Cognitive behavioral psychotherapy for generalized anxiety disorder: a primer

Generalized anxiety disorder is a highly debilitating psychologic disorder associated with cognitive, affective, behavioral and physiologic forms of rigidity and dysfunction. Chronic and uncontrollable worry, a future-oriented and highly negative form of verbal thought, is its hallmark symptom. Cognitive behavioral therapy, the most well-established psychologic treatment for generalized anxiety disorder, entails techniques designed to target and reduce dysfunction in each of these mutually interrelating domains. This review serves as an introduction to cognitive behavioral therapy for generalized anxiety disorder, including conceptualization, treatment methods and evidence for efficacy. Future directions for augmenting treatment efficacy are also discussed.     

Segregation of cognitive and emotional function in the prefrontal cortex: a stereotactic meta-analysis

Imaging studies of major depressive disorder and schizophrenia strongly implicate the prefrontal cortex. Interpretation of such studies is hindered by the limited knowledge of normal functional segregation. Different anatomical regions may be functionally specialised. Elucidating such specialisation may assist design and interpretation of patient studies. In this meta-analysis, 330 emotion induction and cognitive task studies of normal subjects published over the past decade reporting prefrontal activation have been examined. It was hypothesised that emotion induction would result in inferior medial activation and cognitive tasks dorsolateral activation. A significant difference in the pattern of reported activations was found in keeping with this hypothesis. Estimates of most likely reported activation loci for emotion induction and cognitive task studies have been made. In Montreal Neurological Institute (MNI) stereotactic space, these comprise of +/-5, 46, 18 and +/-5, 28, 31 for the medial prefrontal cortex, and +/-42, 28, -16 and +/-54, 28, 18 for the lateral prefrontal cortex, respectively. Additionally, estimates of the boundaries between emotional and cognitive-processing regions have been made. We restricted the effects of various potential sources of bias on the above estimates by attempting to include all relevant studies and independent selection by both authors of at most two activation loci from each study according to prespecified criteria. Such estimates of most likely reported activation loci may allow improved planning, analysis, and interpretation of imaging studies of psychiatric disorder and of normal function.     

Postsynaptic Targets of Type II Auditory Nerve Fibers in the Cochlear Nucleus.

Type II auditory nerve fibers, which provide the primary afferent innervation of outer hair cells of the cochlea, project thin fibers centrally and form synapses in the cochlear nucleus. We investigated the postsynaptic targets of these synapses, which are unknown. Using serial-section electron microscopy of fibers labeled with horseradish peroxidase, we examined the border of the granule-cell lamina in mice, an area of type II termination that receives branches having swellings with complex shapes. About 70% of the swellings examined with the electron microscope formed morphological synapses, which is a much higher value than found in previous studies of type II swellings in other parts of the cochlear nucleus. The high percentage of synapses enabled a number of postsynaptic targets to be identified. Most of the targets were small dendrites. Two of these dendrites were traced to their somata of origin, which were cochlear-nucleus small cells situated at the border of the granule-cell lamina. These cells did not appear to receive any terminals containing synaptic vesicles that were large and round, indicating a lack of input from type I auditory nerve fibers. Nor did type II swellings or targets participate in the synaptic glomeruli formed by mossy terminals and the dendrites of granule cells. Other type II synapses were axosomatic and their targets were large cells, which were presumed multipolar cells and one cell with characteristics of a globular bushy cell. These large cells almost certainly receive additional input from type I auditory nerve fibers, which provide the afferent innervation of the cochlear inner hair cells. A few type II postsynaptic targets—the two small cells as well as a large dendrite—received synapses that had accompanying postsynaptic bodies, a likely marker for synapses of medial olivocochlear branches. These targets thus probably receive convergent input from type II fibers and medial olivocochlear branches. The diverse nature of the type II targets and the examples of segregated convergence of other inputs illustrates the synaptic complexity of type II input to the cochlear nucleus.     

Surgical outcome in 85 patients with primary cardiac tumors

BACKGROUND: We present a large, single institution experience with adult cardiac tumors and address factors affecting outcome. METHODS: A retrospective review was made of all patients who underwent surgery for primary cardiac tumors from April 1975 through August 2002. RESULTS: Eighty-five patients (33 male and 52 female) with a mean age of 54 years were identified with follow-up available for 80 (94%) patients. There were 68 (80%) benign tumors and 17 (20%) malignant tumors. Three tumors recurred and were resected giving a total of 88 surgeries. All benign tumors were grossly resected and the extent of resection for malignant disease ranged from 14 (78%) gross resections and 3 (17%) debulkings to 1 (5%) biopsy. There were 4 (5%) early hospital deaths. Median survival was 9.6 months and 322 months for patients with malignant and benign diseases, respectively. Significant predictors of long-term mortality were malignant disease (P <0.0001) and New York Heart Association class (P <0.03). CONCLUSIONS: Surgical resection provides excellent outcome in patients with benign cardiac tumors. Malignant tumors continue to pose a challenge with good local tumor control but limited survival owing to metastatic disease.     

Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles

Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O6-Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (Ki values: CDK1, 5 +/- 1 microM; CDK2, 12 +/- 3 microM) and formed a triplet of hydrogen bonds (i.e., NH-9 to Glu 81, N-3 to Leu 83, and 2-NH2 to Leu 83). The triplet of hydrogen bonding and CDK inhibition was reproduced by 2,6-diamino-4-cyclohexylmethyloxy-5-nitrosopyrimidine (NU6027, Ki values: CDK1, 2.5 +/- 0.4 microM; CDK2, 1.3 +/- 0.2 microM). Against human tumor cells, NU2058 and NU6027 were growth inhibitory in vitro (mean GI50 values of 13 +/- 7 microM and 10 +/- 6 microM, respectively), with a pattern of sensitivity distinct from flavopiridol and olomoucine. These CDK inhibition and chemosensitivity data indicate that the distinct mode of binding of NU2058 and NU6027 has direct consequences for enzyme and cell growth inhibition.     

Oestrogen receptor expression and the effects of oestrogen and tamoxifen on the growth of human ovarian carcinoma cell lines

To assess the role of oestrogen regulation in the growth of ovarian cancer, we examined the effects of an oestrogen, 17 beta-oestradiol, and an anti-oestrogen, tamoxifen, on oestrogen receptor (ER) -positive and -negative human ovarian carcinoma cell lines. As measured by a dextran-coated charcoal adsorption assay, cell lines PEO1, PEO4 and PEO6 possessed moderate concentrations of ER (96-132 fmol mg-1 protein), PEA1 and PEA2 had low values (12-23 fmol mg-1 protein) and PEO14, TO14, PEO23 and PEO16 were ER-negative. Addition of 17 beta-oestradiol (10 nM or 0.1 nM) to the ER +ve cell line, PEO4, increased the growth rate. This oestrogen stimulation could be blocked by 1 microM tamoxifen. In contrast, the growth rate of the ER -ve cell line PEO14 was unaffected by the addition of 17 beta-oestradiol or tamoxifen. Concentrations of tamoxifen in excess of 8 microM were required to produce complete cytostasis in all lines. This concentration of tamoxifen over 72 hours also inhibited 50% colony formation when cells were plated on plastic. These data indicate that some ovarian carcinoma cell lines contain ER and their growth can be sensitive to oestrogen and anti-oestrogen modulation.