The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer’s Disease

BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.     

Reproductive Function in Epilepsy

Summary: : The hypothalamic-pituitary-gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic-pituitary-gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are needed.     

Familias Unidas: The Efficacy of an Intervention to Promote Parental Investment in Hispanic Immigrant Families

This paper reports a test of the efficacy of Familias Unidas, a Hispanic-specific, ecologically focused, parent-centered preventive intervention, in promoting protection against and reducing risk for adolescent behavior problems. Specifically, the intervention was designed to foster parental investment, reduce adolescent behavior problems, and promote adolescent school bonding/academic achievement, all protective factors against drug abuse and delinquency. One-hundred sixty seven Hispanic families of 6th and 7th grade students from three South Florida public schools were stratified by grade within school and randomly assigned to intervention and no-intervention control conditions. Results indicated that Familias Unidas was efficacious in increasing parental investment and decreasing adolescent behavior problems, but that it did not significantly impact adolescent school bonding/academic achievement. Summer-vacation rates of adolescent behavior problems were six times higher in the control condition than in the intervention condition. Furthermore, change in parental investment during the intervention was predictive of subsequent levels of adolescent behavior problems. The findings suggest that Familias Unidas is efficacious in promoting protection and reducing risk for adolescent problem behaviors in poor immigrant Hispanic families.     

Clonidine decreases plasma and cerebrospinal fluid arginine vasopressin but not oxytocin in humans

To evaluate the alpha 2-noradrenergic regulation of arginine vasopressin (AVP) and oxytocin (OT) in normal humans, we measured the effect of the alpha 2-agonist clonidine on concentrations of these neuropeptides in both plasma and cerebrospinal fluid (CSF). Subjects underwent two lumbar puncture studies, one of which was performed 100 min after oral administration of 5 micrograms/kg clonidine. Plasma AVP and OT were measured at a single time point 10 min before lumbar puncture. Both plasma and CSF AVP were significantly lower in the clonidine condition than in the control (no drug) condition. Neither plasma nor CSF OT differed significantly between conditions. Our data confirm previous reports of alpha 2-noradrenergic inhibition of neurohypophyseal release of AVP into blood, and extend these findings to healthy human subjects. Our data also suggest that AVP appearance in CSF, presumably from extraneurohypophyseal vasopressinergic neurons, is regulated by an inhibitory alpha 2-noradrenergic mechanism.     

Representation of heading direction in far and near head space

Manipulation of objects around the head requires an accurate and stable internal representation of their locations in space, also during movements such as that of the eye or head. For far space, the representation of visual stimuli for goal-directed arm movements relies on retinal updating, if eye movements are involved. Recent neurophysiological studies led us to infer that a transformation of visual space from retinocentric to a head-centric representation may be involved for visual objects in close proximity to the head. The first aim of this study was to investigate if there is indeed such a representation for remembered visual targets of goal-directed arm movements. Participants had to point toward an initially foveated central target after an intervening saccade. Participants made errors that reflect a bias in the visuomotor transformation that depends on eye displacement rather than any head-centred variable. The second issue addressed was if pointing toward the centre of a wide-field expanding motion pattern involves a retinal updating mechanism or a transformation to a head-centric map and if that process is distance dependent. The same pattern of pointing errors in relation to gaze displacement was found independent of depth. We conclude that for goal-directed arm movements, representation of the remembered visual targets is updated in a retinal frame, a mechanism that is actively used regardless of target distance, stimulus characteristics or the requirements of the task.     

Molecular Evidence for the Existence of Two Distinct Subgroups in Cucumber Mosaic Cucumovirus

Infectious full-length cDNA clones from the genomic RNAs of a subgroup II cucumber mosaic cucumovirus strain (Trk7) were obtained. Sequence analysis of the whole genome revealed strong homology (99%) to the genome of Q-CMV, the only subgroup II strain whose entire genomic nucleotide sequence had been available in the database, and an overall 75% homology to those of subgroup I strains. We provide sequence comparisons of different parts of 1a, 2a and 2b proteins of Cucumovirus species, and propose phylogenetic trees based on these protein sequences.     

Cellular carboxypeptidases

Summary: This article focuses on four human carboxypeptidases (CPs): two metallo-CPs and two serine CPs. The metallo-CPs are members of the so-called B-type regulatory CP family, as they cleave only the C-terminal basic amino acids Arg or Lys. The plasma membrane-bound CPM and the mainly, but not exclusively, intracellular CPD are surveyed from this group of enzymes. These enzymes can regulate pep tide hormone activity at the cell surface and possibly intracellularly after receptor-mediated endocytosis and may also participate in peptide hormone processing. The serine CPs, as their name indicates, contain a serine residue in the active center essential for catalytic activity that reacts with organophosphorus inhibitors, Prolylcarboxypeptidase (PRCP) (angiotensinase C) and deamidase (cathepsin A, lysosomal protective protein) are discussed here. These two enzymes are highly concentrated in lysosomes: however, they may also be active extracellularly after their release from lysosomes in soluble form or in a plasma membrane-bound complex. Whereas deamidase cleaves a variety of peptides with C-terminal or penultimate hydrophobic residues (e.g. substance P, angiotensin I, bradykinin, endothelin, fMet-Leu-Phe), PRCP cleaves only peptides with a penultimate Pro residue (e.g. des-Arg°-bradykinin, angiotensin II). These enzymes may also be involved in terminating signal transduction by inactivating peptide ligands after receptor endocytosis.     

Cisplatin, continuous-infusion 5-fluorouracil, and intermediate-dose methotrexate in the treatment of unresectable non-small cell carcinoma of the lung.

Forty-one patients with unresectable non-small cell carcinoma of the lung (NSCCL) were treated with cisplatin 20 mg/m2/d for 5 days as a daily bolus injection, 5-fluorouracil 800 mg/m2/d by continuous infusion for 5 days, and intermediate-dose methotrexate 200 mg/m2 on days 15 and 22 of a 28-day cycle (PFM). One complete and 23 partial responses were observed, yielding an overall response rate of 60%. There was no significant difference in response rates based on histologic subtype or extent of disease (locally unresectable versus metastatic). Median duration of response was 6 months, and the median survival of all patients was 10 months. Two patients with unresectable disease at presentation became resectable after chemotherapy and remain disease-free at 46+ and 53+ months. Toxicity was modest, with oral mucositis the major adverse effect. Clinically important neutropenia was uncommon. PFM is an active regimen in NSCCL and deserves further study in the "neoadjuvant" setting.     

Depression by neuropeptide Y of noradrenergic inhibitory postsynaptic potentials of locus coeruleus neurones

Summary Intracellular recordings were performed in a pontine slice preparation of the rat brain containing the locus coeruleus (LC). The spontaneous firing of action potentials was prevented by passing continuous hyperpolarizing current via the recording electrode. Focal electrical stimulation evoked a synaptic depolarization (PSP) followed by a hyperpolarization (IPSP). Neuropeptide Y (NPY; 0.1 mol/l) inhibited the IPSP only. Pressure ejection of noradrenaline produced hyperpolarization which was potentiated in the presence of NPY (0.1 mol/l). Hence, NPY appears to inhibit the release of noradrenaline from dendrites or recurrent axon collaterals of LC neurones. Correspondence to: P. Illes at the above address     

A phase I trial of combination therapy with continuous-infusion PALA and continuous-infusion 5-FU

Summary Thirty-four patients were treated with N-(phosphonacetyl)-l-aspartate (PALA) at a dose of 850 mg/m²/dayx5 by continuous intravenous infusion (days 1–5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300–630 mg/m²/dayx5 by continuous intravenous infusion (days 2–6). Dose-limiting oral mucositis occurred at a 5-FU dose of 560 mg/m²/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and superficial venous phlebitis. Myelosuppression was rare. One partial response was observed in a patient with metastatic colorectal carcinoma. Plasma PALA levels were monitored in seven patients. Steady-state levels were achieved by the 2nd day of drug infusion and ranged between 10 and 20 g/ml.