p38 MAPK in cardioprotection - are we there yet?

PKs transfer a phosphate from ATP to the side-chain hydroxyl group of a serine, threonine or tyrosine residue of a substrate protein. This in turn can alter that protein's function; modulating fundamental cellular processes including, metabolism, transcription, growth, division, differentiation, motility and survival. PKs are subdivided into families based on homology. One such group are the stress-activated kinases, which as the name suggests, are activated in response to cellular stresses such as toxins, cytokines, mechanical deformation and osmotic stress. Members include the p38 MAPK family, which is composed of α, ß, γ and δ, isoforms which are encoded by separate genes. These kinases transduce extracellular signals and coordinate the cellular responses needed for adaptation and survival. However, in cardiovascular and other disease states, these same systems can trigger maladaptive responses that aggravate, rather than alleviate, the disease. This situation is analogous to adrenergic, angiotensin and aldosterone signalling in heart failure, where inhibition is beneficial despite the importance of these hormones to homeostasis. The question is whether similar benefits could accrue from p38 inhibition? In this review, we will discuss the structure and function of p38, the history of p38 inhibitors and their use in preclinical studies. Finally, we will summarize the results of recent cardiovascular clinical trials with p38 inhibitors.

Identificación de genes clave implicados en el síndrome de Down mediante terapia génica / Identification of key genes involved in Down syndrome pathogenesis by gene therapy

La terapia génica nos ofrece la posibilidad de manipular los virus para convertir un agente infeccioso en un vehículo que transporta en su genoma secuencias de DNA con potencial terapéutico. En este trabajo hemos aprovechado la metodología que nos proporciona la terapia génica para desarrollar vectores virales derivados de virus adenoasociados y lentivirus con el objetivo de identificar genes clave (proteínas o microRNA [miRNA]) implicados en las alteraciones cognitivas presentes en el síndrome de Down (SD). Hemos demostrado que en un contexto de trisomía, como es el modelo de ratón Ts65Dn, la normalización de la expresión de Dyrk1A a través de la administración de los virus adenoasociados AAV2/1-shDyrk1A contribuye a restablecer la regulación de moléculas clave en los procesos de memoria y aprendizaje. Ello permite una atenuación de los defectos en plasticidad sináptica y facilita el desarrollo de una estrategia de aprendizaje visuoespacial más eficiente. Estos estudios refuerzan el papel destacado de Dyrk1A en los procesos cognitivos. Por otro lado, la estrategia de control de la expresión de miRNA desarrollada mediante los lentivirus Lv-anti-miR155-802 nos permite proponer a MeCP2 como un gen cuya desregulación en el síndrome de Down puede tener un papel clave en el deterioro cognitivo (AU)

Viruses have evolved ways of encapsulating and delivering their genes into human cells. Gene therapy takes advantage of this capability to manipulate the viral genome and convert an infectious agent into an efficient vector that delivers therapeutic genes. In the current work we have applied gene therapy approaches based on adeno-associated virus and lentivirus delivery to identify candidate genes (protein-coding or miRNAs) involved in the cognitive deficits in Down Syndrome. We show that the hippocampal injection of the adeno-associated virus AAV2/1-shDyrk1A normalized Dyrk1A expression in the trisomic Ts65Dn mice. As a consequence the regulation of key molecular players in memory and learning processes was rescued and mice showed an attenuation of synaptic plasticity defects and improved efficacy in learning strategies. All together these results reinforce the role of Dyrk1A in cognition. On the other hand, with the lentiviral strategydeveloped to specifically inhibit miR-155 and miR-802 (Lv-anti-miR155/802), we were able to show a tight control of the miRNAs target Mecp2 suggesting that the downregulation of MeCP2 in Down syndromecould be a contributing factor to the cognitive defects (AU)

Dopamine D(1) receptor deletion strongly reduces neurotoxic effects of methamphetamine.

Methamphetamine (METH) is a potent, highly addictive psychostimulant consumed worldwide. In humans and experimental animals, repeated exposure to this drug induces persistent neurodegenerative changes. Damage occurs primarily to dopaminergic neurons, accompanied by gliosis. The toxic effects of METH involve excessive dopamine (DA) release, thus DA receptors are highly likely to play a role in this process. To define the role of D(1) receptors in the neurotoxic effects of METH we used D(1) receptor knock-out mice (D(1)R(-/-)) and their WT littermates. Inactivation of D(1)R prevented METH-induced dopamine fibre loss and hyperthermia, and increases in gliosis and pro-inflammatory molecules such as iNOS in the striatum. In addition, D(1)R inactivation prevented METH-induced loss of dopaminergic neurons in the substantia nigra. To explore the relationship between hyperthermia and neurotoxicity, METH was given at high ambient temperature (29 °C). In this condition, D(1)R(-/-) mice developed hyperthermia following drug delivery and the neuroprotection provided by D(1)R inactivation at 23 °C was no longer observed. However, reserpine, which empties vesicular dopamine stores, blocked hyperthermia and strongly potentiated dopamine toxicity in D(1)R(-/-) mice, suggesting that the protection afforded by D(1)R inactivation is due to both hypothermia and higher stored vesicular dopamine. Moreover, electrical stimulation evoked higher DA overflow in D(1)R(-/-) mice as demonstrated by fast scan cyclic voltammetry despite their lower basal DA content, suggesting higher vesicular DA content in D(1)R(-/-) than in WT mice. Altogether, these results indicate that the D(1)R plays a significant role in METH-induced neurotoxicity by mediating drug-induced hyperthermia and increasing the releasable cytosolic DA pool.

Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: involvement of phospholipaseCgamma activity and glutamate receptor expression.

The involvement of brain-derived neurotrophic factor (BDNF) in cognitive processes and the decrease in its expression in Huntington's disease suggest that this neurotrophin may play a role in learning impairment during the disease progression. We therefore analyzed the onset and severity of cognitive deficits in two different mouse models with the same mutant huntingtin but with different levels of BDNF (R6/1 and R6/1:BDNF+/- mice). We observed that BDNF modulates cognitive function in different learning tasks, even before the onset of motor symptoms. R6/1:BDNF+/- mice showed earlier and more accentuated cognitive impairment than R6/1 mice at 5 weeks of age in discrimination learning; at 5 weeks of age in procedural learning; and at 9 weeks of age in alternation learning. At the earliest age at which cognitive impairment was detected, electrophysiological analysis was performed in the hippocampus. All mutant genotypes showed reduced hippocampal long term potentiation (LTP) with respect to wild type but did not show differences between them. Thus, we evaluated the involvement of BDNF-trkB signaling and glutamate receptor expression in the hippocampus of these mice. We observed a decrease in phospholipaseCgamma activity, but not ERK, in R61, BDNF+/- and R6/1:BDNF+/- hippocampus at the age when LTP was altered. However, a specific decrease in the expression of glutamate receptors NR1, NR2A and GluR1 was detected only in R6/1:BDNF+/- hippocampus. Therefore, these results show that BDNF modulates the learning and memory alterations induced by mutant huntingtin. This interaction leads to intracellular changes, such as specific changes in glutamate receptors and in BDNF-trkB signaling through phospholipaseCgamma.

Plakoglobin expression and localization in zebrafish embryo development.

Plakoglobin (gamma-catenin) and beta-catenin are major components of the adherens junctions and can be localized to the nucleus by activation of the Wnt signalling pathway. In addition, plakoglobin is also found in desmosomes, a vertebrate-specific cell-cell adhesion structure. Plakoglobin expression and localization were examined at the protein level during zebrafish embryonic development by Western blotting and confocal microscopy. Plakoglobin was expressed throughout embryo development at the protein level. Western blotting revealed that embryonic plakoglobin protein content increased between 12- and 24-h post-fertilization (hpf). Confocal microscopy showed that at stages up to 12 hpf, plakoglobin and beta-catenin were co-localized and expressed in both the nucleus and in cell-cell junctions. At 24- and 72-hpf, separate patterns were seen for plakoglobin and beta-catenin. These data indicate that plakoglobin localization in the heart region shifts from adherens junctions to desmosomes during heart chamber development.

Synaptic regulation of the slow Ca2+-activated K+ current in hippocampal CA1 pyramidal neurons: implication in epileptogenesis.

The slow Ca2+-activated K+ current (sI(AHP)) plays a critical role in regulating neuronal excitability, but its modulation during abnormal bursting activity, as in epilepsy, is unknown. Because synaptic transmission is enhanced during epilepsy, we investigated the synaptically mediated regulation of the sI(AHP) and its control of neuronal excitability during epileptiform activity induced by 4-aminopyridine (4AP) or 4AP+Mg2+-free treatment in rat hippocampal slices. We used electrophysiological and photometric Ca2+ techniques to analyze the sI(AHP) modifications that parallel epileptiform activity. Epileptiform activity was characterized by slow, repetitive, spontaneous depolarizations and action potential bursts and was associated with increased frequency and amplitude of spontaneous excitatory postsynaptic currents and a reduced sI(AHP.) The metabotropic glutamate receptor (mGluR) antagonist (S)-alpha-methyl-4-carboxyphenylglycine did not modify synaptic activity enhancement but did prevent sI(AHP) inhibition and epileptiform discharges. The mGluR-dependent regulation of the sI(AHP) was not caused by modulated intracellular Ca2+ signaling. Histamine, isoproterenol, and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid reduced the sI(AHP) but did not increase synaptic activity and failed to evoke epileptiform activity. We conclude that 4AP or 4AP+Mg-free-induced enhancement of synaptic activity reduced the sI(AHP) via activation of postsynaptic group I/II mGluRs. The increased excitability caused by the lack of negative feedback provided by the sI(AHP) contributes to epileptiform activity, which requires the cooperative action of increased synaptic activity.

Anxiety sensitivity and drug or alcohol use in individuals with anxiety and substance use disorders.

Anxiety sensitivity (AS) has been linked to both pathological anxiety and substance use problems. We evaluated relations between AS and substance use situations among individuals with substance use disorders (SUDs) and concurrent DSM-IV anxiety disorders. We predicted that AS would be most strongly associated with substance use in situations involving negative emotions and interpersonal conflict in substance abusers with anxiety disorders. This group was compared to substance abusers with concurrent mood disorders and substance abusers without other disorders (N=88). AS was positively related to negative emotion situations substance use for substance abusers with anxiety disorders and for substance abusers without other disorders. Contrary to predictions, significant differences between these groups were not found. The relationship between AS and negative emotion situations substance use remained after controlling trait anxiety in a combined group (anxiety disorders and substance abuse only groups). AS did not predict substance use for participants with concurrent mood disorders. Identification of factors that place anxious patients at risk for substance use problems will have implications for treatment and for the prevention of this form of maladaptive coping.

Alcohol use disorders and neuropsychological functioning in first-year undergraduates.

The relation between alcohol use disorders and neuropsychological functioning was examined in 489 first-year undergraduates, approximately half of whom had a history of alcoholism in their biological fathers. Factor analyses of 17 neuropsychological tests and subtests produced the following 5 factors that were the basis of subsequent analyses: Language/Verbal Memory, Visuospatial Ability, Motor Speed, Booklet Category Performance, and Attention. Participants with alcohol use disorders showed deficits in visuospatial ability. Those who had alcohol dependence showed deficits in both visuospatial ability and motor speed relative to participants who abused alcohol. The differences in neuropsychological functioning remained even after several potential confounding variables were controlled statistically. Results suggest that alcohol use disorders in first-year college students are associated with deficits in neuropsychological measures that are not attributable to several potential third-variable explanations.

Carcinoma of the ampulla of Vater: prognostic factors after curative surgery: a series of 45 cases.

BACKGROUND: Some adjuvant or neoadjuvant therapy could be important for patients operated on for tumours of the ampulla of Vater, especially for those having a higher risk of recurrence. AIM: To evaluate prognostic factors after curative surgery based on a series of 45 cases of malignant tumours of the Oddi sphincter. PATIENTS: From 1970 to 1992, a curative resection was performed in 45 patients (age 62.8 (SD 10.1) years) with adenocarcinoma of the ampulla. Surgical procedures included pancreatoduodenectomy (n = 42) and resection of the ampulla (n = 3). Actuarial survival was 44 (SD 9)% at five years. METHODS: Various prognostic variables were studied: clinical manifestations, macroscopic aspect, differentiation, noninvasive adenomatous component, mucin histochemistry, immunohistochemistry (CEA, CA19.9, p53, Ki67), and accepted classifications (Blumgart and Kennedy, Martin, Yamaguchi and Enjoji, Talbot et al, pTNM). RESULTS: Variables with prognostic power, in order of importance were: Classification of Talbot et al; CA19.9; pTNM; sialomucins; classification of Yamaguchi and Ejoji; Martin classification; sulphomucins; non-invasive adenomatous component (positive > negative); jaundice; tumour localisation. CONCLUSIONS: This series confirmed the prognostic power of former classifications and showed the prognostic power of other variables (mucin, non-invasive adenomatous component, CA19.9).

Approaches to rationing drugs in hospitals. An Australian perspective.

The increasing need to consider rationing strategies within the healthcare environment is being driven by pressures such as the development of new medical technologies, the aging population, patient awareness and expectations, healthcare professionals' appetite for new treatments, and government restrictions on healthcare costs. Solutions to these pressures will need to be sought urgently to avoid a situation in which quality of healthcare is affordable only for the wealthy. The fundamental principles of equity and fairness will need to be applied universally if the solutions are to be accepted by the community, patients and practitioners. There are several measures that a hospital must have in place before the concept of drug rationing can be contemplated. The approach essentially involves ensuring rational drug approval processes based on critical review of the available data, coupled with ongoing education and audit. Thus, accurate information and clinical budgeting systems, processes which encourage and ensure structural and technical efficiencies within the drug use sequence and an effective Drug and Therapeutics committee are required to facilitate this approach. To assist with its overriding goals of the quality use of medicines and optimal patient care, the Drug and Therapeutics committee needs to implement an effective formulary system, obtain detailed guidelines governing drug use within the institution, conduct an ongoing drug utilisation review programme, and provide education and training. The move to consider allocative decision making (rationing) will become increasingly necessary as limits on structural and technical efficiency measures are reached. An institution will then need to decide whether to treat a particular group of patients, or provide a certain form of treatment. Improved methods for community consultation need to be explored and there must be a partnership between the health provider and the consumer in enunciating the existence of scarcity, determining priorities and ensuring that ethics and equity are not abandoned through this process.

[Contribution of computers and telepathology in cancerologic pathology]. / Apport de l'informatique et de la télépathologie en anatomocytopathologie cancérologique.

The histologic or cytologic diagnosis of a tumoral lesion may be sometimes very difficult to do even for a senior pathologist. Nevertheless, it is necessary to recognize a malignant process with reliability and security. The usual way to solve some difficult problems is firstly to search documentations in books or atlas and then to discuss the slides in common. Sometimes it is necessary to dispatch the original documents to a national or international expert. Now computers are used in any private or public department of Pathology. Some new informatics developments allow to send good digitized pictures to an expert and to discuss with him. It is also possible to elaborate a data base of digitized images which can be edited on CD-Rom. We describe the development and the use of these technics in France and elsewhere. It seems that they could have an increasing role for quality assurance in tumoral pathology.

Family history of alcoholism, alcohol use disorders and the five-factor model of personality.

This study examines NEO-FFI correlates of risk for alcoholism, alcohol use disorders and alcoholism subtyping dimensions in a mixed-gender sample of 468 young adults (mean age = 21.3) presumed to be at high risk (n = 239) or low risk (n = 229) for alcoholism on the basis of a family history of paternal alcoholism. The NEO-FFI is a brief personality inventory measuring each of the key dimensions of the five-factor model of personality (FFMP), a comprehensive, empirically-derived model of personality structure. Familial risk for alcoholism was positively associated with openness and negatively associated with agreeableness and conscientiousness. Alcohol use disorders were positively associated with neuroticism and negatively associated with aggreeableness and conscientiousness. With the exceptions of alcoholism subtyped by comorbid antisocial personality disorder and by familial alcoholism, all of the alcoholic subtypes examined were related to at least one of the five dimensions. We conclude that the FFMP holds promise for studying personality traits in alcohol use disorders and in bringing a unifying perspective to research and clinical work in this area.

Beyond Section 504: satisfaction and empowerment of students with disabilities in higher education.

College and university students with disabilities were surveyed to determine their levels of satisfaction with accessibility, special services, and accommodations at their schools. In addition, students were requested to identify barriers to postsecondary education, improvements in services, and other concerns. Respondents generally expressed satisfaction with the services that they had received. However, the majority indicated that they had encountered barriers to their education, including a lack of understanding and cooperation from administrators, faculty, staff, and other students; lack of adaptive aids and other resources; and inaccessibility of buildings and grounds. Recommendations were made for improving the delivery of services and self-advocacy of students with disabilities.

Improving resources for foster care.

The number of foster children and their psychological and medical morbidity are growing. To gain insight into how to recruit and retain foster homes, characteristics of 64 foster families were determined by interview. Foster parents had low-to-moderate incomes, were approaching middle age, had underutilized home space, and wanted more children. Most enjoyed foster care and planned to continue. Twenty-three percent of the 64 had half of all foster children in the study in their homes at interview and had cared for seven times as many children in the past, including 66% of all the teens and 83% of all the handicapped children who had been in the 64 homes. These "high providers" functioned like group homes for mentally handicapped individuals. Adapting the group-home concept to foster homes could improve care, especially for children with special needs.

The Department of Defense Civilian External Peer Review Program: an interim report.

During a 2-year period (December 1987-December 1989), 165 Department of Defense (DoD) military hospitals world-wide provided 71,800 cases with 83,197 reviews for quality of care evaluations by the Civilian External Peer Review Program (CEPRP). The majority (78,246 of 79,896) of completed peer review determinations (97.9%) generated agreement with care and documentation. It is concluded that health care in military treatment facilities is of high quality, meeting and generally exceeding accepted standards of care. It is also concluded that the DoD CEPRP offers conceptual and practical experience to guide the further evolution and integration of clinical peer review and quality improvement activities.

Prevalence of DSM-III-R disorders among nonclinical compulsive checkers and noncheckers in a college student sample.

The prevalence of lifetime DSM-III-R disorders was assessed in a sample of 100 college students who were classified as compulsive checkers (n = 50) or noncheckers (n = 50) on the basis of their responses to the Checking subscale of the Maudsley Obsessional-Compulsive Inventory (MOCI). DSM-III-R disorders were assessed on the basis of responses to the Diagnostic Interview Schedule, Version III Revised (DIS-III-R), administered by trained, lay interviewers, blind to Ss' checking status. Checkers, compared to noncheckers, were significantly more likely to meet lifetime diagnostic criteria for Major Depressive Episode, Drug Abuse/Dependence, and Social Phobia. Analysis of a subsample (n = 74) selected on the basis of the consistency of responses to the MOCI across two administrations replicated the above effects, with two exceptions: (1) checkers were more likely to meet criteria for Obsessive Compulsive Disorder than were noncheckers, and (2) for males, but not females, Simple Phobia was more prevalent among checkers than among noncheckers. These findings extend our previous work by demonstrating that 'nonclinical' checking behavior is associated with a broad range of psychological syndromes and may, in fact, be more strongly associated with other disorders than it is with Obsessive Compulsive Disorder in a nonclinical sample.

A comparative review of developmental screening tests.

Public Law 99-457 amends the Education of the Handicapped Act to include services for children from birth through 3 years. Inasmuch as detection and referral of children with developmental delays continues to reside largely with pediatricians and other health care professionals, developmental screening, using standardized tests, is increasingly important. To help physicians select from the array of instruments, 19 different screening tests were administered by a pediatrician and rated by a panel of pediatricians and a special educator. While the panel found few tests that fit within the time constraints of pediatric practice, several tests approached standards for educational and psychologic tests. These included the Battelle Developmental Inventory Screening Test, Infant Monitoring System, Developmental Indicators for Assessment of Learning-Revised, Screening Children for Related Early Educational Needs, and the Developmental Profile II.