Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: I. Effects of primary motor cortex rTMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) affects the excitability of the motor cortex and is thought to influence activity in other brain areas as well. We combined the administration of varying intensities of 1-Hz rTMS of the motor cortex with simultaneous positron emission tomography (PET) to delineate local and distant effects on brain activity. METHODS: Ten healthy subjects received 1-Hz rTMS to the optimal position over motor cortex (M1) for producing a twitch in the right hand at 80, 90, 100, 110, and 120% of the twitch threshold, while regional cerebral blood flow (rCBF) was measured using H(2)(15)O and PET. Repetitive transcranial magnetic stimulation (rTMS) was delivered in 75-pulse trains at each intensity every 10 min through a figure-eight coil. The regional relationship of stimulation intensity to normalized rCBF was assessed statistically. RESULTS: Intensity-dependent rCBF increases were produced under the M1 stimulation site in ipsilateral primary auditory cortex, contralateral cerebellum, and bilateral putamen, insula, and red nucleus. Intensity-dependent reductions in rCBF occurred in contralateral frontal and parietal cortices and bilateral anterior cingulate gyrus and occipital cortex. CONCLUSIONS: This study demonstrates that 1-Hz rTMS delivered to the primary motor cortex (M1) produces intensity-dependent increases in brain activity locally and has associated effects in distant sites with known connections to M1.     

Application of intermaxillary fixation screws in maxillofacial trauma.

PURPOSE: The use of intermaxillary fixation (IMF) in the treatment of maxillofacial trauma represents the cornerstone of fracture reduction and immobilization. Many modalities of IMF have been described; recently IMF screws have been introduced into clinical practice, however, hardware failure can occur. We performed a retrospective study evaluating hardware-associated complications for self-drilling/tapping IMF screws. MATERIALS AND METHODS: A retrospective study on 49 patients requiring IMF was performed. The diagnosis, duration of IMF, screw site, use of elastic or wire fixation, and associated complications were recorded. IMF screws were used to adjunct open reduction techniques, for definitive closed reduction, or fracture prevention following dentoalveolar surgery. Follow-up examinations were performed until fracture healing was complete (6 to 8 weeks). RESULTS: A single adverse event occurred in 19 patients (39%) while 4 patients (8%) had more than 1 complication. The most common event was screw loosening; 29% of patients had at least 1 screw dislodged in the treatment period. Of the total number of screws placed (229), 15 (6.5%) became loose, and were equally distributed among the mandible and maxilla. The remaining complications noted were root fracture, 4% (2 of 49); loosened wires, 6% (3 of 49); screw shear, 2% (1 of 49); malocclusion, 2% (1 of 49); and ingested hardware, 2% (1 of 49). CONCLUSIONS: Overall the IMF self-drilling/tapping screws have been shown to be a useful modality to establish maxillomandibular fixation. It is a safe, and time-sparing technique; however, it is not without limitations or potential consequences which the surgeon must be aware of in order to provide safe and effective treatment.     

Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation.

To elucidate the mechanism(s) by which Vav3, a new member of the Vav family proteins, participates in B cell antigen receptor (BCR) signaling, we have generated a B cell line deficient in Vav3. Here we report that Vav3 influences phosphoinositide 3-kinase (PI3K) function through Rac1 in that phosphatidylinositol-3,4,5-trisphosphate (PIP3) generation was attenuated by loss of Vav3 or by expression of a dominant negative form of Rac1. The functional interaction between PI3K and Rac1 was also demonstrated by increased PI3K activity in the presence of GTP-bound Rac1. In addition, we show that defects of calcium mobilization and c-Jun NH2-terminal kinase (JNK) activation in Vav3-deficient cells are relieved by deletion of a PIP3 hydrolyzing enzyme, SH2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP). Hence, our results suggest a role for Vav3 in regulating the B cell responses by promoting the sustained production of PIP3 and thereby calcium flux.     

Restoring and preserving trust in biomedical research.

Recent media depictions of the dangers of biomedical research have fueled public and regulatory scrutiny of academic research institutions. The authors argue that if these institutions are to preserve the trust that the public has historically bestowed upon them, they must go beyond mere compliance with regulatory mandates. Several steps are suggested that institutions can take to strengthen and supplement ongoing compliance efforts, steps the authors believe will bolster the public's confidence in the integrity of academic research institutions. These steps grow out of the authors' analysis of three key components of institutional trustworthiness: (1) shared goals between research institutions and the communities they serve, (2) robust institutional oversight of research activities, and (3) training programs that build professional character. The authors' recommendations include the use of research advisory councils to assure the public that research goals reflect community interests, more collaborative relationships between institutional review boards and members of investigative teams, and educational programs that emphasize the importance of professional integrity in biomedical research. These efforts will help preserve public confidence that an institution's research priorities are appropriate and that the research it conducts is ethical. Preserving this public trust is central to the long-term success of biomedical research and the institutions in which such research takes place.     

Heat shock protein hsp72 induction in cortical and striatal astrocytes and neurons following infarction

Transient global and transient focal ischemia induced the 72 kDa heat shock protein (hsp72) in neurons in cortex, striatum, and other regions known to be injured during transient ischemia. A novel finding was the induction of hsp72 in islands (cylinders in three dimensions) of cells composed of astrocytes around the perimeter and neurons in the interior. Since histology showed pale staining in these regions, it is proposed that these islands represent areas of focal infarction in the distribution of small cortical and lenticulostriate arteries. Although the factors responsible for hsp72 induction during ischemia and infarction are unknown, these results suggest differences in mechanisms of hsp72 induction in astrocytes compared to neurons.     

Adeno-associated virus vector-mediated systemic delivery of IFN-beta combined with low-dose cyclophosphamide affects tumor regression in murine neuroblastoma models.

PURPOSE: Type I IFNs (IFN-alpha/beta) have shown significant antitumor activity in preclinical models but limited efficacy and significant toxicity in clinical trials. We hypothesized that the antitumor activity of type I IFNs could be enhanced by chronic, low-dose systemic delivery and sought to test this in murine neuroblastoma models. EXPERIMENTAL DESIGN: Continuous liver-generated expression of human IFN-beta (hINF-beta) was achieved through a gene therapy-mediated approach using adeno-associated virus vectors encoding hIFN-beta (AAV hINF-beta). Orthotopic localized retroperitoneal and disseminated models of neuroblastoma were established using three different xenografts. Immunohistochemical analysis and ELISA were used to evaluate the antiangiogenic effect of therapy. RESULTS: The development of both localized orthotopic (retroperitoneal) and disseminated neuroblastoma was prevented in all mice expressing hINF-beta. Continued growth of established retroperitoneal tumors, treated with AAV hINF-beta as monotherapy, was significantly restricted, and survival for mice with established, disseminated disease was significantly prolonged following administration of AAV hINF-beta. Analysis of treated tumors revealed a significant antiangiogenic effect. Mean intratumoral vessel density was diminished and expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor were both decreased. Finally, combination therapy in which AAV hIFN-beta was used together with low-dose cyclophosphamide resulted in regression of both established retroperitoneal and disseminated disease. CONCLUSIONS: AAV-mediated delivery of hIFN-beta when used as monotherapy was able to restrict neuroblastoma growth due in part to inhibition of angiogenesis. When used in combination with conventional chemotherapy, AAV hIFN-beta was able to effect complete tumor regression.