Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity.

The NMDA receptor has been widely investigated in recent years as a target for the pharmacological management of seizures, pain and a variety of neurological disorders. Its role in normal central nervous system (CNS) activity and development, as well as in the development of CNS abnormalities and neurodegeneration has also been of interest. The NMDA receptor is one of three pharmacologically distinct subtypes of ionotropic receptor channels that are sensitive to the endogenous excitatory amino acid, L-glutamate. The ontogeny of the NMDA receptor, a multiple tetrameric and heteromeric channel complex with at least six known subunits, is controlled by three gene families and varies in developmental profile with species and regional brain area. NMDA receptors play a role in excitatory synaptic transmission, in the activity-dependent synaptic plasticity underlying learning and memory, and in pre- and postnatal CNS development, including brain cell differentiation, axonal growth and degeneration of unused neurons. The results of recent studies suggest that sustained alteration of NMDA receptor activation during critical periods of development may have deleterious effects on normal CNS development and function. Neonatal rats administered the NMDA receptor antagonists 2-amino-5-phosphonovalerate (AP5) and MK-801 during the first two weeks of life develop abnormal axonal arborization in the retinal connections to the superior colliculus, interfering with normal visual responses. Results from monkey studies suggest that chronic developmental exposure to high doses of a NMDA antagonist, remacemide, has pronounced and long-lasting effects on learning. Recent findings indicate that if NMDA receptors are blocked during a specific period in neonatal life (first two weeks postnatally in the rat), massive apoptotic neurodegeneration results, due not to excitotoxic overstimulation of neurons but to deprivation of stimulation. These observations require further laboratory evidence and support in order to establish their relevance to drug-induced human neurodevelopmental concerns. It is necessary to investigate the relevance of these findings in other animal species in addition to the rat, most notably, nonhuman primates, where neuronal cytoarchitecture and development are significantly different than the rodent but more like the human.     

Dystrophic calcification and mineralization during bone induction: biochemical differences

The calcification of implants of glutaraldehyde-cross linked collagenous tissues and collagen was studied in young and old rats and compared to bone induction by non-crosslinked osteogenically active demineralized bone matrix (DBM). Glutaraldehyde-crosslinked implants of DBM, tendon, and cartilage calcified in young but not in old animals and accumulated only trace amounts of BGP (Bone Gla protein, osteocalcin). Alkaline phosphatase activity and BGP was high in implants of DBM and undetectable in crosslinked implants. To try and understand why bone formation is so significantly reduced in older Fischer 344 rats, we developed a system which consists of cylinders of DBM sealed at the ends with a Millipore filter. Cells originating from 20 day old embryo donors were introduced into the chambers prior to subcutaneousmplantation. After 4 weeks of implantation in 26 month old rats, the cylinders containing embryonic calvaria or muscle cells were found to be full of bone and/or cartilage.     

Multiple behavioral effects of diazepam in rhesus monkeys

The acute effects of diazepam (Valium) were assessed using a battery of complex food-reinforced operant tasks that included responding in delayed matching to sample (DMTS, n = 5), conditioned position response (CPR, n = 7) progressive ratio (PR, n = 8), temporal response differentiation (TRD, n = 4), and incremental repeated acquisition (IRA, n = 9) tests. Diazepam (0.25-4.0 mg/kg IV) produced significant dose-dependent decreases in the number of reinforcers obtained in the TRD and IRA tasks only. TRD accuracy was significantly decreased at doses of 0.25, 1.0, 2.0, and 4.0 mg/kg when compared to vehicle injections. Significant decreases in IRA accuracy generally did not occur at doses below 1.0 mg/kg. DMTS accuracy was decreased at 0.5 mg/kg for some time delays but showed no clear dose-delay interaction. Performance in the CPR and PR tests showed no significant effects of diazepam exposure over the dose range tested. These results indicate that diazepam selectively disrupts performance of operant tasks in monkeys designed to model human correlates of time perception, learning ability and visual attention/short-term memory while not affecting tasks designed to model motivation and position/color discrimination.     

A comparison of interoceptive and exteroceptive discrimination in the pigeon

In pigeons performing a conditional discrimination under a second-order, color-tracking procedure, stimulus control of responding was established using a blinking versus a nonblinking light as exteroceptive stimuli (light-discrimination group). Another group performing under the same second-order schedule of reinforcement was trained to discriminate the interoceptive stimuli produced by an IM injection of 1.5 mg/kg phencyclidine (PCP) versus saline (drug-discrimination group). In the drug-discrimination group, administration of PCP or pentobarbital resulted in dose-dependent increases in PCP-appropriate responding, while, in general, d-amphetamine did not result in appreciable drug-appropriate responding. In the light-discrimination group, all three drugs over the same dose ranges resulted in decreased discriminative control over responding. In both groups, doses of PCP and pentobarbital which resulted in intermediate (30 to 70%) levels of stimulus-appropriate responding were associated with responding at a single key position rather than tracking a key color. In contrast, intermediate responding after d-amphetamine administration was not associated with position responding in either group. These results emphasize the similarity between discriminative control maintained by interoceptive drug stimuli and exteroceptive visual stimuli.     

Le traitement des cancers de la prostate hormonorésistants

Two recent randomized Phase-III studies (TAX 327 and SWOG 9916) have demonstrated that Docetaxel improved the survival rate of patients with hormone-resistant prostate cancer. Other drugs such as Mitoxantrone, Vinorelbine, Saraplatin and Epothilone are recommended as second-line treatment where Docetaxel treatment has failed. Treatment with Atrasentan, an endothelin-receptor antagonist, or other inhibitors of angiogenesis combined with Docetaxel is presently under evaluation. Zoledronic acid, alone or in association with chemotherapy, and the use of radioisotopes (strontium-89, samarium 153 and radium 223) are palliative treatment options for multiple painful bone metastases in hormone-resistant cancer. Collectively, these treatment options reduce the risk of mortality, prevent the complications associated with disease progression and improve the patients' quality of life. Better understanding of the alternative pathways for androgen receptor signaling, the role of estrogen receptors, cytokines and stromal growth factors contributing to hormone resistance may lead to new treatment strategies.     

Molar absorptivities of bilirubin (NIST SRM 916a) and its neutral and alkaline azopigments

Three laboratories in the U.S. and two in the Netherlands determined molar absorptivities (epsilon) of Standard Reference Material (SRM) 916a Bilirubin from the National Institute of Standards and Technology. In caffeine reagent the average epsilon values were 50,060 and 48, 980 L.mol-1.cm-1 at 432 and 457 nm, respectively. The epsilon value of the blue azopigment, obtained with the Reference Method for total serum bilirubin, was 76,490 L.mol-1.cm-1 at 598 nm. When the addition of alkaline tartrate was omitted, the molar absorptivity of the red azopigment was 56,600 L.mol-1.cm-1 at 530 nm.     

Direct detection of Staphylococcus aureus from adult and neonate nasal swab specimens using real-time polymerase chain reaction

Nasal carriage of Staphylococcus aureus is considered a source of subsequent infection in health care settings. Utilization of real-time polymerase chain reaction (PCR) for detection of S. aureus has the potential to dramatically affect infection control practice by rapidly identifying S. aureus-colonized patients. We developed and validated the use of real-time PCR for detection of S. aureus colonization in two patient populations. Paired nasal swabs were collected from 299 neonates and from 151 adult patients at Evanston Hospital. One swab was used for culture and the other placed into a bacterial lysis solution containing achromopeptidase. The DNA liberated was used as the template for real-time PCR with primers for the femA gene. SYBR Green was used for amplicon detection. In the neonatal population the sensitivity, specificity, predictive value positive and predictive value negative for culture and PCR was 92% versus 96%, 100% versus 100%, 100% versus 100%, and 98% versus 99%, respectively. In the adults the results were 90% versus 100%, 100% versus 98%, 100% versus 96%, and 95% versus 100%, respectively. Real-time PCR was able to detect S. aureus in 2 hours compared to 1 to 4 days for culture and provided sensitivity equal to or greater than culture.     

Low oral doses of bisphenol A increase volume of the sexually dimorphic nucleus of the preoptic area in male, but not female, rats at postnatal day 21

Perinatal treatment with relatively high doses of bisphenol A (BPA) appears to have little effect on volume of the rodent sexually dimorphic nucleus of the preoptic area (SDN-POA). However, doses more relevant to human exposures have not been examined. Here, effects of pre- and post-natal treatment with low BPA doses on SDN-POA volume of postnatal day (PND) 21 Sprague–Dawley rats were evaluated. Pregnant rats were orally gavaged with vehicle, 2.5 or 25.0 μg/kg BPA, or 5.0 or 10.0 μg/kg ethinyl estradiol (EE₂) on gestational days 6–21. Beginning on the day after birth, offspring were orally treated with the same dose their dam had received. On PND 21, offspring (n = 10–15/sex/group; 1/sex/litter) were perfused and volume evaluation was conducted blind to treatment. SDN-POA outline was delineated using calbindin D28K immunoreactivity. Pairwise comparisons of the significant treatment by sex interaction indicated that neither BPA dose affected female volume. However, females treated with 5.0 or 10.0 μg/kg EE₂ exhibited volumes that were larger than same-sex controls, respectively (p < 0.001). Males treated with either BPA dose or 10.0 μg/kg/day EE₂ had larger volumes than same-sex controls (p < 0.006). These data indicate that BPA can have sex-specific effects on SDN-POA volume and that these effects manifest as larger volumes in males. Sensitivity of the methodology as well as the treatment paradigm was confirmed by the expected EE₂-induced increase in female volume. These treatment effects might lead to organizational changes within sexually dimorphic neuroendocrine pathways which, if persistent, could theoretically alter adult reproductive physiology and socio-sexual behavior in rats.