Combination of intracortically administered VEGF and environmental enrichment enhances brain protection in developing rats

Postnatal development of the visual cortex is modulated by experience, especially during the critical period. In rats, a stable neuronal population is only acquired after this relatively prolonged period. Vascular endothelial growth factor (VEGF) is the most important angiogenic factor and also has strong neuroprotective, neurotrophic and neurogenic properties. Similar effects have been described for rearing in enriched environments. Our aim is to investigate the vascular and neuronal effects of combining VEGF infusion and environmental enrichment on the visual cortex during the initial days of the critical period. Results showed that a small percentage of Cleaved Caspase-3 positive cells colocalized with neuronal markers. The lesion produced by the cannula implantation resulted in decreased vascular, neuronal and Caspase-3 positive cell densities. Rearing under enriched environment was unable to reverse these effects in any group, whereas VEGF infusion alone partially corrected those effects. A higher effectiveness was reached by combining both the procedures, the most effective combination being when enriched-environment rearing was introduced only after minipump implantation. In addition to the angiogenic effect of VEGF, applied strategies also had synergic neuroprotective effects, and the combination of the two strategies had more remarkable effects than those achieved by each strategy applied individually.     

Physical exercise is required for environmental enrichment to offset the quantitative effects of dark-rearing on the S-100β astrocytic density in the rat visual cortex

After birth, exposure to visual inputs modulates cortical development, inducing numerous changes in all of the components of the visual cortex. Most of the cortical changes thus induced occur during what is called the critical period. Astrocytes play an important role in the development, maintenance and plasticity of the cortex as well as in the structure and function of the vascular network. Visual deprivation induces a decrease in the astroglial population, whereas enhanced experience increases it. Exposure to an enriched environment has been shown to prevent the effects of dark‐rearing in the visual cortex. Our purpose was to study the effects of an enriched environment on the density of astrocytes per reference surface at the visual cortex of dark‐reared rats, in order to determine if enhanced experience is able to compensate the quantitative effects of visual deprivation and the role of physical exercise on the enrichment paradigm. Pregnant Sprague‐Dawley rats were raised in one of the following rearing conditions: control rats with standard housing (12‐h light/dark cycle); in total darkness for the dark‐rearing experiments; and dark‐rearing in conditions of enriched environment without and with physical exercise. The astrocytic density was estimated by immunohistochemistry for S‐100β protein. Quantifications were performed in layer IV. The somatosensorial cortex barrel field was also studied as control. The volume of layer IV was stereologically calculated for each region, age and experimental condition. From the beginning of the critical period, astrocyte density was higher in control rats than in the enriched environment group without physical exercise, with densities of astrocytes around 20% higher at all of the different ages. In contrast, when the animals had access to voluntary exercise, densities were significantly higher than even the control rats. Our main result shows that strategies to apply environmental enrichment should always consider the incorporation of physical exercise, even for sensorial areas such as the visual area, where complex enriched experience by itself is not enough to compensate the effects of visual deprivation.     

Accuracy analysis of complete-arch digital scans in edentulous arches when using an auxiliary geometric device

Statement of problem

Obtaining reliable digital scans of edentulous patients is challenging because of the absence of anatomic landmarks/geometric variations along the dental arch. Whether adding an auxiliary geometric device (AGD) will improve scanning is unclear.

Morbidity in 303 first‐episode bipolar I disorder patients

Baldessarini RJ, Salvatore P, Khalsa H‐MK, Gebre‐Medhin P, Imaz H, González‐Pinto A, Perez J, Cruz N, Maggini C, Tohen M. Morbidity in 303 first‐episode bipolar I disorder patients.
Bipolar Disord 2010: 12: 264–270. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: To test the hypotheses that: (i) depressive‐dysthymic‐dysphoric (D‐type) morbidity is more prevalent than manic‐hypomanic‐psychotic (M‐type) morbidity even from first episodes of bipolar I disorder (BPD‐I) and despite treatment; (ii) initial presentations predict later morbidity; (iii) morbidity varies internationally; and (iv) early and later morbidity are similar. Methods: We followed SCID‐based, DSM‐IV BPD‐I patients (n = 303) systematically and prospectively for two years to estimate the percent of weeks in specific morbid states from first lifetime major episodes. Results: Total morbidity accounted for 44% of the first two years, and D‐type exceeded M‐type illnesses by 2.1‐fold (30%/14%) among morbidities ranking: mixed states (major + minor) ≥ dysthymia ≥ mania ≥ major depression > hypomania > psychosis. In 164 cases, morbidities at 0.5–2.5 and 2.5–4.5 years were very similar. Depressive or mixed initial episodes predicted a 3.6‐fold excess of D‐type morbidity, and initial M‐type episodes predicted a 7.1‐fold excess of M‐type morbidity over two years. Morbidity in European (EU) sites was nearly half that in the U.S., and 22% greater overall among men than women. In five comparable studies, illness accounted for 54% of follow‐up time, and the ratio of D/M morbidity averaged 3.0. Conclusions: In accord with four midcourse studies, morbidity from BPD‐I onset, despite treatment by community standards, averaged 44%, was 68% D‐type morbidity, and was strongly predicted by first‐episode polarity. Lower morbidity in EU than U.S. sites may reflect differences in healthcare or social systems.     

Effects of visual experience on vascular endothelial growth factor expression during the postnatal development of the rat visual cortex

The development of the cortical vascular network depends on functional maturation. External inputs are an essential requirement in the modeling of the visual cortex, mainly during the critical period, when the functional and structural properties of visual cortical neurons are particularly susceptible to alterations. Vascular endothelial growth factor (VEGF) is the major angiogenic factor, a key signal in the induction of vessel growth. Our study focused on the role of visual stimuli on the development of the vascular pattern correlated with VEGF levels. Vascular density and the expression of VEGF were examined in the primary visual cortex of rats reared under different visual environments (dark rearing, dark-rearing in conditions of enriched environment, enriched environment, and laboratory standard conditions) during postnatal development (before, during, and after the critical period). Our results show a restricted VEGF cellular expression to astroglial cells. Quantitative differences appeared during the critical period: higher vascular density and VEGF protein levels were found in the enriched environment group; both dark-reared groups showed lower vascular density and VEGF levels, which means that enriched environment without the physical exercise component does not exert effects in dark-reared rats.     

Lack of experience-mediated differences in the immunohistochemical expression of blood-brain barrier markers (EBA and GluT-1) during the postnatal development of the rat visual cortex

The development of the cortical vascular tree depends on functional development. External inputs are an essential requirement in the modeling of the visual cortex, mainly during the critical period, when congruous blood supply is needed. The blood brain barrier (BBB) function regulates the passage of substances between the blood and the brain parenchyma, which is one of the main differential features of central nervous system (CNS) microvessels. The endothelial barrier antigen (EBA) has been reported as a specific marker for the BBB physiological function in rats. We studied the postnatal development of EBA expression in the visual cortex of rats reared under opposite paradigms of visual experience, e.g., standard laboratory conditions, dark rearing, and enriched environment at 14, 21, 28, 35, 42, 49, 56, and 63 days postnatal (dpn). Parallel sections were immunohistochemically processed for endothelial barrier antigen (EBA) and glucose transporter-1 (GluT-1). Total vasculature was quantified by Lycopersicon esculentum (LEA) lectin histochemistry. No differences in EBA expression were found between groups, although quantitative differences were recorded paralleling differences in vascular density. Paradoxically, there was no expression in certain cortical vessels which were GluT-1 immunopositive and positivity was consistent in non-barrier areas such as the pineal gland. These findings were completely independent of age or experimental conditions. Therefore, the role of the EBA antigen in the BBB remains unclear: it has been undeniably linked to vascular permeability, but its presence in non-barrier vessels suggests another vascular function. Although visual experience modifies vascular density in the visual cortex, it has not been shown to have an influence on the maturation of the BBB function.     

Mitogen-activated protein kinase routes as targets in the action of diaza-anthracene compounds with a potent growth-inhibitory effect on cancer cells

1,8-Diaza-anthracene-tetraones are novel intermediates in the synthesis of the antifolate antibiotic diazaquinomycin A that was found before to have potent antitumor activity. Three of them (CV65, CV66, and CV70) were found to inhibit growth of a panel of several human tumor cell lines. The IC50s ranged from 0.05 to 1.5 microM and are comparable with that of doxorubicin. Among the three drugs, CV70 showed the highest cytotoxic activity. The growth-inhibitory action of these compounds was unrelated to the p53 status of the cells. At micromolar concentrations, all three compounds induced apoptosis, CV70 being the most proapoptotic. The incubation of HeLa cells with CV65, CV66, and CV70, at concentrations between 10 and 20 microM, inhibited the activation of c-Jun NH2-terminal kinase by various stimuli and prevented growth factor-induced extracellular signal-regulated kinase (ERK) 5 activation. At least one drug, CV65, also inhibited p38. This was surprising because proapoptotic antitumor drugs activate stress signaling pathways. Activation of ERK1/ 2 by growth factors or phorbol esters was unaffected by preincubation of cells with CV compounds. In vitro, CV compounds inhibit the enzyme quinone reductase but not c-Jun NH2-terminal kinase or ERK5. Because doxorubicin also inhibits quinone reductase, we conclude that the inhibitory effect of CV compounds on stress signaling kinases is not a direct effect on the kinases and is likely attributable to upstream elements of the activation cascades.     

Vascular endothelial growth factor: adaptive changes in the neuroglialvascular unit

Brain postnatal development is modulated by adaptation and experience. Experience-mediated changes increase neuronal activity leading to increased metabolic demands that involve adaptive changes including ones at the microvascular network. Therefore, vascular environment plays a key role in central nervous system (CNS) development and function in health and disease. Trophic factors are crucial in CNS development and cell survival in adults. They participate in protection and proliferation of neuronal, glial and endothelial cells. Among the most important molecules are: the proangiogenic vascular endothelial growth factor (VEGF), the neurotrophin brain derived neurotrophic factor (BDNF), insulin growth factor (IGF-I) and the glycoprotein erythropoietin (EPO). We propose the term angioglioneurins to define molecules acting on the three components of the neurogliovascular unit. We have previously reported the effects of environmental modifications on the three components of the neurogliovascular unit during the postnatal development. We have also described the main role played by VEGF in the experience-induced postnatal changes. Angioglioneurin administration, alone or in combination with other neuroprotective strategies such as environmental enrichment, has been proposed as a non-invasive therapeutic strategy against several CNS diseases.     

Documento de consenso para el manejo de la esquistosomiasis en atención primaria

La esquistosomiasis humana es la enfermedad parasitaria con mayor morbimortalidad a nivel mundial después de la malaria. Es endémica en más de 78 países tropicales y subtropicales, sobre todo de África Subsahariana, estimándose que 236 millones de personas están infectadas. Puede causar graves complicaciones de salud a nivel genitourinario y hepatoesplénico, llegando a ocasionar la muerte de 300.000 personas cada año. El número de casos importados en los países occidentales se ha ido incrementado en los últimos años debido a la llegada de un importante número de migrantes procedentes de regiones endémicas y de un creciente número de viajeros que han visitado las mismas. Por otro lado, recientemente se han comunicado brotes de transmisión autóctona en Córcega (Francia) y Almería (España). Por todos estos aspectos, las autoridades sanitarias europeas han recomendado el cribado serológico de la enfermedad en todas las personas migrantes procedentes de zonas endémicas y que lleven menos de 5 años en Europa. Dado que atención primaria es habitualmente el primer punto de contacto de estas personas con el sistema sanitario, los médicos deben conocer los principales aspectos de la enfermedad, y ser dotados de los medios necesarios para su diagnóstico y tratamiento. Este documento ha sido elaborado por profesionales pertenecientes a 5 sociedades científicas de atención primaria (SEMFyC, SEMG, SEMERGEN), Pediatría (SEIP) y Medicina Tropical y Salud Internacional (SEMTSI), con objeto de establecer unas recomendaciones claras para el diagnóstico y el manejo de la esquistosomiasis en atención primaria.Palabras clave: Schistosoma, Esquistosomiasis, Atención primaria, Cribado, Migrantes