Normal and epilepsy-associated pathologic function of the dentate gyrus.

The dentate gyrus plays critical roles both in cognitive processing, and in regulation of the induction and propagation of pathological activity. The cellular and circuit mechanisms underlying these diverse functions overlap extensively. At the cellular level, the intrinsic properties of dentate granule cells combine to endow these neurons with a fundamental reluctance to activate, one of their hallmark traits. At the circuit level, the dentate gyrus constitutes one of the more heavily inhibited regions of the brain, with strong, fast feedforward and feedback GABAergic inhibition dominating responses to afferent activation. In pathologic states such as epilepsy, a number of alterations within the dentate gyrus combine to compromise the regulatory properties of this circuit, culminating in a collapse of its normal function. This epilepsy-associated transformation in the fundamental properties of this critical regulatory hippocampal circuit may contribute both to seizure propensity, and cognitive and emotional comorbidities characteristic of this disease state.

Comparative evaluation of oxidative and antioxidative capacity during high-flux hemodialysis using two different membranes.

AIM: In patients with end-stage renal disease (ESRD) cardiovascular morbidity and mortality are increased. Apart from traditional and uremia-specific factors oxidative stress has been implicated as a main risk factor. This study investigated the influence of two different high-flux hemodialysis membranes on parameters of oxidative stress during a dialysis session. PATIENTS AND METHODS: 14 stable ESRD patients were enrolled in the study and randomly assigned to high-flux hemodialysis using either a polyamide membrane (Polyflux 14; PA group) or a new polysulfone membrane (Diacap Polysulfone HI PS 15; PS group). All patients received 6 treatments with the same membrane. During the 5th treatment parameters of dialysis efficiency, biocompatibility (cell counts, complement C3a, thrombin-antithrombin complex) and oxidative stress (lipid peroxides, total antioxidative capacity) were measured. RESULTS: Parameters of dialysis efficiency and biocompatibility were similar in both treatment groups. At the beginning of the dialysis session both groups showed a low to moderate level of oxidative stress and a reduced total antioxidative capacity as compared to healthy controls. Both parameters deteriorated significantly during the extracorporeal procedure with a similar magnitude in both membrane groups. No correlation between oxidative or antioxidative capacity and parameters of biocompatibility or dialysis efficiency could be found. CONCLUSIONS: Dialysis with synthetic high-flux membranes induces a temporary deterioration of oxidative stress parameters in ESRD patients despite good dialysis efficiency and biocompatibility.

Paradoxical effects of ketamine on the memory of fetuses of different ages.

Brain N-methyl-D-aspartate (NMDA) glutamate receptors have been implicated as important mediators of both learning and neuronal development. The current study investigated how ketamine (a well-known NMDA-receptor blocking drug) influences taste-mediated conditioned motor responses (CMRs) in perinatal rats. Dams pregnant with either embryonic day 18 (E18) or E19 rat fetuses were injected with 0 or 100 mg/kg ketamine HCl (i.p.). One-half hour later, a reversible spinal block was performed on the dam and fetuses received oral lavage with 10 microl, 0.3% saccharin (SAC) or water (control) in utero. After the oral injection, fetuses received either a saline (control) or lithium chloride (LiCl) injection (81 mg/kg, i.p.). The uterus was replaced and, 2 days later (E20 or E21), some rats received oral lavage with SAC. Other litters were born via normal vaginal delivery or Cesarean section and orally exposed to SAC on post-natal day 3 (P3). Motor responses were observed immediately after the oral lavage of SAC. If SAC had been paired with LiCl in utero, pups generally exhibited conditioned suppression of orofacial movements (as compared to controls). Ketamine significantly attenuated this taste-mediated CMR of animals conditioned on E19. However, the same treatments did not disrupt CMRs of rats treated with ketamine before CS-US pairing on E18. Our findings indicate an age-dependent role for NMDA receptors in the formation of CMRs in perinatal rats.

Detection of novelty by perinatal rats.

This study investigated the development of fetal/neonatal rats' ability to distinguish between a novel and familiar taste. Here, we report that neonatal rats alter their orofacial movements (e.g., mouth movements and licks) upon tasting saccharin (SAC) if it was experienced previously. We also sought to determine the origins and duration of this response. Fetuses of embryonic ages E17, E18, or E19 received an oral injection of 10 microL 0.3% SAC while in utero. These animals were then reexposed to SAC on postnatal day 3, (P3) and observations of orofacial motor responses were recorded. Only neonates that first experienced SAC on E19 exhibited a SAC-induced stimulation of mouthing and licking on P3. These data suggested that a taste-recognition memory (TRM) is maintained for up to 5 days (i.e., E19 to P3). However, in this paradigm, the youngest fetuses also have the longest retention interval. Could these data also reflect the limitations of the E17 and E18 fetuses in retaining the TRM? In a second study, we shortened the taste exposure-reexposure interval to 2 days in an attempt to detect the TRM in younger fetuses. As expected, E19 rats exhibited a TRM when tested on E21. However, neither the E17 nor E18 fetuses showed SAC-induced increases in mouthing and licking when tested 2 days after their initial exposure (E19 or E20). Finally, in order to determine whether a TRM could be detected in fetuses as well as neonates (see above), we conducted an additional study wherein E21 fetuses were tested before parturition. Like E21 neonates, E21 rat fetuses that had received SAC on E19 showed a differential response to SAC depending on whether it was novel or familiar. Thus, although E21 fetal orofacial movements were less frequent than those of the E21 neonate, the fetal-testing procedures were not sufficient to obscure the detection of a TRM. In summary, the data indicate that E19 rat fetuses can acquire a TRM and retain it for at least 2-5 days, whereas E17 and E18 fetuses cannot.

Transformation to continuous growth of primary human T lymphocytes by human T-cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector.

The role of the X region of the genome of the human T-cell leukemia virus type I (HTLV-I) in the immortalization of lymphocytes has been difficult to distinguish from its role in viral replication as this region encodes at least two genes, tax and rex, required for replication and the expression of viral proteins. To determine whether the X region does encode immortalizing functions, a fragment of the HTLV-I provirus capable of expressing known X-region proteins was inserted into the genome of a transformation-defective, replication-competent Herpesvirus saimiri. Infection of fresh mitogen-activated human cord blood and thymocytes yielded immortal T-cell lines that had the same phenotype (CD4+, CD5+, HLA class II+, interleukin 2 receptor alpha-chain +) as lymphocytes transformed by cocultivation with HTLV-I. These experiments demonstrate that the X region encodes the functions of HTLV-I that immortalize a distinct subpopulation of human T cells. The experiments also demonstrate the utility of the H. saimiri vector for the transduction of heterologous genes into human T cells.