Improvement of a Cohesive Zone Model for Fatigue Delamination Rate Simulation.

The cohesive zone model (CZM) has found wide acceptance as a tool for the simulation of delamination in composites and debonding in bonded joints and various implementations of the cohesive zone model dedicated to fatigue problems have been proposed in the past decade. In previous works, the authors have developed a model based on cohesive zone to simulate the propagation of fatigue defects where damage acts on cohesive stiffness, with an initial (undamaged) stiffness representative of that of the entire thickness of an adhesive layer. In the case of a stiffness that is order of magnitude higher than the previous one (for instance, in the simulation of the ply-to-ply interface in composites), the model prediction becomes inaccurate. In this work, a new formulation of the model that overcomes this limitation is developed. Finite element simulations have been conducted on a mode I, constant bending (constant G)-loaded double cantilever beam (DCB) joint to assess the response of the new model with respect to the original one for varying initial stiffness K0 and cohesive strength σ0. The results showed that the modified model is robust with respect to changes of two orders of magnitude in initial stiffness and of a factor of two in σ0.

Calidad de vida de la población adulta con acúfenos / Quality of life of the adult population with tinnitus

El acúfeno es la percepción de un sonido en ausencia de un estímulo acústico externo. Se estima que comprometen gravemente la calidad de vida de los adultos y se asocia con un deterioro significativo en el desempeño de las actividades cotidianas; a menudo conduce a estados psicopatológicos tales como ansiedad y depresión. El presente trabajo adquiere un particular interés debido al aumento de la población mundial de adultos mayores, que son los que con mayor frecuencia sufren acúfenos. HIPÓTESIS: Los pacientes con acúfenos se ven afectados negativamente en su calidad de vida. OBJETIVOS: Determinar la calidad de vida de una muestra de pacientes con acúfenos. Determinar el nivel y el perfil audiológico mediante la audiometría y la logoaudiometría. Evaluar la funcionalidad del oído medio a través de la impedanciometría. Determinar y analizar las características de los acúfenos y la respuesta en el Test de Inhibición residual del acúfeno. Correlacionar las características del acúfeno con el perfil audiológico. Pacientes y métodos: Estudio observacional, transversal, analítico en el que se incluyeron pacientes adultos con acúfenos uni o bilaterales, normo oyentes o hipoacúsicos. En los mismos se realizó un examen Otorrinolaringológico y los estudios complementarios auditivos (Audiometría, Logoaudiometría, Impedanciometría, Acufenometría y Test de inhibición residual del acúfeno). La calidad de vida se evaluó con el cuestionario Tinnitus Handicap Inventory Questionnaire. Las variables continuas se describieron con sus respectivos valores de posición y dispersión y las variables categóricas con porcentajes. La correlación de las características del acúfeno con el perfil audiológico se realizó con test de Chi cuadrado. Se consideró significativa una p < 0,05. Resultados: El análisis de este estudio incluyó 93 pacientes y 149 acúfenos siendo estos: unilaterales (N=36), bilaterales (N= 111) y de localización cefálica (N=2). No se encontraron diferencias entre ambos géneros: 49 (53%) fueron de sexo masculino, mientras que el 44 (47%) fueron de sexo femenino. Los pacientes tenían una edad media (desviación estándar) de 52.5 (13.1) años. La calidad de vida a partir del THI demostró que 38 (41%) pacientes tenían alteración de la calidad vida leve (grado II), 20 ( 22%) no presentaron alteraciones (grado I) y en 20 (22%) la alteración fue moderada (grado III). Al analizar el perfil y el nivel audiológico, 82/149 (55%) de los acúfenos estudiados presentaron un perfil audiológico de tipo de hipoacusia neurosensorial y 49/149 (33%) eran normo oyentes. Por otro lado, 83/149 (91%) de los oídos estudiados no tenían alteraciones en oído medio. Ante el Test de Inhibición residual del acúfeno, se observó que 68 (46%) tuvieron respuestas parciales, 55 (37%) respuesta completa, 19 (12%) negativa y 7 (5%) tuvieron "efecto rebound". Según el tono, se observó que el perfil predominante era el de hipoacusia neurosensorial, 6 (75%) con acúfenos de banda estrecha y 74 (57%) con acúfenos agudos. Por otro lado, el perfil normo oyente se observó en 8 (67%) acúfenos de tono grave (p= 0.006). Con respecto al ruido del acúfeno, 5 (50%) pacientes presentaron ruidos pulsátiles y 7 (50%) intermitentes, siendo audiológicamente normo oyentes. Setenta y dos (58%) pacientes con hipoacusia neurosensorial presentaron ruidos continuos (p= 0.012). Según la localización, dos pacientes (100%) tenían acúfenos cefálicos y perfil audiológico normo oyente. Por otro lado, 21 (58%) pacientes presentaron acúfenos unilaterales y 61 (55%) bilaterales, ambos asociados en su mayoría a hipoacusia neurosensorial. (p= 0.42). Por último, ante la inhibición residual, 27 acúfenos en oídos con perfil audiológico normal (50%) presentaron respuesta completa. Mientras que oídos con perfil de hipoacusia neurosensorial, 44 (65%) presentaron respuesta parcial, 11 (58%) negativa y 6 (86%) efecto rebound. (p=0,05) Conclusión: Los acúfenos afectan negativamente la calidad de vida de quienes los padecen pero estos no los limitan en sus actividades diarias y pueden ser inhibidos con los estímulos acústicos. La mayoría de los acúfenos estudiados fueron inhibidos ante estímulos sonoros, lo cual nos abre puertas a las futuras conductas terapéuticas a seguir en cada caso. (AU)

Tinnitus is the perception of a sound in the absence of an external acoustic stimulus. They are estimated to severely compromise the quality of life of adults and is associated with a significant deterioration in the performance of daily activities; Often leads to psychopathological states such as anxiety and depression. The present work acquires a particular interest due to the increase of the world-wide population of older adults, who are the most frequent sufferers of tinnitus. HYPHOTESIS: Patients with tinnitus are negatively affected in their quality of life. Objectives: To determine the quality of life of a sample of patients with tinnitus. To determine the level and the audiological profile through audiometry and logoaudiometry. To evaluate the functionality of the middle ear through the impedanciometry. To determine and analyze the characteristics of tinnitus and the response in the residual inhibition test of tinnitus. Correlate the characteristics of the tinnitus with the audiological profile. Patients and methods: An observational, crosssectional, analytical study in which adult patients with uni or bilateral tinnitus, normo hearing or hypoacusic tinnitus were included. An otorhinolaryngological examination and complementary auditory studies (Audiometry, audiometry, impedance measurement, acuphenometry and residual inhibition of tinnitus) were performed. Quality of life was assessed using the Tinnitus Handicap Inventory Questionnaire. Continuous variables were described with their respective position and dispersion values and categorical variables with percentages. The correlation of the characteristics of the tinnitus with the audiological profile was performed with Chi square test. A p <0.05 was considered significant. RESULTS: The analysis of the study included 93 patients and 149 tinnitus. These were: unilateral (N = 36), bilateral (N = 111) and cephalic (N = 2). No differences were found between the two genders: 49 (53%) were male, while 44 (47%) were female. Patients had a mean age (standard deviation) of 52.5 (13.1) years. Quality of life from THI showed that 38 (41%) patients had altered quality of life (grade II), 20 (22%) Did not present alterations (grade I) and in 20 (22%) the alteration was moderate (grade III). When analyzing the profile and the audiological level, 82/149 (55%) of the tinnitus studied presented an audiological profile of type of sensorineural hearing loss and 49/149 (33%) were normal hearing. On the other hand, 83/149 (91%) of the ears studied had no alterations in the middle ear. Before the residual inhibition test of tinnitus, 68 (46%) had partial responses, 55 (37%) complete response, 19 (12%) negative and 7 (5%) had a "rebound effect". According to the tone, the predominant profile was sensorineural hypoacusis, 6 (75%) with narrow-band tinnitus and 74 (57%) with acute tinnitus. On the other hand, the normal hearing profile was observed in 8 (67%) severe tinnitus tinnitus (p = 0.006). Concerning tinnitus noise, 5 (50%) patients presented intermittent pulsing and 7 (50%) noises, being audiologically normal hearing. Seventy-two (58%) patients with neurosensory hearing loss had continuous noises (p = 0.012). According to the location, two patients (100%) had cephalic tinnitus and a normal hearing profile. On the other hand, 21 (58%) patients presented unilateral and 61 (55%) bilateral tinnitus, both of which were associated with sensorineural hearing loss. (P = 0.42). Finally, due to residual inhibition, 27 tinnitus in ears with normal audiological profile (50%) presented complete response. While ears with a sensorineural hearing loss profile, 44 (65%) presented partial response, 11 (58%) negative and 6 (86%) rebound effect. (P = 0.05). CONCLUSION: Tinnitus adversely affects the quality of life of those who suffer from them but these do not limit them in their daily activities and can be inhibited by acoustic stimuli. Most of the tinnitus studied were inhibited by sound stimuli, which opens the door to future therapeutic behaviors to be followed in each case. (AU)

The role of T and B cells in human atherosclerosis and atherothrombosis.

Far from being merely a passive cholesterol accumulation within the arterial wall, the development of atherosclerosis is currently known to imply both inflammation and immune effector mechanisms. Adaptive immunity has been implicated in the process of disease initiation and progression interwined with traditional cardiovascular risk factors. Although the body of knowledge regarding the correlation between atherosclerosis and immunity in humans is growing rapidly, a relevant proportion of it derives from studies carried out in animal models of cardiovascular disease (CVD). However, while the mouse is a well-suited model, the results obtained therein are not fully transferrable to the human setting due to intrinsic genomic and environmental differences. In the present review, we will discuss mainly human findings, obtained either by examination of post-mortem and surgical atherosclerotic material or through the analysis of the immunological profile of peripheral blood cells. In particular, we will discuss the findings supporting a pro-atherogenic role of T cell subsets, such as effector memory T cells or the potential protective function of regulatory T cells. Recent studies suggest that traditional T cell-driven B2 cell responses appear to be atherogenic, while innate B1 cells appear to exert a protective action through the secretion of naturally occurring antibodies. The insights into the immune pathogenesis of atherosclerosis can provide new targets in the quest for novel therapeutic targets to abate CVD morbidity and mortality.

PARP-1 activation causes neuronal death in the hippocampal CA1 region by increasing the expression of Ca(2+)-permeable AMPA receptors.

An excessive activation of poly(ADP-ribose) polymerases (PARPs) may trigger a form of neuronal death similar to that occurring in neurodegenerative disorders. To investigate this process, we exposed organotypic hippocampal slices to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG, 100µM for 5min), an alkylating agent widely used to activate PARP-1. MNNG induced a pattern of degeneration of the CA1 pyramidal cells morphologically similar to that observed after a brief period of oxygen and glucose deprivation (OGD). MNNG exposure was also associated with a dramatic increase in PARP-activity and a robust decrease in NAD(+) and ATP content. These effects were prevented by PARP-1 but not PARP-2 inhibitors. In our experimental conditions, cell death was not mediated by AIF translocation (parthanatos) or caspase-dependent apoptotic processes. Furthermore, we found that PARP activation was followed by a significant deterioration of neuronal membrane properties. Using electrophysiological recordings we firstly investigated the suggested ability of ADP-ribose to open TRPM2 channels in MNNG-induced cells death, but the results we obtained showed that TRPM2 channels are not involved. We then studied the involvement of glutamate receptor-ion channel complex and we found that NBQX, a selective AMPA receptor antagonist, was able to effectively prevent CA1 neuronal loss while MK801, a NMDA antagonist, was not active. Moreover, we observed that MNNG treatment increased the ratio of GluA1/GluA2 AMPAR subunit expression, which was associated with an inward rectification of the IV relationship of AMPA sEPSCs in the CA1 but not in the CA3 subfield. Accordingly, 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca(2+)-permeable GluA2-lacking AMPA receptors, reduced MNNG-induced CA1 pyramidal cell death. In conclusion, our results show that activation of the nuclear enzyme PARP-1 may change the expression of membrane proteins and Ca(2+) permeability of AMPA channels, thus affecting the function and survival of CA1 pyramidal cells.

STANDING, a four-step bedside algorithm for differential diagnosis of acute vertigo in the Emergency Department.

Vertigo is generally due to a benign disorder, but it is the most common symptom associated with misdiagnosis of stroke. In this pilot study, we preliminarily assessed the diagnostic performance of a structured bedside algorithm to differentiate central from non-central acute vertigo (AV). Adult patients presenting to a single Emergency Department with vertigo were evaluated with STANDING (SponTAneous Nystagmus, Direction, head Impulse test, standiNG) by one of five trained emergency physicians or evaluated ordinarily by the rest of the medical staff (control group). The gold standard was a complete audiologic evaluation by a clinicians who are experts in assessing dizzy patients and neuroimaging. Reliability, sensibility and specificity of STANDING were calculated. Moreover, to evaluate the potential clinical impact of STANDING, neuroimaging and hospitalisation rates were compared with control group. A total of 292 patients were included, and 48 (16.4%) had a diagnosis of central AV. Ninety-eight (33.4%) patients were evaluated with STANDING. The test had good interobserver agreement (k = 0.76), with very high sensitivity (100%, 95%CI 72.3-100%) and specificity (94.3%, 95%CI 90.7-94.3%). Furthermore, hospitalisation and neuroimaging test rates were lower in the STANDING than in the control group (27.6% vs. 50.5% and 31.6% vs. 71.1%, respectively). In conclusion, STANDING seems to be a promising simple structured bedside algorithm that in this preliminary study identified central AV with a very high sensitivity, and was associated with significant reduction of neuroimaging and hospitalisation rates.

Hippocampal sleep spindles preceding neocortical sleep onset in humans.

The coexistence of regionally dissociated brain activity patterns -with some brain areas being active while other already showing sleep signs- may occur throughout all vigilance states including the transition from wakefulness to sleep and may account for both physiological as well as pathological events. These dissociated electrophysiological states are often characterized by multi-domain cognitive and behavioral impairment such as amnesia for events immediately preceding sleep. By performing simultaneous intracerebral electroencephalographic recordings from hippocampal as well as from distributed neocortical sites in neurosurgical patients, we observed that sleep spindles consistently occurred in the hippocampus several minutes before sleep onset. In addition, hippocampal spindle detections consistently preceded neocortical events, with increasing delays along the cortical antero-posterior axis. Our results support the notion that wakefulness and sleep are not mutually exclusive states, but rather part of a continuum resulting from the complex interaction between diffuse neuromodulatory systems and intrinsic properties of the different thalamocortical modules. This interaction may account for the occurrence of dissociated activity across different brain structures characterizing both physiological and pathological conditions.

MPP(+) -dependent inhibition of Ih reduces spontaneous activity and enhances EPSP summation in nigral dopamine neurons.

BACKGROUND AND PURPOSE: 1-Methyl-4-phenylpyridinium (MPP(+) ), a potent parkinsonizing agent in primates and rodents, is a blocker of mitochondrial complex I, therefore MPP(+) -induced parkinsonism is believed to depend largely on mitochondrial impairment. However, it has recently been proposed that other mechanisms may participate in MPP(+) -induced toxicity. We tackled this issue by probing the effects of an acute application of MPP(+) on substantia nigra pars compacta (SNc) dopamine (DA) neurons. EXPERIMENTAL APPROACH: The effects of MPP(+) on SNc DA neurons in acute midbrain slices were investigated with electrophysiology techniques. KEY RESULTS: MPP(+) (50 µM) was able to (i) hyperpolarize SNc DA neurons by ∼6 mV; (ii) cause an abrupt and marked (over 50%) reduction of the spontaneous activity; and (iii) inhibit the hyperpolarization-activated inward current (Ih ). MPP(+) shifted Ih activation curve towards negative potentials by ∼11 mV both in Wistar rats and in C57/BL6 mice. Inhibition was voltage- and concentration-dependent (Imax = 47%, IC50 = 7.74 µM). MPP(+) slowed Ih activation kinetics at all potentials. These effects were not dependent on (i) block of mitochondrial complex I/fall of ATP levels; (ii) activation of type 2 DA receptor; and (iii) alteration of cAMP metabolism. Finally, MPP(+) -dependent inhibition of Ih facilitated temporal summation of evoked EPSPs in SNc DA, but not in CA1 hippocampal neurons. CONCLUSION AND IMPLICATIONS: Reduced functionality of Ih in SNc DA neurons, via increased responsiveness towards synaptic excitation, might play a role in MPP(+) -induced parkinsonism and, possibly, in the pathogenesis of human Parkinson's.

Topical mannitol reduces inflammatory edema in a rat model of arthritis.

The hexahydric alcohol mannitol is widely used to shift fluids from the intracellular to the extracellular compartments, to increase diuresis and improve mucus clearance in the airways. In principle, because of its physicochemical properties, topical mannitol might also draw fluids out of epidermis or mucosa. Here, we report that topical mannitol applications on the hind paws of rats with adjuvant-induced arthritis reduced paw thickness and tissue edema without affecting the inflammatory infiltrates. Of note, the anti-edema effects of acute (4 h) mannitol application occurred earlier than those prompted by a similar treatment with classic anti-inflammatory drugs such as diclofenac or ketoprofen. Yet, the extent of edema reduction was higher with diclofenac or ketoprofen than with mannitol when the drugs were applied in a chronic (16 h) paradigm. Together, data demonstrate that topical application of mannitol exerts potent and fast anti-edema effects in a rat model of joint inflammation, suggesting a possible utilization in patients affected by osseo-arthritic disorders.

The impact of one night of sleep deprivation on moral judgments.

Recent studies have shown the existence of a relationship between sleep and moral judgment. In this study, we investigated whether one night of sleep deprivation affects the ability to judge the appropriateness of moral dilemmas. Forty-eight students had to judge 30 moral dilemmas at test, after a night of home sleep, and another 30 dilemmas at retest, following one night of continuous wakefulness. The 60 dilemmas (20 moral impersonal, 20 moral personal, and 20 non-moral) were selected from Greene's dilemmas. Both groups judged the appropriateness of personal and impersonal dilemmas in the same way. A close to significant effect of sleep deprivation was observed on the reaction times for impersonal moral dilemmas, to which the deprived subjects responded faster (p = .05) than the control subjects. However, this was not the case for personal ones, for which no difference was significant. This result shows a greater ease/speed in responding to the (impersonal) dilemmas, which induce low emotional engagement after sleep deprivation, although the willingness to accept moral violations is not affected. This suggests that one night of sleep loss selectively influences the response speed only for moral impersonal dilemmas, probably due to disinhibition processes. The quality of moral judgment dilemmas does not seem to be easily influenced by a single night of sleep deprivation, but only by a longer lack of sleep.

Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase.

BACKGROUND AND PURPOSES: Thienyl-isoquinolone (TIQ-A) is a relatively potent PARP inhibitor able to reduce post-ischaemic neuronal death in vitro. Here we have studied, in different stroke models in vivo, the neuroprotective properties of DAMTIQ and HYDAMTIQ, two TIQ-A derivatives able to reach the brain and to inhibit PARP-1 and PARP-2. EXPERIMENTAL APPROACH: Studies were carried out in (i) transient (2 h) middle cerebral artery occlusion (tMCAO), (ii) permanent MCAO (pMCAO) and (iii) electrocoagulation of the distal portion of MCA in conjunction with transient (90 min) bilateral carotid occlusion (focal cortical ischaemia). KEY RESULTS: In male rats with tMCAO, HYDAMTIQ (0.1-10 mg·kg(-1)) injected i.p. three times, starting 4 h after MCAO, reduced infarct volumes by up to 70%, reduced the loss of body weight by up to 60% and attenuated the neurological impairment by up to 40%. In age-matched female rats, HYDAMTIQ also reduced brain damage. Protection, however, was less pronounced than in the male rats. In animals with pMCAO, HYDAMTIQ administered 30 min after MCAO reduced infarct volumes by approximately 40%. In animals with focal cortical ischaemia, HYDAMTIQ treatment decreased post-ischaemic accumulation of PAR (the product of PARP activity) and the presence of OX42-positive inflammatory cells in the ischaemic cortex. It also reduced sensorimotor deficits for up to 90 days after MCAO. CONCLUSION AND IMPLICATIONS: Our results show that HYDAMTIQ is a potent PARP inhibitor that conferred robust neuroprotection and long-lasting improvement of post-stroke neurological deficits.

Enfermedad mitocondrial y ototoxicidad". Enfermedad mitocondrial sindrómica, mutación G7444A / Mitochondrial disease and ototoxicity

Como parte del programa de “screening” genético para la pérdida de la audición; se realizó el estudio de mutaciones en los genes rRNA 12S y tRNAser (UCN), a partir del DNA mitocondrial, que están asociadas con la pérdida de audición inducida por antibióticos aminoglucósidos (ATB-AG) y de presentación no sindrómica. Se estudiaron 40 pacientes con sorderaneurosensorial, la cual podría haber sido causada posterior al tratamiento con ATB-AG. El sujeto afectado y el control, luego del examen físico completo y extracción de DNA a partir de sangre periférica, se amplificó y estudió segmentos en el gen 12S rRNA y en el gen tRNAser (UCN) por PCR-RFLP. En presencia de una mutación, se analizó el genoma mitocondrial completo en el probando y su familia por línea materna. Estos resultadosse han correlacionado con los valores de la relación dela citocromo oxidasa / citrato sintasa, el cual indica unapobre actividad de la citocromo oxidasa. La clínica en el“pedigree” por línea materna y los estudios moleculares,bioquímicos y morfológicos, podría indicar que se tratade una presentación sindrómica de la mutación 7444G>Aen Córdoba - Argentina.

As part of the "screening" for genetic hearing loss,was performed to study mutations in 12S rRNA and tRNAser(UCN) genes from mitochondrial DNA, which are associatedwith hearing loss induced by antibiotics aminoglycosides(ATB-AG) and non-syndromic presentation. We studied40 patients with sensorineural hearing loss, which could have been caused subsequent to treatment with ATB - AG. The affected individual and control, after a completephysical examination and extraction of DNA fromperipheral blood, was amplified and studied segments inthe 12S rRNA and tRNAser (UCN) genes by PCR-RFLP. In the presence of a mutation, we analyzed the complete mitochondrial genome in the proband and his family from maternal line. These results werecorrelated with the values of the ratio of the cytochromeoxidase / citrate synthase, which indicates a poor activity of cytochrome oxidase. The clinic in the "pedigree" frommaternal line and molecular, biochemical and morphological might indicate that it is a syndromic presentation of the mutation 7444G> A in Córdoba - Argentina.

Electroencephalographic sleep inertia of the awakening brain.

Sleep inertia (SI) denotes a period of hypovigilance, confusion and impaired cognitive and behavioral performance that immediately follows awakening. Based on the observation that the reactivation of some cortical areas is faster than other upon awakening, here we examined regional differences between presleep and postsleep waking period. Moreover, we also compared rapid eye movements (REM) and stage 2 non-rapid eye movements (NREM) awakenings in a within-subject design. Presleep and postsleep waking electroencephalogram (EEG; 5 min with eyes-closed and 5 min with eyes-open) of 18 healthy subjects (12 males, mean age=23.8±2.3 years) were recorded from 19 derivations. Participants slept for two consecutive nights in the laboratory. In one night they were awakened from stage 2 NREM, while in the other from REM sleep. EEG power spectra were calculated across the following bands: delta (1-4 Hz), theta (5-7 Hz), alpha (8-12 Hz), beta-1 (13-16 Hz) and beta-2 (17-24 Hz). Moreover, a detailed hertz-by-hertz analysis has been repeated in the 2-4 Hz frequency range. Postsleep wakefulness, compared to presleep, is characterized by a generalized decrease of higher beta-1 and beta-2 EEG power over almost all scalp locations. A detailed analysis of topographical modifications in the low-frequency range showed that postsleep wakefulness is characterized by an increased delta activity in the posterior scalp locations, and by a concomitant frontal decrease compared to presleep. Moreover, it was found a prevalence of EEG power in the high frequency ranges (beta-1 and beta-2) upon awakening from stage 2 compared to REM awakenings over the left anterior derivations. Altogether these findings support the hypothesis that a generalized reduction in beta activity and increased delta activity in more posterior areas upon awakening may represent the EEG substratum of the sleep inertia phenomenon.

Selective PARP-2 inhibitors increase apoptosis in hippocampal slices but protect cortical cells in models of post-ischaemic brain damage.

BACKGROUND AND PURPOSE: Poly(ADP-ribose) polymerases (PARP)-1 and PARP-2 play complementary tasks in the maintenance of genomic integrity, but their role in cell death or survival processes is rather different. A recently described series of selective PARP-2 inhibitors (UPF-1035, UPF-1069) were used to study the role of PARP-1 and PARP-2 in post-ischaemic brain damage. EXPERIMENTAL APPROACH: We evaluated post-ischaemic brain damage in two different in vitro models: rat organotypic hippocampal slices exposed to oxygen-glucose deprivation (OGD) for 20-30 min, a model characterized by apoptosis-like cell death and mouse mixed cortical cell cultures exposed to 60 min OGD, a model in which cells die with mostly necrosis-like features. KEY RESULTS: In organotypic hippocampal slices, PARP-2 inhibition with UPF-1069 (0.01-1 micromolxL(-1)) caused a concentration-dependent exacerbation (up to 155%) of OGD-induced CA1 pyramidal cell death. Higher concentrations, acting on both PARP-1 and PARP-2, had no effect on OGD injury. In mouse mixed cortical cells exposed to OGD, on the contrary, UPF-1069 (1-10 micromolxL(-1)) significantly reduced post-ischaemic damage. CONCLUSION AND IMPLICATIONS: Selective PARP-2 inhibitors increased post-OGD cell death in a model characterized by loss of neurons through a caspase-dependent, apoptosis-like process (hippocampal slice cultures), but they reduced post-OGD damage and increased cell survival in a model characterized by a necrosis-like process (cortical neurons). UPF-1069 may be a valuable tool to explore the function of PARP-2 in biological systems and to examine the different roles of PARP isoenzymes in the mechanisms of cell death and survival.

Mono-galloyl glucose derivatives are potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors and partially reduce PARP-1-dependent cell death.

BACKGROUND AND PURPOSE: Maintenance of poly(ADP-ribose) (PAR) polymers at homoeostatic levels by PAR glycohydrolase (PARG) is central in cell functioning and survival. Yet the pharmacological relevance of PARG inhibitors is still debated. Gallotannin, a complex mixture of hydrolysable tannins from oak gall, inhibits PARG but which of its constituents is responsible for the inhibition and whether the pharmacodynamic properties are due to its antioxidant properties, has not yet been established. EXPERIMENTAL APPROACH: A structure-activity relationship study was conducted on different natural and synthetic tannins/galloyl derivatives as potential PARG inhibitors, using a novel in vitro enzymic assay. Cytotoxicity was assayed in cultured HeLa cells. KEY RESULTS: Mono-galloyl glucose compounds were potent inhibitors of PARG, with activities similar to that of ADP-(hydroxymethyl) pyrrolidinediol, the most potent PARG inhibitor yet identified. When tested on HeLa cells exposed to the PAR polymerase (PARP)-1-activating compound 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), 3-galloyl glucose weakly inhibited PAR degradation. Conversely, the more lipophilic, 3-galloyl-1,2-O-isopropylidene glucose, despite being inactive on the pure enzyme, efficiently prolonged the half-life of the polymers in intact HeLa cells. Also, PARG inhibitors, but not radical scavengers, reduced, in part, cell death caused by MNNG. CONCLUSIONS AND IMPLICATIONS: Taken together, our findings identify mono-galloyl glucose derivatives as potent PARG inhibitors, and emphasize the active function of this enzyme in cell death.

Psychomotor performance is not influenced by brief repeated exposures to mobile phones.

The present study investigated the presence of a cumulative effect of brief and repeated exposures to a GSM mobile phone (902.40 MHz, 217 Hz modulated; peak power of 2 W; average power of 0.25 W; SAR = 0.5 W/kg) on psychomotor functions. To this end, after each of 3 15-min exposures, both an acoustic simple reaction time task (SRTT) and a sequential finger tapping task (SFTT) were administered to 24 subjects. The present study was unable to detect the cumulative effects of brief and repeated EMF exposure on human psychomotor performance, although there was a non-statistical trend to shorter reaction times. In summary, these data show an absence of effects with these particular exposure conditions; however, possible cognitive effects induced by different signal characteristics cannot be excluded.

Visceral hypersensitivity and intolerance symptoms in lactose malabsorption.

Lactose malabsorption is not always associated with intolerance symptoms. The factors responsible for symptom onset are not yet completely known. As differences in visceral sensitivity may play a role in the pathogenesis of functional symptoms, we evaluated whether an alteration of visceral sensitivity is present in subjects with lactose intolerance. Thirty subjects, recruited regardless of whether they were aware of their capacity to absorb lactose, underwent an evaluation of intestinal hydrogen production capacity by lactulose breath test, followed by an evaluation of lactose absorption by hydrogen breath test after lactose administration and subsequently an evaluation of recto-sigmoid sensitivity threshold during fasting and after lactulose administration, to ascertain whether fermentation modifies intestinal sensitivity. The role of differences in gastrointestinal transit was excluded by gastric emptying and mouth-to-caecum transit time by (13)C-octanoic and lactulose breath tests. Lactulose administration induced a significant reduction of discomfort threshold in subjects with lactose intolerance but not in malabsorbers without intolerance symptoms or in subjects with normal lactose absorption. Perception threshold showed no changes after lactulose administration. Severity of symptoms in intolerant subjects was significantly correlated with the reduction of discomfort thresholds. Visceral hypersensitivity should be considered in the induction of intolerance symptoms in subjects with lactose malabsorption.

High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo.

High mobility group proteins are chromatin binding factors with key roles in maintenance of nuclear homeostasis. The evidence indicates that extracellularly released high mobility group box 1 (HMGB1) protein behaves as a cytokine, promoting inflammation and participating to the pathogenesis of several disorders in peripheral organs. In this study, we have investigated the expression levels and relocation dynamics of HMGB1 in neural cells, as well as its neuropathological potential. We report that HMGB1 is released in the culture media of neurons and astrocytes challenged with necrotic but not apoptotic stimuli. Recombinant HMGB1 prompts induction of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2, interleukin-1beta, and tumor necrosis factor alpha, and increases excitotoxic as well as ischemic neuronal death in vitro. Dexamethasone reduces HMGB1 dependent immune glia activation, having no effect on the protein's neurotoxic effects. HMGB1 is expressed in the nucleus of neurons and astrocytes of the mouse brain, and promptly (1 h) translocates into the cytoplasm of neurons within the ischemic brain. Brain microinjection of HMGB1 increases the transcript levels of pro-inflammatory mediators and sensitizes the tissue to the ischemic injury. Together, data underscore the neuropathological role of nuclear HMGB1, and point to the protein as a mediator of post-ischemic brain damage.

Neurophysiological effects of mobile phone electromagnetic fields on humans: a comprehensive review.

In recent years a growing number of people have begun to use mobile phone technology. This phenomenon has raised questions and doubts about possible effects on users' brains. This literature review focuses on the human electrophysiological and neuro-metabolic effects of mobile phone (MP)-related electromagnetic fields (EMFs) published in the last 10 years. To this end, all relevant papers have been reported and, subsequently, a literature selection has been carried out by taking several criteria into account, such as: blind techniques, randomization or counter-balancing of conditions and subjects, detail of exposure characteristics and the statistical analyses used. As a result, only the studies meeting the selection criteria have been described, evaluated and discussed further. The main goal of this review is to provide a clear scenario of the most reliable experiments carried out over the last decade and to offer a critical point of view in their evaluation. It is concluded that MP-EMFs may influence normal physiology through changes in cortical excitability and that in future research particular care should be dedicated to both methodological and statistical control, the most relevant criteria in this research field.

Low serum tryptophan levels, reduced macrophage IDO activity and high frequency of psychopathology in HCV patients.

Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (TRP) metabolism, is induced in various tissues of patients with bacterial and viral infection or with neoplastic diseases. This induction is considered the main cause of the decreased serum TRP levels, the reduced brain serotonin synthesis and the occurrence of psychopathological disorders often detected in patients with chronic infections or different forms of cancer. We studied 89 subjects including: (a) 39 patients with chronic hepatitis C virus (HCV) infection and mild liver damage (b) 40 healthy controls, and (c) 10 patients with chronic hepatitis B virus (HBV) infection. We measured serum TRP and kynurenine levels and IDO activity in macrophages. Furthermore, each patient had an accurate psychopathological evaluation. HCV-infected patients had lower (-28%) serum TRP concentrations than healthy volunteers or HBV-infected patients with comparable liver damage. Depression and anxiety symptoms were particularly common in HCV patients. Unexpectedly, serum kynurenine levels and IDO activity in cultured macrophages (under both basal or stimulated conditions) were lower in HCV patients than in controls. Our study shows that HCV patients have reduced serum TRP levels and confirms that they frequently suffer from anxiety and depression-related symptoms. The reduced IDO activity found in the macrophages of these patients suggest that HCV infection may hamper macrophage functions.