Extracellular HIV-1 virus protein R causes a large inward current and cell death in cultured hippocampal neurons: Implications for AIDS pathology

The small HIV-1 accessory protein Vpr (virus protein R) is a multifunctional protein that is present in the serum and cerebrospinal fluid of AIDS patients. We previously showed that Vpr can form cation-selective ion channels across planar lipid bilayers, introducing the possibility that, if incorporated into the membranes of living cells, Vpr might form ion channels and consequently perturb the maintained ionic gradient. In this study, we demonstrate, by a variety of approaches, that Vpr added extracellularly to intact cells does indeed form ion channels. We use confocal laser scanning microscopy to examine the subcellular localization of fluorescently labeled Vpr. Plasmalemma depolarization and damage are examined using the anionic potential-sensitive dye bis(1,3-dibutylbarbituric acid) trimethine oxonol and propidium iodide (PI), respectively, and the effect of Vpr on whole-cell current is demonstrated directly by using the patch-clamp technique. We show that recombinant purified extracellular Vpr associates with the plasmalemma of hippocampal neurons to cause a large inward cation current and depolarization of the plasmalemma, eventually resulting in cell death. Thus, we demonstrate a physiological action of extracellular Vpr and present its mechanistic basis. These findings may have important implications for neuropathologies in AIDS patients who possess significant amounts of Vpr in the cerebrospinal fluid.

Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains α-, β-, and γ-synuclein

Pathogenic α-synuclein (αS) gene mutations occur in rare familial Parkinson’s disease (PD) kindreds, and wild-type αS is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer’s disease, but β-synuclein (βS) and γ-synuclein (γS) have not yet been implicated in neurological disorders. Here we show that in PD and DLB, but not normal brains, antibodies to αS and βS reveal novel presynaptic axon terminal pathology in the hippocampal dentate, hilar, and CA2/3 regions, whereas antibodies to γS detect previously unrecognized axonal spheroid-like lesions in the hippocampal dentate molecular layer. The aggregation of other synaptic proteins and synaptic vesicle-like structures in the αS- and βS-labeled hilar dystrophic neurites suggests that synaptic dysfunction may result from these lesions. Our findings broaden the concept of neurodegenerative “synucleinopathies” by implicating βS and γS, in addition to αS, in the onset/progression of PD and DLB.

Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology

Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid β (Aβ) peptide, the major constituent of AD plaques. We expressed human APP751 containing these mutations in the brains of transgenic mice. Two transgenic mouse lines develop pathological features reminiscent of AD. The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670/671 combined with the V717I mutation causes Aβ deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. The immunoreactivity is exclusively found in congophilic senile plaques of both lines. In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age. These mice resemble major features of AD pathology and suggest a central role of Aβ in the pathogenesis of the disease.

Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease

For many inborn errors of metabolism, early treatment is critical to prevent long-term developmental sequelae. We have used a gene-therapy approach to demonstrate this concept in a murine model of mucopolysaccharidosis type VII (MPS VII). Newborn MPS VII mice received a single intravenous injection with 5.4 × 106 infectious units of recombinant adeno-associated virus encoding the human β-glucuronidase (GUSB) cDNA. Therapeutic levels of GUSB expression were achieved by 1 week of age in liver, heart, lung, spleen, kidney, brain, and retina. GUSB expression persisted in most organs for the 16-week duration of the study at levels sufficient to either reduce or prevent completely lysosomal storage. Of particular significance, neurons, microglia, and meninges of the central nervous system were virtually cleared of disease. In addition, neonatal treatment of MPS VII mice provided access to the central nervous system via an intravenous route, avoiding a more invasive procedure later in life. These data suggest that gene transfer mediated by adeno-associated virus can achieve therapeutically relevant levels of enzyme very early in life and that the rapid growth and differentiation of tissues does not limit long-term expression.

Vitamin B12 and hepatitis C: Molecular biology and human pathology

Cobalamins are stored in high concentrations in the human liver and thus are available to participate in the regulation of hepatotropic virus functions. We show that cyanocobalamin (vitamin B12) inhibited the HCV internal ribosome entry site (IRES)-dependent translation of a reporter gene in vitro in a dose-dependent manner without significantly affecting the cap-dependent mechanism. Vitamin B12 failed to inhibit translation by IRES elements from encephalomyocarditis virus (EMCV) or classical swine fever virus (CSFV). We also demonstrate a relationship between the total cobalamin concentration in human sera and HCV viral load (a measure of viral replication in the host). The mean viral load was two orders of magnitude greater when the serum cobalamin concentration was above 200 pM (P < 0.003), suggesting that the total cobalamin concentration in an HCV-infected liver is biologically significant in HCV replication.

Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death.

Although cyclin-dependent kinase 5 (Cdk5) is closely related to other cyclin-dependent kinases, its kinase activity is detected only in the postmitotic neurons. Cdk5 expression and kinase activity are correlated with the extent of differentiation of neuronal cells in developing brain. Cdk5 purified from nervous tissue phosphorylates neuronal cytoskeletal proteins including neurofilament proteins and microtubule-associated protein tau in vitro. These findings indicate that Cdk5 may have unique functions in neuronal cells, especially in the regulation of phosphorylation of cytoskeletal molecules. We report here generation of Cdk5(-/-) mice through gene targeting and their phenotypic analysis. Cdk5(-/-) mice exhibit unique lesions in the central nervous system associated with perinatal mortality. The brains of Cdk5(-/-) mice lack cortical laminar structure and cerebellar foliation. In addition, the large neurons in the brain stem and in the spinal cord show chromatolytic changes with accumulation of neurofilament immunoreactivity. These findings indicate that Cdk5 is an important molecule for brain development and neuronal differentiation and also suggest that Cdk5 may play critical roles in neuronal cytoskeleton structure and organization.

Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine.

Human aging is impacted severely by cardiovascular disease and significantly but less overtly by renal dysfunction. Advanced glycation endproducts (AGEs) have been linked to tissue damage in diabetes and aging, and the AGE inhibitor aminoguanidine (AG) has been shown to inhibit renal and vascular pathology in diabetic animals. In the present study, the effects of AG on aging-related renal and vascular changes and AGE accumulation were studied in nondiabetic female Sprague-Dawley (S-D) and Fischer 344 (F344) rats treated with AG (0.1% in drinking water) for 18 mo. Significant increases in the AGE content in aged cardiac (P < 0.05), aortic (P < 0.005), and renal (P < 0.05) tissues were prevented by AG treatment (P < 0.05 for each tissue). A marked age-linked vasodilatory impairment in response to acetylcholine and nitroglycerine was prevented by AG treatment (P < 0.005), as was an age-related cardiac hypertrophy evident in both strains (P < 0.05). While creatinine clearance was unaffected by aging in these studies, the AGE/ creatinine clearance ratio declined 3-fold in old rats vs. young rats (S-D, P < 0.05; F344, P < 0.01), while it declined significantly less in AG-treated old rats (P < 0.05). In S-D but not in F344 rats, a significant (P < 0.05) age-linked 24% nephron loss was completely prevented by AG treatment, and glomerular sclerosis was markedly suppressed (P < 0.01). Age-related albuminuria and proteinuria were markedly inhibited by AG in both strains (S-D, P < 0.01; F344, P < 0.01). These data suggest that early interference with AGE accumulation by AG treatment may impart significant protection against the progressive cardiovascular and renal decline afflicting the last decades of life.

Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.

Mutations in the human Cu,Zn superoxide dismutase gene (SOD1) are found in 20% of kindreds with familial amyotrophic lateral sclerosis. Transgenic mice (line G1H) expressing a human SOD1 containing a mutation of Gly-93 --> Ala (G93A) develop a motor neuron disease similar to familial amyotrophic lateral sclerosis, but transgenic mice (line N1029) expressing a wild-type human SOD1 transgene do not. Because neurofilament (NF)-rich inclusions in spinal motor neurons are characteristic of amyotrophic lateral sclerosis, we asked whether mutant G1H and/or N1029 mice develop similar NF lesions. NF inclusions (i.e., spheroids, Lewy body-like inclusions) were first detected in spinal cord motor neurons of the G1H mice at 82 days of age about the time these mice first showed clinical evidence of disease. Other neuronal intermediate filament proteins (alpha-internexin, peripherin) also accumulated in these spheroids. The onset of accumulations of ubiquitin immunoreactivity in the G1H mice paralleled the emergence of vacuoles and NF-rich spheroids in neurons, but they did not colocalize exclusively with spheroids. In contrast, NF inclusions were not seen in the N1029 mice until they were 132 days old, and ubiquitin immunoreactivity was not increased in the N1029 mice even at 199 days of age. Astrocytosis in spinal cord was associated with a marked increase in glial fibrillary acidic protein immunoreactivity in the G1H mice, but not in the N1029 mice. Finally, comparative studies revealed a striking similarity between the cytoskeletal pathology in the G1H transgenic mice and in patients with amyotrophic lateral sclerosis. These findings link a specific SOD1 mutation with alterations in the neuronal cytoskeleton of patients with amyotrophic lateral sclerosis. Thus, neuronal cytoskeletal abnormalities may be implicated in the pathogenesis of human familial amyotrophic lateral sclerosis.

Personalidad, género y vulnerabilidad a la depresión :(Women and vulnerability to depression : some personality and clinical factors)

En este trabajo se exploraron relaciones existentes entre las características de personalidad, género y la presencia de depresión, siguiendo la linea de investigación de Carrillo, Rojo y Staats (2004). Se intentó encontrar perfiles de personalidad caracterizados por determinados rasgos que fueran significativamente distintos entre hombres y mujeres y que a su vez se asociaran a una mayor presencia de síntomas depresivos. Esto se llevó a cabo en dos muestras de distintos países y culturas por separado: Chile (N= 448, 257 varones (57.37%) y 190 mujeres (42.41%), y un rango etario de 17-65) y España (N = 578, 196 varones (33.9%) y 381 mujeres (65,9%), y un rango etario de 17-67 ), con el propósito de aportar evidencia respecto de cómo afecta la cultura, como factor ambiental, en la conformación de la personalidad a partir de repertorios de aprendizajes. Orientado a eso en el presente trabajo se intentó buscar asociaciones significativas entre las dimensiones de Personalidad propuestas por Eysenk (1975), en el EPQ y EPQ-R, por los factores de Personalidad de los Cinco grandes a partir del NEO PI y del NEO PI-R (Costa y McCrae, 1985, citado en Carrillo et al. 2004) y otras variables clínicas, como rasgos de personalidad esquizotipicos, frecuencia e intensidad de emociones, habilidades sociales y sintomatología clínica. Las características de personalidad se compararon en función del género y finalmente se analizó si las diferencias de personalidad pudieron predecir depresión a partir del Beck Depression Inventory, (Beck, Rush, Shaw y Emery, 1979)...

Group Dynamics in Sex Offender Treatment Involving Individuals with Personality Disorders

This qualitative investigation primarily employing a phenomenological perspective and psychoanalytic interview approach intends to provide contextual understanding of group dynamics in sex offender treatment involving individuals with strong features of personality disorders or Axis II psychopathology according to the Diagnostic and Statistical Manual of Mental Disorder (4 ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000). Of note, this study particularly focuses on the cluster B type (Narcissistic, Borderline, Histrionic, and Antisocial Personality Disorders), based on the assumption that this type is more interpersonally operational in its nature. The present study is based on semi-structured interviews of three clinicians who arecurrently providing group treatment for sex offenders. The interview was designed to elicit the participants' clinical observations of group dynamics involving group members with features of the Axis II, Cluster B type. In this study, 11 therapeutic factors postulated by Yalom (2005) were utilized to qualitatively investigate group dynamics. Analyses of qualitative data highlighted how group members with features of the Axis II, Cluster B type may distinctively affect group dynamics. Based on the results, group members with Axis II diagnoses, as reported bythe therapists who responded to this study, were observed to present with altruistic behaviors in group. In addition, motivation appeared to be one of the most influential factors in promoting and maintaining therapeutic group behaviors. Group members with antisocial features appeared to present with low motivation for treatment, and individualswith a pervasive history of criminal institutionalization seemed more prone to disengagement in group. Individuals with borderline and histrionic traits seemed to be interpersonally oriented and affectively engaged in group process. Persons with a narcissistic tendency also appeared to be interpersonally invested and showed altruistic behaviors, yet the importance of confirming their superiority seemed to outweigh the need for acceptance or approval from other group members. As briefly discussed above, the qualitative analyses of the current data showed that individuals with Axis II disorders, Cluster B type uniquely affect group dynamics, which suggest clinical considerations foreffective treatment planning, maintenance, and outcomes.

Therapeutic Personality Assessment with Couples: A Short-Term Therapy Model

This paper focuses on the importance of psychological assessment as a short-term therapeutic tool for use in couples therapy. Personality assessment, when used collaboratively, can be a vital contribution to the therapeutic environment and can help couples can insight into each other's character traits and behavior patterns. This paper addresses the need for a short-term model of couples therapy for couples where one partner is incarcerated. The author proposes using a slightly modified version of Finn's Therapeutic Assessment for couples - Therapeutic Personality Assessment for Couples for a Prison Setting (TPAC-PS). A future research paradigm is suggested to test the validity of the TPAC-PS model.

Adaptive Institutional Transference in the Treatment of Individuals with Borderline Personality Disorder.

This paper introduces "adaptive institutional transference" (AIT) and describes how it develops in some clients in response to psychotherapist transfer in psychology training clinics. Individuals with borderline personality disorder are especially likely to develop AIT because of difficulties related to abandonment depression. Directors, supervisors, and student psychotherapists in psychology training clinics should be aware of these dynamics because they have important treatment implications, which are described. Limitations and ideas for future exploratory and qualitative research are also discussed .

General mental ability as moderator of personality traits as predictors of early career success

In this paper, we examine the effects of general mental ability (GMA) and the personality traits defined in the big five model on extrinsic and intrinsic indicators of career success, in a sample of 130 graduates who were in the early stages of their careers. Results from hierarchical regression analyses indicated that GMA does not predict any of the success indicators. In contrast, the combination of GMA and three of the Big Five Personality traits, conscientiousness, neuroticism, and openness, is significantly associated with greater early career success and has incremental predictive validity.