Frequency-dependent shift from paired-pulse facilitation to paired-pulse depression at unitary CA3-CA3 synapses in the rat hippocampus

Paired recordings between CA3 interconnected pyramidal neurons were used to study the properties of short-term depression occurring in these synapses under different frequencies of presynaptic firing (   n = 22  ). In stationary conditions (0.05-0.067 Hz) pairs of presynaptic action potentials (50 ms apart) evoked EPSCs whose amplitude fluctuated from trial to trial with occasional response failures. In 15/20 cells, paired-pulse ratio (PPR) was characterized by facilitation (PPF) while in the remaining five by depression (PPD). Increasing stimulation frequency from 0.05-0.067 Hz to 0.1-1 Hz induced low frequency depression (LFD) of EPSC amplitude with a gradual increase in the failure rate. Overall, 9/12 cells at 1 Hz became almost 'silent'. In six cells in which the firing rate was sequentially shifted from 0.05 to 0.1 and 1 Hz, changes in synaptic efficacy were so strong that PPR shifted from PPF to PPD. The time course of depression of EPSC1 could be fitted with single exponentials with time constants of 98 and 36 s at 0.1 and 1 Hz, respectively. In line with the inversion of PPR at 1 Hz, the time course of depression of EPSC2 was faster than EPSC1 (7 s). Recovery from depression could be obtained by lowering the frequency of stimulation to 0.025 Hz. These results could be explained by a model that takes into account two distinct release processes, one dependent on the residual calcium and the other on the size of the readily releasable pool of vesicles.     

TGF-beta signaling regulates CD8+ T cell responses to high- and low-affinity TCR interactions

Absence of transforming growth factor-beta (TGF-beta) signaling to T cells in mice results in an increase in T cell numbers, an activated CD44 high, CD69-, CD25- T cell phenotype and a T cell-mediated injury to many organs. It is not known if such T cell activation in the absence of TGF-beta signaling is spontaneous or due to aberrant T cell responses to a physiological stimulus. We used adoptive transfer of CD8+ T cells from mice double transgenic for the OT-1 TCR and the TGF-beta1-dominant negative transgene [OT-dominant-negative receptor (DNR)] to investigate the role of TGF-beta in regulating CD8+ T cell activation in vivo. The activation and expansion of single-transgenic OT and double-transgenic OT-DNR cells to oral antigens, high-affinity and low-affinity peptides were indistinguishable. Activation with high-affinity peptide and CFA however resulted in greater expansion of OT-DNR cells in comparison to OT cells. Low-affinity peptide and adjuvant did not result in OT cell activation or expansion but results in up-regulation of CD44 on OT-DNR cells. These data show that TGF-beta functions in vivo to limit the scale of CD8+ T cell expansion after high-affinity peptide-MHC interactions. TGF-beta also limits T cell activation to the highest affinity peptide-MHC interactions. The increase in T cell number and activation present in TGF-beta-deficient and TGF-beta DNR-expressing mice may be due to the loss of these two phenomena.     

The role of the nasal region in craniofacial growth: An investigation using path analysis

This study focuses on the role of the nasal region and its interactions with adjacent facial elements during early ontogeny. A series of linear measurements, areas and volumes were extracted from a collection of 227 medical CT-scans of children from 0 to 6 years of age. These measurements describe aspects of the form of the orbit, maxilla, peri-alveolar (subnasal) region, nasal area, eye, oral region, masseter, and temporal muscles. Hypothesized interactions were then examined using path analysis. Two paths were designed: the first to investigate potential interactions in, and relative contributions of the nasal derivatives and adjacent regions to overall facial growth and development; the second path sees the addition of facial soft tissue measurements and aims to assess their effects on skeletal components, and on overall facial growth and development. The results of the first path indicate a large contribution of the nasal and subnasal regions to facial development. This indicates that the nasal septum and the developing dentition provide an important but variable contribution to facial ontogeny during early years. This result is confirmed in the second path, where the soft tissue elements were added to the diagram. Results of the second path indicate that the soft tissues contribute only locally to the development of some skeletal elements of the face. This indicates that the contribution of skeletal components has a more direct effect on facial height than soft tissue matrices, however there are complex interactions between soft tissues and skeletal elements throughout ontogeny.     

A synergistic effect of a combined bivalent DNA-protein anti-HIV-1 vaccine containing multiple T- and B-cell epitopes of HIV-1 proteins

Immunogenic properties of the combined vaccine CombiHIVvac, comprising polyepitope HIV-1 immunogens, one being the artificial polyepitope protein TBI, containing the T- and B-cell epitopes from Env and Gag proteins, and the DNA vaccine construct pcDNA-TCI coding for the artificial protein TCI, carrying over 80 T-cell epitopes (both CD4+ CTL and CD8+ Th) from Env, Gag, Pol, and Nef proteins, are studied in this work. The data reported demonstrate clearly that a combination of two B- and T-cell immunogens (TBI and TCI) in one construct results in a synergistic increase in the antibody response to both TBI protein and the proteins from HIV-1 lysate. The level of antibodies induced by immunization with the constructs containing either immunogen alone (TBI protein or the plasmid pcDNA-TCI) was significantly lower as compared to that induced by the combined vaccine. The analysis performed suggests that the presence of CD4+ T-helper epitopes, which can be presented by MHC class II, in the protein TCI may be the main reason underlying the increased synthesis of antibodies to TBI protein due to a CD4-mediated stimulation of B-cell proliferation and differentiation.     

Giant cell tumor of bone express p63.

p63 contributes to skeletal development and tumor formation; however, little is known regarding its activity in the context of bone and soft tissue neoplasms. The purpose of this study was to investigate p63 expression in giant cell tumor of bone and to determine whether it can be used to discriminate between other giant cell-rich tumors. Seventeen cases of giant cell tumor of bone were examined to determine the cell type expressing p63 and identify the isoforms present. Total RNA or cell protein was extracted from mononuclear- or giant cell-enriched fractions or intact giant cell tumor of bone and examined by RT-PCR or western blot, respectively. Immunohistochemistry was used to evaluate p63 expression in paraffin embedded sections of giant cell tumor of bone and in tumors containing multinucleated giant cells, including: giant cell tumor of tendon sheath, pigmented villonodular synovitis, aneurysmal bone cyst, chondroblastoma, and central giant cell granuloma. The mononuclear cell component in all cases of giant cell tumor of bone was found to express all forms of TAp63 (alpha, beta, and gamma), whereas only low levels of the TAp63 alpha and beta isoforms were detected in multinucleated cells; DeltaNp63 was not detected in these tumors. Western blot analysis identified p63 protein as being predominately localized to mononuclear cells compared to giant cells. This was confirmed by immunohistochemical staining of paraffin-embedded tumor sections, with expression identified in all cases of giant cell tumor of bone. Only a proportion of cases of aneurysmal bone cyst and chondroblastoma showed p63 immunoreactivity whereas it was not detected in central giant cell granuloma, giant cell tumor of tendon sheath, or pigmented villonodular synovitis. The differential expression of p63 in giant cell tumor of bone and central giant cell granuloma suggest that these two tumors may have a different pathogenesis. Moreover, p63 may be a useful biomarker to differentiate giant cell tumor of bone from central giant cell granuloma and other giant cell-rich tumors, such as giant cell tumor of tendon sheath and pigmented villonodular synovitis.     

Enhancing encoding of a motor memory in the primary motor cortex by cortical stimulation

Motor training results in encoding of motor memories, a form of use-dependent plasticity. Here we tested the hypothesis that transcranial magnetic stimulation (TMS) synchronously applied to a motor cortex engaged in a motor training task could enhance this plastic process. Healthy volunteers were studied in four sessions: training consisting of performance of directionally specific voluntary thumb movements (Train alone), training with TMS delivered during the execution of the training movement in a strictly temporal relationship to the motor cortex contralateral (Train+TMS synchronous(contra)) and ipsilateral (Train+TMS synchronous(ipsi)) to the training hand, and training with TMS delivered asynchronous to the training movement to the motor cortex contralateral to the training hand (Train+TMS asynchronous(contra)). Train alone, Train+TMS synchronous(contra), and Train+TMS asynchronous(contra) but not Train+TMS synchronous(ipsi) elicited a clear motor memory. The longevity of the encoded memory was significantly enhanced by Train+TMS synchronous(contra) when compared with Train alone and Train+TMS asynchronous(contra). Therefore use-dependent encoding of a motor memory can be enhanced by synchronous Hebbian stimulation of the motor cortex that drives the training task and reduced by stimulation of the homologous ipsilateral motor cortex, a result relevant for studies of cognitive and physical rehabilitation.     

Cystic lesions of the jaws - a clinicopathological study of 322 cases and review of the literature

Three hundred and twenty-two patients (192 male and 130 female) with cystic lesions of the jaw were successfully diagnosed and treated. One hundred and fifty-five (48%) were radicular cysts, 80 (25%) were dentigerous cysts, 23 (7%) were odontogenic keratocyst (=keratocystic odontogenic tumor), 19 (6%) were eruption cysts, 16 (5%) were traumatic bone cysts, and 29 (9%) were non-odontogenic cysts. There were 95 in the pediatric age group (1 month to 16 years) and 227 in the adult age group (17 years and older). Male to female ratio was 1 in the pediatric age group and 1.7 in the adult age group. The treatment modalities were: marsupialization, enucleation, enucleation with bone grafting, or resection. The distribution and characteristics of jaw cysts in children are different from those in adults. In children there is a relatively high rate of developmental cysts, whereas in adults the inflammatory cysts are more common. Following enucleation of a cystic jaw lesion, the entire surgical specimen and not only a biopsy specimen, should be examined histopathologically to prevent any possibility of an intramural squamous cell carcinoma that may be overlooked. The differences in prevalence of each type of jaw cyst during a lifetime may point toward a multifactorial polygenic pattern rather than a monogenic pattern.