Pathological alterations in GABAergic interneurons and reduced tonic inhibition in the basolateral amygdala during epileptogenesis

An acute brain insult such as traumatic head/brain injury, stroke, or an episode of status epilepticus can trigger epileptogenesis, which, after a latent, seizure-free period, leads to epilepsy. The discovery of effective pharmacological interventions that can prevent the development of epilepsy requires knowledge of the alterations that occur during epileptogenesis in brain regions that play a central role in the induction and expression of epilepsy. In the present study, we investigated pathological alterations in GABAergic interneurons in the rat basolateral amygdala (BLA), and the functional impact of these alterations on inhibitory synaptic transmission, on days 7 to 10 after status epilepticus induced by kainic acid. Using design-based stereology combined with glutamic acid decarboxylase (GAD) 67 immunohistochemistry, we found a more extensive loss of GABAergic interneurons compared to the loss of principal cells. Fluoro-Jade C staining showed that neuronal degeneration was still ongoing. These alterations were accompanied by an increase in the levels of GAD and the α1 subunit of the GABA_A receptor, and a reduction in the GluK1 (previously known as GluR5) subunit, as determined by Western blots. Whole-cell recordings from BLA pyramidal neurons showed a significant reduction in the frequency and amplitude of action potential–dependent spontaneous inhibitory postsynaptic currents (IPSCs), a reduced frequency but not amplitude of miniature IPSCs, and impairment in the modulation of IPSCs via GluK1-containing kainate receptors (GluK1Rs). Thus, in the BLA, GABAergic interneurons are more vulnerable to seizure-induced damage than principal cells. Surviving interneurons increase their expression of GAD and the α1 GABA_A receptor subunit, but this does not compensate for the interneuronal loss; the result is a dramatic reduction of tonic inhibition in the BLA circuitry. As activation of GluK1Rs by ambient levels of glutamate facilitates GABA release, the reduced level and function of these receptors may contribute to the reduction of tonic inhibitory activity. These alterations at a relatively early stage of epileptogenesis may facilitate the progress towards the development of epilepsy.     

Mechanical behavior of hydroxyapatite biomaterials: an experimentally validated micromechanical model for elasticity and strength

Hydroxyapatite (HA) biomaterials production has been a major field in biomaterials science and biomechanical engineering. As concerns prediction of their stiffness and strength, we propose to go beyond statistical correlations with porosity or empirical structure-property relationships, as to resolve the material-immanent microstructures governing the overall mechanical behavior. The macroscopic mechanical properties are estimated from the microstructures of the materials and their composition, in a homogenization process based on continuum micromechanics. Thereby, biomaterials are envisioned as porous polycrystals consisting of HA needles and spherical pores. Validation of respective micromechanical models relies on two independent experimental sets: biomaterial-specific macroscopic (homogenized) stiffness and uniaxial (tensile and compressive) strength predicted from biomaterial-specific porosities, on the basis of biomaterial-independent ("universal") elastic and strength properties of HA, are compared with corresponding biomaterial-specific experimentally determined (acoustic and mechanical) stiffness and strength values. The good agreement between model predictions and the corresponding experiments underlines the potential of micromechanical modeling in improving biomaterial design, through optimization of key parameters such as porosities or geometries of microstructures, in order to reach the desired values for biomaterial stiffness or strength.     

Hypertension in the elderly: an evidence-based review

The progressive ageing of world population, and the increasing prevalence hypertension in elderly people are leading to the consideration that hypertension in the elderly is one of the main topic in hypertension treatment. Multiple mechanisms, including stiffening of large arteries, endothelial dysfunction, cardiac remodeling, autonomic dysregulation, renal aspects, contribute to the great prevalence of hypertension in the elderly and to increased cardiovascular morbidity and mortality. Treatment of hypertension can hardly put back older patients in a low risk category, especially if target organ damage is present. Nevertheless, blood pressure control can successfully prevent stroke, cognitive decline, coronary heart disease and heart failure, and reduce mortality in the elderly, and even in patients > 80 years, as recently demonstrated. Blood pressure should be lowered below 140/90 mmHg also in older patients. However the HYVET study suggests that a goal of 150/90 mmHg can be reasonable in patients aged 80 years or more. Drug treatment should be titrated with particular caution to adverse responses and excessive blood pressure lowering.     

A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy

Dystrophic epidermolysis bullosa (DEB) is a severe skin fragility disorder associated with trauma-induced blistering, progressive soft tissue scarring, and increased risk of skin cancer. DEB is caused by mutations in type VII collagen. In this study, we describe the generation of a collagen VII hypomorphic mouse that serves as an immunocompetent animal model for DEB. These mice expressed collagen VII at about 10% of normal levels, and their phenotype closely resembled characteristics of severe human DEB, including mucocutaneous blistering, nail dystrophy, and mitten deformities of the extremities. The oral blistering experienced by these mice resulted in growth retardation, and repeated blistering led to excessive induction of tissue repair, causing TGF-beta1-mediated contractile fibrosis generated by myofibroblasts and pseudosyndactyly in the extremities. Intradermal injection of WT fibroblasts resulted in neodeposition of collagen VII and functional restoration of the dermal-epidermal junction. Treated areas were also resistant to induced frictional stress. In contrast, untreated areas of the same mouse showed dermal-epidermal separation following induced stress. These data demonstrate that fibroblast-based treatment can be used to treat DEB in a mouse model and suggest that this approach may be effective in the development of clinical therapeutic regimens for patients with DEB.     

Treatment of cutaneous leishmaniasis by photodynamic therapy

BACKGROUND: Cutaneous leishmaniasis represents a common health problem and standard treatments are often ineffective or yield poor cosmetic results. OBJECTIVE: We compared the efficacy of photodynamic therapy (PDT) with paromomycin sulfate in 10 lesions of cutaneous leishmaniasis. METHODS: Five lesions were treated by PDT with Metvix (Photocure, Oslo, Norway) and 75 J/cm(2) red light. PDT was performed twice weekly and, after 12 weeks, once weekly. The other 5 lesions were treated with paromomycin sulfate once daily. All nonresponding lesions of the paromomycin-treated plaques finally also underwent PDT. RESULTS: All 5 lesions treated by PDT and 2 of the paromomycin sulfate-treated plaques were clinically and histologically Leishmania free. Three lesions with poor response to paromomycin sulfate finally responded to subsequent PDT. Ten months after therapy there was no recurrence, and cosmetic outcome after PDT was excellent. CONCLUSION: PDT may be an effective therapeutic alternative in cutaneous leishmaniasis.     

Multiple eccrine poromas arising in chronic radiation dermatitis

A 70-year-old white man developed 7 eccrine poromas in an area of chronic radiation dermatitis of his right lower extremity over a period of 37 years. To our knowledge, multiple eccrine poromas unequivocally linked to chronic X-ray damage are hitherto unreported.