Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: A challenge for neuroprotection.

There is currently no approved neuroprotective pharmacotherapy for acute conditions such as stroke and cerebral asphyxia. One of the reasons for this may be the multiplicity of cell death mechanisms, because inhibition of a particular mechanism leaves the brain vulnerable to alternative ones. It is therefore essential to understand the different cell death mechanisms and their interactions. We here review the multiple signaling pathways underlying each of the three main morphological types of cell death - apoptosis, autophagic cell death and necrosis - emphasizing their importance in the neuronal death that occurs during cerebral ischemia and hypoxia-ischemia, and we analyze the interactions between the different mechanisms. Finally, we discuss the implications of the multiplicity of cell death mechanisms for the design of neuroprotective strategies.

Discounting Spotted Apples: Investigating Consumers’ Willingness to Accept Cosmetic Damage in an Organic Product, November 2006

Organic producers have limited methods of avoiding plant diseases that result in cosmetic damage to produce. Therefore, the appearance of organic produce is often less than perfect. We use an experimental auction to investigate how cosmetic damage affects consumers’ willingness to pay for organic apples. We find that 75% of the participants are willing to pay more for organic than for conventional apples given identical appearance. However, at the first sight of any imperfection in the appearance of the organic apples, this segment is significantly reduced. Furthermore, we find that there is a significant effect of interaction between cosmetic damage and product methods. Even though most consumers say they buy organic products to avoid pesticides, we find that cosmetic damage has a larger impact on the willingness to pay for organic apples than for conventional apples.

Physical activity modulates heat shock protein-72 expression and limits oxidative damage accumulation in a healthy elderly population aged 60 90 years

BACKGROUND: Reactive oxygen species production increases during aging, whereas protective mechanisms such as heat shock proteins (HSPs) or antioxidant capacity are depressed. Physical activity has been hypothesized to provide protection against oxidative damage during aging, but results remain controversial. This study aimed to investigate the effect of different levels of physical activity during aging on Hsp72 expression and systemic oxidative stress at rest and in response to maximal exercise. METHODS: Plasma antioxidant capacity (Trolox equivalent antioxidant capacity, TEAC), thiobarbituric acid-reactive species (TBARS), advanced oxidized proteins products (AOPP), and Hsp72 expression in leukocytes were measured before and after maximal exercise testing in 32 elderly persons (aged 73.2 years), who were assigned to two different groups depending on their level of physical activity during the past 12 months (OLow = moderate to low level; OHigh = higher level). RESULTS: The OHigh group showed higher aerobic fitness and TEAC (both representing 120% of OLow values) as well as lower oxidative damage (50% of OLow values) and Hsp72 expression. Exercise led to a lower increase in oxidative damage in the OHigh group. Aerobic fitness was positively correlated with TEAC and negatively with lipid peroxidation (TBARS). Hsp72 expression was negatively correlated with TEAC but positively correlated with TBARS levels. CONCLUSIONS: The key finding of this study is that, in people aged 60 to 90 years, long-term high level of physical activity preserved antioxidant capacity and limited oxidative damage accumulation. It also downregulated Hsp72 expression, an adaptation potentially resulting from lower levels of oxidative damage.

Syndrome de l'artère poplitée piégée [Popliteal artery entrapment syndrome].

Popliteal entrapment is a rare compression syndrome involving vascular (and neurologic) structures of the popliteal fossa. In this article we review the popliteal artery entrapment syndrome (PAES). PAES is a cause of intermittent claudication that can be, although rarely, complicated with acute limb-threatening ischemia. PAES occurs more often in young adult. Concerning pathophysiology, PAES is provoked by an abnormal relationship between popliteal artery and muscular-tendon structures within the popliteal fossa. A surgical repair is usually required to resolve mechanical compression or vascular damage.

Development of the Crohn's disease digestive damage score, the Lémann score.

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011).

Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice

This study addressed the contribution of acidic sphingomyelinase (ASMase) in TNF-alpha-mediated hepatocellular apoptosis. Cultured hepatocytes depleted of mitochondrial glutathione (mGSH) became sensitive to TNF-alpha, undergoing a time-dependent apoptotic cell death preceded by mitochondrial membrane depolarization, cytochrome c release, and caspase activation. Cyclosporin A treatment rescued mGSH-depleted hepatocytes from TNF-alpha-induced cell death. In contrast, mGSH-depleted hepatocytes deficient in ASMase were resistant to TNF-alpha-mediated cell death but sensitive to exogenous ASMase. Furthermore, although in vivo administration of TNF-alpha or LPS to galactosamine-pretreated ASMase(+/+) mice caused liver damage, ASMase(-/-) mice exhibited minimal hepatocellular injury. To analyze the requirement of ASMase, we assessed the effect of glucosylceramide synthetase inhibition on TNF-alpha-mediated apoptosis. This approach, which blunted glycosphingolipid generation by TNF-alpha, protected mGSH-depleted ASMase(+/+) hepatocytes from TNF-alpha despite enhancement of TNF-alpha-stimulated ceramide formation. To further test the involvement of glycosphingolipids, we focused on ganglioside GD3 (GD3) because of its emerging role in apoptosis through interaction with mitochondria. Analysis of the cellular redistribution of GD3 by laser scanning confocal microscopy revealed the targeting of GD3 to mitochondria in ASMase(+/+) but not in ASMase(-/-) hepatocytes. However, treatment of ASMase(-/-) hepatocytes with exogenous ASMase induced the colocalization of GD3 and mitochondria. Thus, ASMase contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the mitochondrial targeting of glycosphingolipids.

Cardiac and neurologic outcome of cardiac rhabdomyoma considerations for prenatal counseling

Abstract : Cardíac rhabdomyomas are benign cardiac tumors with few cardiac complications but with a known association to tuberous sclerosis that affects the neurologic outcome of the patients. Thís study analyses the long-term cardiac and neurological outcome of patients with cardiac rhabdomyomas in order to allow comprehensive prenatal counseling. qll prenatal and postnatal cases with echocardiographic diagnosis of cardiac rhabdomyomas encountered from August 1982 -September 2007 have been recorded. Independent factors, such às the number and the location of the tumors, have been analyzed for association with a diagnosis of tuberous sclerosis, in order to predict the cardiac and neurologic outcome of the patients. Cardiac complications include arrhythmias, outflow tract obstruction, secondary cardiogenic shock. Arrhythmias are the most often encountered problems during the neonatal period. Supraventricular tachycardia is the commonest rhythm disturbance identified. However, no specific dimension or location of the cardiac rhabdomyomas may predict the rhythm disturbances. The importance of the diagnosis of tuberous sclerosis in patients presenting with cardiac rhabdomyomas is exemplified by the neurodevelopmental complications showing 80% of cases with epilepsy and 63% of cases with a delayed development. The presence of multiple cardiac tumors in patients suggests a higher risk to be affected by tuberous sclerosis, compared to patients with a single tumor. Cardiac rhabdomyomas generally regress aftér birth and after the perinatal period cardiac-related problems are rare, but tuberous sclerosis and the associated neurodevelopmental complications dominate the clinical picture and should form an important aspect of the prenatal counseling of parents. Résumé : Les rhabdomyomes cardiaques sont des tumeurs cardiaques bénignes avec toutefois des complications. cardiaques possibles et surtout avec une association pour la sclérose tubéreuse de Bourneville qui détermine le pronostic neurologique. Cette étude présente une analyse du suivi cardiologique. et neurologique à long terme d'enfants avec un diagnostic de rhabdomyomes cardiaques dans le but de mieux informer les parents lors de la consultation anténatale. L'ensemble des cas de rhabdomyomes cardiaques diagnostiqués au moyen de l'échocardiographie pendant la période anténatale ainsi que postnatale a été répertorié d'août 1982 à septembre 2007. Des facteurs indépendants, tels que le nombre et la localisation des tumeurs, ont été analysés pour leur association avec le diagnostic de la sclérose tubéreuse de Bourneville, afin de prédire le pronostic cardiaque et neurologique de ces patients. Les complications cardiaques retrouvées sont les arythmies, les obstructions des voies d'éjection ventriculaire et le choc cardiogène secondaire. Les arythmies sont les problèmes les plus fréquemment rencontrés pendant la période néonatale.. La tachycardie supraventriculaire est le trouble de rythme le plus souvent identifié. Néanmoins, il n'y a pas de dimension ou de localisation.- spécifique d'un rhabdomyome cardiaque qui pourrait prédire ces troubles du rythme. L'importance de l'association au diagnostic de la sclérose tubéreuse de Bourneville chez les patients atteints de rhabdomyomes est démontrée à travers les complications du développement neurologique avec une attéinte épileptique dans 80% des cas ainsi qu'un retard de développement dans 63% des cas. La présence de multiples tumeurs cardiaques chez un patient suggère un risque accru d'être atteint de la sclérose tubéreuse de Bourneville comparé à un patient atteint d'une tumeur unique. Les rhabdomyomes cardiaques régressent après la naissance et après la période périnatale les complications cardiaques deviennent rares. Toutefois, l'association à la sclérose tubéreuse de Bourneville domine le tableau clinique avec des complications au niveau du développement neurologique et formé donc un aspect important lors de la consultation anténatale.

Severe neurologic manifestations from cervical spine instability in spondylo-megaepiphyseal-metaphyseal dysplasia.

Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; OMIM 613330) is a dysostosis/dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization. © 2012 Wiley Periodicals, Inc.

The role of bradykinin B(1) and B(2) receptors for secondary brain damage after traumatic brain injury in mice.

Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B(1)-, and B(2)-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter. Brain edema, contusion volume, and functional outcome were assessed 24 h and 7 days after CCI. Tissue bradykinin was maximally increased 2 h after trauma (P<0.01 versus sham). Kinin B(1) receptor mRNA was upregulated up to four-fold 24 h after CCI. Immunohistochemistry showed that B(1) and B(2) receptors were expressed in the brain and were significantly upregulated in the traumatic penumbra 1 to 24 h after CCI. B(2)R(-/-) mice had significantly less brain edema (-51% versus WT, 24 h; P<0.001), smaller contusion volumes ( approximately 50% versus WT 24 h and 7 d after CCI; P<0.05), and better functional outcome 7 days after TBI as compared with WT mice (P<0.05). The present results show that bradykinin and its B(2) receptors play a causal role for brain edema formation and cell death after TBI.

Pure amnesia after unilateral left polar thalamic infarct: topographic and sequential neuropsychological and metabolic (PET) correlations.

A 54-year-old patient who had an isolated small polar thalamic infarct and acute global amnesia with slight frontal type dysfunction but without other neurological dysfunction was studied. Memory improved partially within 8 months. At all stages the impairment was more severe for verbal than non-verbal memory. Autobiographic recollections and newly acquired information tended to be disorganised with respect to temporal order. Procedural memory was unaffected. Both emotional involvement and pleasure in reading were lost. On MRI, the infarct was limited to the left anterior thalamic nuclei and the adjacent mamillothalamic tract. The regional cerebral metabolic rate of glucose (measured with PET) was decreased on the left in the thalamus, amygdala, and posterior cingulate cortex 2 weeks after the infarct, and in the thalamus and posterior cingulate cortex 9 months later. These findings stress the specific role of the left anterior thalamic region in memory and confirm that longlasting amnesia from a thalamic lesion can occur without significant structural damage to the dorsomedial nucleus. Furthermore, they suggest that the anterior thalamic nuclei and possibly their connections with the posterior cingulate cortex play a role in emotional involvement linked to ipsilateral hemispheric functions.

Gonadal alterations in male whitefish Coregonus fatioi: no evidence for genetic damage reducing viability in early life stages.

In recent years, numerous cases of morphological gonadal alterations in fish have been recorded throughout the world and across a wide range of species. In the whitefish Coregonus fatioi from the pre-alpine Lake Thun (Switzerland), the frequency of gonadal alterations is particularly high and the variety of alteration types large. Little is known about the proximal causes and the direct consequences of these morphological features on population persistence. In particular, the potential for the observed alterations to be the phenotypic expression of reduced genetic quality has not yet been addressed. In this study, we used offspring survival during embryogenesis as a proximate indicator of male genetic quality and tested whether the presence of gonadal alterations in males is an indicator of reduced quality. Embryos resulted from in vitro fertilizations of gametes from 126 males and females. We found no significant correlation between embryo survival and gonadal alteration in adults. Our findings suggest that in C. fatioi of Lake Thun, alterations in gonad morphology are not a phenotypic expression of variation in genetic quality.

On The Spot Damage Detection Methodology for Highway Bridges, July 2010

Vibration-based damage identification (VBDI) techniques have been developed in part to address the problems associated with an aging civil infrastructure. To assess the potential of VBDI as it applies to highway bridges in Iowa, three applications of VBDI techniques were considered in this study: numerical simulation, laboratory structures, and field structures. VBDI techniques were found to be highly capable of locating and quantifying damage in numerical simulations. These same techniques were found to be accurate in locating various types of damage in a laboratory setting with actual structures. Although there is the potential for these techniques to quantify damage in a laboratory setting, the ability of the methods to quantify low-level damage in the laboratory is not robust. When applying these techniques to an actual bridge, it was found that some traditional applications of VBDI methods are capable of describing the global behavior of the structure but are most likely not suited for the identification of typical damage scenarios found in civil infrastructure. Measurement noise, boundary conditions, complications due to substructures and multiple material types, and transducer sensitivity make it very difficult for present VBDI techniques to identify, much less quantify, highly localized damage (such as small cracks and minor changes in thickness). However, while investigating VBDI techniques in the field, it was found that if the frequency-domain response of the structure can be generated from operating traffic load, the structural response can be animated and used to develop a holistic view of the bridge’s response to various automobile loadings. By animating the response of a field bridge, concrete cracking (in the abutment and deck) was correlated with structural motion and problem frequencies (i.e., those that cause significant torsion or tension-compression at beam ends) were identified. Furthermore, a frequency-domain study of operational traffic was used to identify both common and extreme frequencies for a given structure and loading. Common traffic frequencies can be compared to problem frequencies so that cost-effective, preventative solutions (either structural or usage-based) can be developed for a wide range of IDOT bridges. Further work should (1) perfect the process of collecting high-quality operational frequency response data; (2) expand and simplify the process of correlating frequency response animations with damage; and (3) develop efficient, economical, preemptive solutions to common damage types.

Ultraviolet damage to the eye revisited: eye-sun protection factor (E-SPF®), a new ultraviolet protection label for eyewear.

Ultraviolet (UV) radiation potentially damages the skin, the immune system, and structures of the eye. A useful UV sun protection for the skin has been established. Since a remarkable body of evidence shows an association between UV radiation and damage to structures of the eye, eye protection is important, but a reliable and practical tool to assess and compare the UV-protective properties of lenses has been lacking. Among the general lay public, misconceptions on eye-sun protection have been identified. For example, sun protection is mainly ascribed to sunglasses, but less so to clear lenses. Skin malignancies in the periorbital region are frequent, but usual topical skin protection does not include the lids. Recent research utilized exact dosimetry and demonstrated relevant differences in UV burden to the eye and skin at a given ambient irradiation. Chronic UV effects on the cornea and lens are cumulative, so effective UV protection of the eyes is important for all age groups and should be used systematically. Protection of children's eyes is especially important, because UV transmittance is higher at a very young age, allowing higher levels of UV radiation to reach the crystalline lens and even the retina. Sunglasses as well as clear lenses (plano and prescription) effectively reduce transmittance of UV radiation. However, an important share of the UV burden to the eye is explained by back reflection of radiation from lenses to the eye. UV radiation incident from an angle of 135°-150° behind a lens wearer is reflected from the back side of lenses. The usual antireflective coatings considerably increase reflection of UV radiation. To provide reliable labeling of the protective potential of lenses, an eye-sun protection factor (E-SPF®) has been developed. It integrates UV transmission as well as UV reflectance of lenses. The E-SPF® compares well with established skin-sun protection factors and provides clear messages to eye health care providers and to lay consumers.