-bisphosphate, has been investigated in hepatocytes isolated from genetically obese (fa/fa) Zucker rats and from their corresponding lean (Fa/-) littermates. As compared to lean rat hepatocytes, liver cells isolated from obese animals showed a lower rate of basal gluconeogenesis (0.9 +/- 0.2 vs 5.4 +/- 0.5 micromol of lactate converted to glucose/g cell x 30 min, n=4) and higher levels of fructose 2,6-bisphosphate (11.5 +/- 1.0 vs 5.9 +/- 0.4 nmol/g cell, n=8-9). In lean rat hepatocytes, the presence of glipizide in the incubation medium caused a dose-dependent inhibition of the rate of lactate conversion to glucose (maximal inhibition=46%; EC50 value=26 microM), and simultaneously raised the cellular content of fructose-2,6-bisphosphate (maximal increment=40%; EC50 value=10 microM). In contrast, in hepatocytes isolated from obese rats, the inhibition of gluconeogenesis and the increment in fructose-2,6-bisphosphate levels elicited by glipizide were significantly reduced (maximal effects of 22 and 13%, respectively). Similarly, the activation of glycogen phosphorylase and the increase in hexose 6-phosphate levels in response to glipizide were less marked in obese rat hepatocytes than in liver cells isolated from lean animals. These results demonstrate that the efficacy of sulfonylureas as inhibitors of hepatic gluconeogenesis is reduced in the genetically obese (fa/fa) Zucker rat.

Casein kinase 2 inactivation by Mg2+, Mn2+ and Co2+ ions.

Mg2+ as well as Mn2+, and Co2+, which may substitute Mg2+ in the mental ion requirement of casein kinase 2 (Gatica et al., FEBS Lett: 315:173-173, 1993), have been repeatedly reported to display an optimal concentration at which activity of casein kinase 2 is maximal. As far as we know this intriguing property has always been observed with casein as substrate. This phosphoprotein is not the natural substrate of the enzyme, and it is well known that it binds divalent metal ions, which provoke the aggregation and precipitation of the protein. Since an optimal concentration of metal ion might have a regulatory role, we have examined if it is a consequence of the particular properties of casein, or it is an inherent property of the enzyme, extensive to other substrates. We have used the type II regulatory subunit of protein kinase A which is a physiological substrate of the enzyme, and the peptide RRREEETEEE as a specific substrate. No optimal concentration of Mg2+ is observed when these two substrates are used. The results explain, however, why that optimum is observed with casein. Although low concentration of Mn2+, and Co2+ render about 25% of the maximal activity found with Mg2+, they inactivate the enzyme almost fully at concentrations at which Mg2+ yield the maximal activity.

Impairment of the modulation by glucose of hepatic gluconeogenesis in the genetically obese (fa/fa) Zucker rat.

Genetically obese (fa/fa) Zucker rats show oral glucose intolerance, an alteration that has been attributed at least in part to an impaired suppression of hepatic glucose output after the ingestion of glucose. In this work, we studied the influence of different concentrations of glucose (2.5-30 mM) on gluconeogenesis from a mixture of [14C]lactate-pyruvate as well as on fructose 2,6-bisphosphate levels, pyruvate kinase activity, and flux through the reaction catalyzed by 6-phosphofructo-1-kinase, in hepatocytes isolated from fed obese (fa/fa) or lean (Fa/-) rats. In hepatocytes isolated from lean rats, incubation with increasing concentrations of glucose caused a dose-dependent inhibition of gluconeogenesis (5.02 +/- 0.54 and 1.82 +/- 0.33 mumol lactate converted to glucose/g cells.20 min in hepatocytes incubated in the presence of 2.5 and 30 mM glucose, respectively; n = 4 experiments; P < 0.01) together with a significant elevation of the fructose 2,6-bisphosphate content and a stimulation of the flux through 6-phosphofructo-1-kinase reaction. Glucose also provoked a dose-dependent activation of pyruvate kinase in the absence of changes in the cellular concentration of cAMP. In liver cells from obese animals, gluconeogenesis was not significantly modified by raising the glucose concentration in the incubation medium (1.26 +/- 0.11 and 0.83 +/- 0.14 mumol lactate converted to glucose/g cells.20 min in hepatocytes incubated with 2.5 and 30 mM glucose, respectively; n = 4 experiments; P = 0.11) despite significant increases in both fructose 2,6-bisphosphate levels and flux through the 6-phosphofructo-1-kinase reaction. In these cells, pyruvate kinase was only slightly activated by high glucose concentrations. These results indicate that, unlike fructose 2,6-bisphosphate levels and flux through the 6-phosphofructo-1-kinase reaction, hepatic gluconeogenesis is unresponsive to high glucose concentrations in genetically obese (fa/fa) rats.

Decreased responsiveness of basal gluconeogenesis to insulin action in hepatocytes isolated from genetically obese (fa/fa) Zucker rats.

In vivo studies have demonstrated that hepatic glucose production is poorly responsive to insulin in genetically obese Zucker rats. In this work, we have investigated the modulation by insulin of basal gluconeogenesis, fructose 2,6-bisphosphate levels, and pyruvate kinase and 6-phosphofructo 2-kinase activities in hepatocytes isolated from fed obese (fa/fa) or lean (Fa/-) rats. Gluconeogenesis was estimated by the conversion of a mixture of [14C]lactate-pyruvate to [14C]glucose. Basal gluconeogenesis was significantly reduced in hepatocytes isolated from obese rats compared to that measured in hepatocytes from lean animals (0.63 +/- 0.09 vs. 1.47 +/- 0.05 mumol lactate converted to glucose/g cells.20 min; n = 3-4; P < 0.001). In hepatocytes isolated from lean rats, insulin, without affecting the cellular cAMP concentration, caused a dose-dependent inhibition of the rate of gluconeogenesis, which was accompanied by a significant increase in fructose 2,6-bisphosphate levels and activation of both pyruvate kinase and 6-phosphofructo 2-kinase. In contrast, in hepatocytes isolated from obese (fa/fa) rats, neither basal gluconeogenesis nor any of the other metabolic parameters mentioned were significantly modified by insulin, even when assayed at high hormonal concentrations (10 nM). These results demonstrate a lack of responsiveness of hepatic gluconeogenesis to short term insulin action in genetically obese (fa/fa) rats.

A polylysine-induced aggregation of substrate accompanies the stimulation of casein kinase II by polylysine.

Casein kinase II (CK-II) activation by polylysine parallels an aggregation of substrates promoted by the polycation. CK-II is known to be stimulated by basic polypeptides and polyamines. The mechanism by which this stimulation takes place, however, is not yet fully understood. Here we show that, in the usual CK-II assay, polylysine induces the aggregation of casein. This aggregation has been monitored by turbidimetry, electron microscopy and gel filtration. The polylysine-concentration-dependence of the casein aggregation parallels the polylysine-concentration-dependence of the enzyme stimulation. In the presence of polylysine the enzyme is incorporated into the casein aggregates promoted by the polycation, thus supporting the view that this substrate aggregation is directly related to the mechanism of CK-II stimulation. Preliminary results show that a similar parallelism occurs with other natural substrates of the enzyme. The physiological meaning of this substrate aggregation, and its possible relation to other polylysine-stimulated enzymes and polylysine-aggregated proteins, are discussed.

Dipyridamole stimulates types II cAMP-dependent protein kinase in vitro.

Dipyridamole activates in vitro type II cAMP-dependent protein kinase. This agent stimulates the autophosphorylation of the regulatory subunit in the presence of cAMP but not so in the absence of the cyclic nucleotide. The activation was also observed with exogenous substrates such as casein, histone 2A and MAP2. This stimulation did not seem to be related to the cAMP binding to the R II subunit of the enzyme. Competition binding experiments showed that dipyridamole does not compete with adenosine for the A1 receptor. The results suggest that the reported regulatory properties of dipyridamole on lipid metabolism (González-Nicolás et al. Int J Biochem 21: 883-888, 1989) might be mediated through a direct action--an activation--on the catalytic subunit of a cAMP-dependent protein kinase.

Campaña de prevención de ceguera diabética en el área metropolitana norte de Santiago / Diabetic visual loss prevention in the north metropolitan area in Santiago

En prevención de ceguera diabética, es importante detectar en forma oportuna a los pacientes de alto riesgo de pérdida de visión. El presente trabajo pretende evaluar el rendimiento del examen oftalmoscópico en pacientes de más de 4 años de antiguedad reconocida de la enfermedad, tengan o no sintomatología visual. Se examinó a 641 pacientes diabéticos en control en distintos consultorios del Area Norte de Santiago, en 47 visitas a estos establecimientos; 414 pacientes (64,5%) no presentaban retinopatía diabética; 193 casos (30,1%) presentaban retinopatía diabética de base, y 34 (5,3%), tenían una retinopatía diabética proliferante; 43 pacientes (6,7%) fueron tratados con fotocoagulación con láser

Cisticercosis subretinal: tres formas de evolución / Subretinal cisticercosis: 3 evolution ways

La cisticercosis endocular es cada día más rara. La ubicación subretinal pesquisada oportunamente permite efectuar un tratamiento eficaz. Se presentan 3 casos clínicos que ilustran la vía de solución que lleva esta afección. El caso 1, ubicación subretinal para papilar superior, se extrae vía transescleral sin dificultades y con buena evolución. El caso 2, ubicado paramacular temporal permite efectuar fotocoagulación con xenon que lleva a la destrucción de la larva. El caso 3, no recibe tratamiento y un año después de diagnosticado se comprueba ptisis bulbi. Se concluye que la cisticercosis subretinal es susceptible de ser tratada con éxito con cirugía o fotocoagulación, según el caso, y que el curso natural de esta parasitosis no tratada lleva a la pérdida del ojo funcional y anatómica. La pérdida de visión está en directa relación con el daño macular

Maculopatía fótica: caso clínico / Photic maculopathy: clinical case

A propósito de un caso de daño macular originado en un cortocircuito de corriente eléctrica de 220 volts., comprobado angiográficamente, se revisan los mecanismos de daño retinal que reconocen a la luz como causa etiológica. Se comenta lo inusual del daño fotoquímico como causa de compromiso retinal y se analizan sus implicancias laborales