The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents.

Inhibition of phosphodiesterase 9 (PDE9) has been reported to enhance rodent cognitive function and may represent a potential novel approach to improving cognitive dysfunction in Alzheimer's disease. PF-04447943, (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one), a recently described PDE9 inhibitor, was found to have high affinity (Ki of 2.8, 4.5 and 18 nM) for human, rhesus and rat recombinant PDE9 respectively and high selectivity for PDE9 versus PDEs1-8 and 10-11. PF-04447943 significantly increased neurite outgrowth and synapse formation (as indicated by increased synapsin 1 expression) in cultured hippocampal neurons at low (30-100 nM) but not high (300-1000 nM) concentrations. PF-04447943 significantly facilitated hippocampal slice LTP evoked by a weak tetanic stimulus at a concentration of 100 nM but failed to affect response to the weak tetanus at either 30 or 300 nM, or the LTP produced by a theta burst stimulus. Systemic administration of PF-04447943 (1-30 mg/kg p.o.) dose-dependently increased cGMP in the cerebrospinal fluid 30 min after administration indicating target engagement in the CNS of rats. PF-04447943 (1-3 mg/kg p.o.) significantly improved cognitive performance in three rodent cognition assays (mouse Y maze spatial recognition memory model of natural forgetting, mouse social recognition memory model of natural forgetting and rat novel object recognition with a scopolamine deficit). When administered at a dose of 3 mg/kg p.o., which improved performance in novel object recognition, PF-04447943 significantly increased phosphorylated but not total GluR1 expression in rat hippocampal membranes. Collectively these data indicate that PF-04447943 is a potent, selective brain penetrant PDE9 inhibitor that increased indicators of hippocampal synaptic plasticity and improved cognitive function in a variety of cognition models in both rats and mice. Results with PF-04447943 are consistent with previously published findings using a structurally diverse PDE9 inhibitor, BAY73-6199, and further support the suggestion that PDE9 inhibition may represent a novel approach to the palliative remediation of cognitive dysfunction.

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder.

In a large Scottish pedigree, a balanced translocation t(1;11)(q42.1;q14.3) segregates with major mental illness, including schizophrenia, bipolar disorder, and recurrent major depression. The translocation is predicted to result in the loss of the C-terminal region of the protein product of Disrupted In SChizophrenia 1 (DISC1), a gene located on 1q42.1. Since this initial discovery, DISC1 has been functionally implicated in several processes, including neurodevelopment. Based on the genetic and functional evidence that DISC1 may be associated with schizophrenia, we sequenced portions of DISC1 in 28 unrelated probands with schizophrenia and six unrelated probands with schizoaffective disorder, ascertained as part of a large sibpair study. We detected a 4 bp deletion at the extreme 3' end of exon 12 in a proband with schizophrenia. The mutation was also present in a sib with schizophrenia, a sib with schizoaffective disorder, and the unaffected father, while the mutation was not detected in 424 control individuals. The mutation is predicted to cause a frameshift and encode a truncated protein with nine abnormal C-terminal amino acids. The truncated transcript is detectable, but at a reduced level, in lymphoblastoid cell lines from three of four mutation carriers. These findings are consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders.

RF-powered BIONs for stimulation and sensing.

Virtually all bodily functions are controlled by electrical signals in nerves and muscles. Electrical stimulation can restore missing signals but this has been difficult to achieve practically because of limitations in the bioelectric interfaces. Wireless, injectable microdevices are versatile, robust and relatively inexpensive to implant in a variety of sites and applications. Several variants are now in clinical use or under development to perform stimulation and/or sensing functions and to operate autonomously or with continuous coordination and feedback control.

Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder.

BACKGROUND: N-acetyl aspartate (NAA) is an amino acid present in high concentrations in neurons and is thus a putative neuronal marker. In vivo proton magnetic resonance spectroscopy ((1)H MRS) studies have shown lower NAA concentrations in patients with various neurodegenerative disorders, suggesting decreased neuronal number, size, or function. Dorsolateral prefrontal (DLPF) NAA has not been extensively assessed in bipolar disorder patients, but it could be decreased in view of consistent reports of decreased DLPF cerebral blood flow and metabolism in mood disorders. We measured DLPF NAA in patients with bipolar disorder and healthy control subjects using in vivo (1)H MRS. METHODS: We obtained ratios of NAA, choline, and myoinositol (mI) to creatine-phosphocreatine (Cr-PCr) in bilateral DLPF 8-mL voxels of 20 bipolar patients (10 Bipolar I, 10 Bipolar II) and 20 age- and gender-matched healthy control subjects using (1)H MRS. RESULTS: DLPF NAA/Cr-PCr ratios were lower on the right hemisphere (p<.03) and the left hemisphere (p<.003) in bipolar disorder patients compared with healthy control subjects. CONCLUSIONS: These preliminary data suggest that bipolar disorder patients have decreased DLPF NAA/Cr-PCr. This finding could represent decreased neuronal density or neuronal dysfunction in the DLPF region.

Learn to use the Internet at Body Positive.

AIDS: Body Positive's Electronic Treatment Education Project (ETEP), funded by the National Library of Medicine (NLM), teaches people how to research treatment information and other issues related to HIV/AIDS on the Internet. The ETEP training is conducted over two days. The first day is an introduction to the Internet and its potential for addressing treatment issues, and the second class provides information on specific web sites. Students learn to critically evaluate the sites. The Internet is an excellent tool to research the ever-changing information related to HIV treatment. Information is included for class registration.^ieng

5-Hydroxytryptamine2A (5-HT2A) receptor desensitization can occur without down-regulation.

The connection between agonist-induced desensitization and down-regulation of 5-hydroxytryptamine2A (5-HT2A) receptors was examined in a clonal cell line that stably expresses the 5-HT2A receptor. Brief (2-hr) and prolonged (24-hr) exposure to the agonist quipazine or the agonist 4-iodo-(2,5-dimethoxy)- phenylisopropylamine (DOI) diminished 5-HT2A receptor-mediated phosphoinositide hydrolysis; no change in 5-HT2A receptor number or affinity was measured after 24 hr of exposure to DOI or quipazine. Immunohistochemical studies demonstrated that a 24-hr exposure to DOI did not alter surface 5-HT2A receptor immunoreactivity. Western blot analysis with G alpha q- and G alpha 11-selective antibodies indicate that a 24-hr agonist exposure did not alter the levels of phospholipase C-dependent G proteins. These results suggest that desensitization after prolonged DOI exposure can occur via a process independent of the levels of phospholipase C-coupled G proteins. Studies with a mutant 5-HT2A receptor (F340L) indicated that binding per se is not sufficient for desensitization. Down-regulation of the protein kinase C isozymes alpha and epsilon by overnight exposure to phorbol-12,13-dibutyrate attenuated the intermediate phase (i.e., after 2-6 hr of agonist exposure) of DOI- and quipazine-induced desensitization. These results indicate that the intermediate phase of DOI-induced desensitization is mediated by the alpha- and/or epsilon-protein kinase C isozymes but that neither is involved in the later phase (i.e., after 24 hr of agonist exposure) of desensitization.(ABSTRACT TRUNCATED AT 250 WORDS)

Neural correlates of working memory in a visual letter monitoring task: an fMRI study.

Complex mental operations rely on the coordinated activity of widely distributed brain regions constituting neurocognitive networks. Using multislice echoplanar functional magnetic resonance imaging (fMRI) we have contrasted regional brain activity during a control and an experimental condition which differed with respect to the demands placed on verbal working memory. Subjects were seven right-handed healthy male volunteers. Analysis of group and individual data revealed activation in the anterior and posterior parasagittal cortex in all subjects, left parietal cortex (six subjects) and left dorsolateral prefontal cortex (five subjects). These results suggest that verbal working memory is subserved by a neurocognitive network comprising cortical regions involved in attention, executive function and short term mnemonic processes.

Differential ergoline and ergopeptine binding to 5-hydroxytryptamine2A receptors: ergolines require an aromatic residue at position 340 for high affinity binding.

In this paper we show that a highly conserved aromatic residue, phenylalanine at the 340-position, is essential for ergoline binding to 5-hydroxytryptamine2A receptors. We hypothesized that F340 was essential for a specific aromatic-aromatic interaction (e.g., pi-pi or hydrophobic) between the phenyl moiety of F340 and the aromatic ring of the ergoline nucleus. To test this hypothesis, eight point mutations of adjacent (F340 and F339) and nonadjacent (F125) phenylanaines were made, using conservative (phenylalanine to tyrosine) and nonconservative (phenylalanine to leucine, alanine, or serine) substitutions. The binding affinities of all of the tested simple ergolines were greatly reduced by specific mutations of F340 in which aromatic-aromatic interactions (e.g., F340A and F340L) were abolished, but they were unaffected when the replacement residue was aromatic (e.g., F340Y). In contrast, the binding affinities of four ergopeptines (bromocryptine, ergocryptine, ergocornine, and ergotamine) were relatively unaffected by the F340L substitution. Neither ergoline nor ergopeptine affinities were consistently altered by F339 mutations. These results support the notion that aromatic-aromatic interactions (either pi-pi of hydrophobic) with F340 are essential for the binding of simple ergolines but not ergopeptines to 5-hydroxytryptamine2A receptors. Our findings support models of ergoline and ergopeptine binding to serotonin receptors that suggest that the nature of the substituent at the 8-position of the ergoline nucleus may give rise to different modes of binding for the two classes of agents, particularly with respect to the phenyl ring of F340.

Spindle cell variants of embryonal rhabdomyosarcoma in the paratesticular region. A report of the Intergroup Rhabdomyosarcoma Study.

We reviewed 173 cases of paratesticular rhabdomyosarcoma (RMS) of Intergroup Rhabdomyosarcoma Studies (IRS)-I, -II, and -III for evaluation of possible histological factors that might account for the good prognosis of these patients. Almost all cases (161 of 173 cases, 93.1%) occurring in this site were of embryonal histology. A spindle-cell subtype of embryonal RMS was identified that presented a storiform growth pattern with abundant collagen between the tumor cells in most cases. Other tumors of this subtype showed an arrangement of tumor cells in bundles with a low to moderate amount of collagen, resembling a leiomyosarcoma. The other embryonal RMS in this site had the classical embryonal cytology. The spindle-cell subtype was highly differentiated by immunohistochemistry and electron microscopy. Lymph node metastasis was found in seven of 43 patients (16.3%) with a RMS of spindle-cell subtype, compared with 40 of 112 patients (35.7%) with RMS of non-spindle-cell type. Clinical data from patients with spindle-cell subtypes of the paratesticular lesions revealed that they almost always had an association with clinical groups of limited disease (32 patients, 74.4%, with Group I; 10 patients, 23.3%, with Group II disease) and a significantly better prognosis (95.5% survival at 5 years) when compared with patients with the classic embryonal variant of RMS (80% survival at 5 years, p < 0.035). The incidence and anatomic distribution of this spindle cell subtype of embryonal RMS was estimated on 800 randomly selected patients from IRS-II. It was found in the head and neck, extremities, orbit, and some other sites, but 30.6% were located in the paratesticular area. Patients with spindle cell RMS of nonparatesticular sites usually had more extensive disease compared with patients having paratesticular lesions; two thirds of the cases had gross residual tumor after surgery or metastatic tumor at diagnosis. We conclude that spindle-cell RMS is a subtype of embryonal RMS with a very favorable prognosis. The site factor of the paratesticular localization may allow earlier diagnosis of the spindle-cell lesions compared with other sites. Other unknown factors may also play a role.

Rhabdoid tumors of soft tissues: a clinicopathologic study of 26 cases enrolled on the Intergroup Rhabdomyosarcoma Study.

Twenty-six cases of malignant soft tissue tumors with features similar to renal rhabdoid tumors were identified among approximately 3,000 childhood sarcomas entered on Intergroup Rhabdomyosarcoma Studies I-III. The tumors consisted of polygonal cells with vesicular nuclei and prominent nucleoli and cytoplasmic intermediate filament inclusions as identified by electron microscopy and immunohistochemistry. The growth pattern was predominantly solid or solid-trabecular. Immunohistochemistry showed vimentin, wide spectrum keratin, and epithelial membrane antigen to be the most consistent antigenic phenotypes. Eleven patients were infants less than 1 year of age. The tumors affected predominantly soft tissues of proximal extremities, trunk, and retroperitoneum/pelvis/abdomen. Nineteen patients died within 1 to 82 months (median, 6 months) from the start of treatment. Five patients have survived the disease for 2 to 13 years. When compared with the survival analysis of 991 Intergroup Rhabdomyosarcoma Study II patients, it was obvious that this group of tumors fares very poorly (P less than .001). The tumor belongs to the group of soft tissue neoplasms showing mesenchymal and subtle epithelial differentiation, similar to epithelioid sarcoma. Because of its identifiable histology, site and age distribution, and poor outcome, it warrants a status as an independent entity.

[Aneurysm of the ampulla of Galen. Nosologic reflections and endovascular therapy]. / Anévrysmes de l'ampoule de Galien. Réflexions nosologiques et thérapeutiques endovasculaires.

Nosologic concepts distinguish three types of aneurysm of Galen's ampulla: true aneurysms, related aneurysms, false aneurysms, whatever the type the majority of these malformations can be treated by the endovascular approach, frequently the most effective alternative therapy. Experience acquired during treatment of intracerebral arteriovenous angioma allows perfect control of direct, high output arteriovenous fistula by injection of pure isobutyl cyanoacrylate. Occlusion of shunts should be combined with prevention of consequences, that is to say extensive venous thrombosis. Two cases are reported that demonstrate the value of post-embolization heparin therapy.

Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas.

Histopathologic prognostic factors of 295 pretreatment tumors of a total 641 neuroblastomas and ganglioneuroblastomas were studied with the use of the following proposed tumor classification. The tumors were divided into 2 groups: stroma-poor (235 cases) and stroma-rich (60 cases) according to their organizational pattern (stromal development). The stroma-poor group was classified further into 2 subgroups: favorable stroma-poor (84% survival) and unfavorable stroma-poor (4.5% survival) according to the patient's age at diagnosis, degree of maturation, and nuclear pathology [mitosis-karyorrhexis index (MKI)] of the neuroblastic cells. The stroma-rich group was further classified into 3 subgroups: well differentiated (100% survival), intermixed (92% survival), and nodular (18% survival) on the basis of morphology of the immature element in the tumor tissue without regard to patient's age or quantitative maturation. Favorable stroma-poor and well-differentiated and intermixed stroma-rich groups seem to make good prognosis groups (87% survival), which show gradual progression along a maturational sequence according to the age of the patient. Unfavorable stroma-poor and nodular stroma-rich groups form poor prognosis groups (7% survival) and show morphological evidence of malignant or aggressive behavior, such as inappropriate immaturity for age, higher MKI, and gross nodule formation by immature neuroblasts.

Sequelae associated with head injuries in patients who were not hospitalized: a follow-up survey.

Data about sequelae associated with head injuries in patients presenting at a suburban hospital but not hospitalized were collected from emergency department medical records and two follow-up telephone interviews. During the study period 669 patients with head injuries were discharged from the emergency department. Of these, 288 were asked to participate in the study, 275 (95%) agreed, and 262 (91%) were eventually contacted. Participants and nonparticipants were compared on six variables and differed significantly only on age--younger patients were more likely to be included. Forty-eight hours after trauma, 52% of the respondents suffered headaches, 14% complained of dizziness, and 13% complained of drowsiness. One week after trauma, the complaints were headaches in 27%, dizziness in 11%, and drowsiness in 9%. Twenty-seven per cent had not resumed normal activity at 48 hours after trauma, and 13% had not at 1 week. Sixty-six per cent of the patients followed the patient instructions regarding head injuries.