Faculty Bibliography

OBJECTIVE: This article describes the Center for Outcome Measurement in Brain Injury (COMBI), an Internet resource that provides information on brain injury outcome measures. Funded by the National Institute on Disability and Rehabilitation Research (NIDRR), the COMBI is a collaborative project of eight Traumatic Brain Injury (TBI) Model System centers. Information the COMBI provides includes rating scales and form(s) syllabus and administration guidelines, descriptions of properties, references in the literature, a frequently asked questions (FAQ) section, training and testing materials, and contact information. CONCLUSIONS: As a dissemination effort, the results of the COMBI project have been outstanding with over 1,500 users accessing information every month. The project has a truly international scope, with 20% of its users being outside the United States

A review of saphenectomy site complications following lower extremity revascularization was conducted. Leg incisions used for 133 consecutive infrainguinal bypass procedures were categorized by location. Patient and procedural risk factors were analyzed for risk of wound complications. Procedure, limb and patient outcome were reported via life table analysis. Incisional wound complications followed 32/133 procedures (24%), including 15 groin, eight saphenectomy, five distal and four vein/distal incisions. There were five grade I and three grade II saphenectomy complications. Only weight (body mass index) predicted the likelihood of wound complication (P < 0.05). The 6-month primary patency rate was 79% (mean follow-up 22 months). Four-year assisted primary patency, limb salvage and survival rates were 75, 87 and 57%, respectively. Most bypass-related wound complications (24/32, 75%) involve arterial access incisions. Incisional complications are related to body mass index. Only 6% of GS vein bypass procedures develop saphenectomy site complications. Limiting saphenectomy size may not significantly reduce incisional morbidity following bypass grafting

OBJECTIVE: This study was conducted to stimulate respiratory muscles by functional magnetic stimulation (FMS) of the spinal nerves (T1-L5) to obtain maximum expiratory function. DESIGN: A prospective before and after trial. SETTING: Functional Magnetic Stimulation Laboratory, Spinal Cord Injury Service, VA Palo Alto Health Care System, Palo Alto, CA. PARTICIPANTS: Twelve normal able-bodied subjects. INTERVENTION: A commercially available magnetic stimulator with a round magnetic coil (MC) was used. Respiratory muscle activation was achieved by placing the MC at each spinous process ranging from T1 to L5 vertebral levels. MAIN OUTCOME MEASURE: The planned major outcome was to determine the optimal MC placement for producing maximal expiratory pressure (MEP) and expiratory reserve volume (ERV) by FMS. These measurements were compared with the subjects' voluntary maximal efforts. A profile with varying stimulation intensities was also obtained in select individuals for determining the highest expiratory pressure. RESULTS: Stimulation at the T9 spinal level resulted in the highest mean MEP and ERV. Stimulation between T8 and L5 produced similar MEP and ERV as obtained from the T9 MC placement. The mean maximum MEP and ERV produced by FMS were 76.8 +/- 6.4 cm H2O (7.52 +/- 0.62 kPa) and 1.28 +/- 0.15 L, which were 67% and 79% of the subjects' voluntary maximal efforts, respectively. A stimulation intensity of 80% resulted in the highest expiratory pressure. CONCLUSION: FMS of lower thoracic and lumbar regions produced significant expiratory pressures and volumes. FMS of the expiratory muscles may prove to be a valuable technique for restoring cough in patients with spinal cord injury or other neurologic diseases, and in critical care or perioperative settings

In recent years, we have been pursuing our mapping investigations of the substrate for brain-stimulation reward in regions of the anterior hypothalamic and lateral preoptic areas. However, one problem is that stimulation of these sites often generates overt seizures so that their suppression via a pharmacological means would be very useful. The sedative-hypnotic benzodiazepine, brotizolam, is reportedly a long-lasting anticonvulsant. Hence, its effects on motor seizures elicited from stimulation of the lateral preoptic area were evaluated in the first experiment. Both tested doses (5.0 and 7.5 mg/kg) of the drug were shown to significantly decrease the number, and marginally, the severity of stimulation-induced seizures; furthermore, this effect was relatively long lasting, up to about 3 h. The higher dose of brotizolam did not alter the single-pulse thresholds for self-stimulation, a requirement for evaluations of poststimulation excitability, the purpose of the second experiment. Here, our interest was in documenting whether the membrane properties of the stimulated neurons, as assessed by refractory periods, were altered by brotizolam. No differences in the time course of recovery were observed; refractoriness began between 0.4 and 0.8 ms, and reached 50% recovery by 2.0 ms, which is consistent with the pattern of poststimulation excitability typically measured at these sites. Thus, in addition to its long-lasting suppression of motor seizures in rats, brotizolam does not alter the time course of recovery from refractoriness of the neurons that mediate brain-stimulation reward in the lateral preoptic area

Bombesin's purported role in satiety mechanisms prompted this investigation of its effects on thresholds for stimulation-induced feeding and self-stimulation in the rat. Single electrodes were implanted in the lateral hypothalamus and the ability of each electrode to support self-stimulation and stimulation-induced feeding was evaluated at four current levels between 80 and 320 microA. The frequency thresholds associated with each current value were assessed following four intraperitoneal doses of bombesin, 2, 4, 8, and 16 micrograms/kg, as well as a saline dose. Bombesin increased the thresholds for stimulation-induced feeding at doses known to reduce food intake without influencing self-stimulation thresholds. From these findings we conclude that (1) the effects of peripheral bombesin on stimulation-induced feeding are analogous to its effects on normal feeding and (2) the data provide additional evidence for a pharmacological dissociation between stimulation-induced feeding and reward

Biochemical and immunofluorescence analyses revealed that phosphodiesterase variants encoded by the PDE4D gene are targeted to discrete subcellular structures. In quiescent FRTL-5 thyroid cells, the rolipram-sensitive phosphodiesterase (PDE) activity (cAMP-PDE) was recovered both in the soluble and particulate fractions of the homogenate. Although an immunoreactive 93-kDa PDE (PDE4D3) variant was recovered in both compartments, a 105-kDa variant with the properties of PDE4D4 was recovered mostly in the particulate fraction. The PDE4D3 form was readily solubilized with nonionic detergents. Conversely, the PDE4D4 form required buffers containing ionic detergents for extraction, suggesting that different mechanisms target these variants to insoluble structures. A 15-min stimulation with thyroid-stimulating hormone (TSH) led to an activation of the cAMP-PDE in both compartments and was correlated with a shift in electrophoretic mobility of the PDE4D3 polypeptide. Long term incubation with TSH caused an increase of the PDE activity in the soluble fraction and the appearance of a 68-kDa immunoreactive polypeptide with the properties of PDE4D2. Immunofluorescence analysis showed, in addition to diffuse staining, a signal localized on regions adjacent to the plasma membrane on cytoskeletal structures and in a perinuclear region of quiescent cells. Long term incubation with TSH caused an increase in the immunofluorescence signal in the soluble compartment. These data demonstrate that three PDE4D splicing variants are targeted to discrete subcellular compartments and that hormones cause the activation of these isoforms in a temporally and spatially dependent manner

To determine the properties of the cAMP-specific, rolipram-sensitive phosphodiesterases (cAMP-PDEs) that are expressed in different organs, monoclonal and polyclonal antibodies were raised against different epitopes present in the cAMP-PDE sequences. Of the several antibodies generated against peptides and fusion proteins, one monoclonal and four polyclonal antibodies recognized both the native cAMP-PDEs as well as the denatured proteins on Western immunoblot analysis. An immunoprecipitation assay demonstrated that these antibodies recognized the recombinant rat PDE4A, PDE4B, and PDE4D proteins with different avidity. The polyclonal antibody K118 and the monoclonal M3S1 were most specific for rat PDE4B and PDE4D forms, respectively, whereas the AC55 antiserum displayed the highest affinity for PDE4A forms. This selectivity was confirmed by Western blot analysis using recombinant rat PDE4A, PDE4B, and PDE4D proteins expressed in a heterologous system. These antibodies were used to characterize the cAMP-PDEs expressed in the rat brain. An immunoblot of extract of cortex and cerebellum demonstrated that at least seven different polypeptides specifically cross-reacted with the different antibodies, indicating that multiple cAMP-PDEs are expressed in this tissue. On the basis of cross-reactivity with PDE4D but not PDE4A or PDE4B antibodies, 93- and 105-kDa PDE4D species were detected in the cortex and cerebellum extract. These forms are different from the 68-kDa PDE4D form expressed in endocrine cells after hormonal stimulation. Although the 93-kDa form was recovered in both the soluble and particulate fractions, the 105-kDa polypeptide was mostly particulate in the cortex and cerebellum extracts. PDE4B forms of 90-87 kDa were recovered in both soluble and particulate compartments of the brain extract. These forms were different from the previously identified PDE4A variants of 110 and 75 kDa. These data demonstrate that the presence of multiple cAMP-PDE genes is translated into cAMP-PDE proteins of different sizes and distinct immunological properties and that multiple variants derived from these cAMP-PDE genes are expressed in different regions of the brain and different subcellular compartments. These immunological tools will be useful to identify different cAMP-PDE forms expressed in organs targeted for pharmacological intervention with PDE4 inhibitors

Reproductive function in all vertebrates is controlled by the brain-pituitary-gonadal axis. In teleost fish, endocrine cells within the adenohypophysis are grouped together and each collection of cells is innervated by specific neuropeptide fibers. An important regulatory step in reproductive control is gonadotropin-releasing hormone (GnRH), whose delivery to the pituitary is responsible for its release of gonadotropins. The hormone GnRH has been shown to play a critical role in the social control of reproduction in a teleost fish, Haplochromis burtoni. However, there has been no direct evidence that the preoptic area GnRH neurons project to the pituitary. In this study, we used a retrograde tracer and immunohistochemistry to identify those GnRH containing neurons that project to the adenohypophysis. We compared reproductively active territorial males with quiescent non-territorial males to discover whether the connectivity of the preoptic area GnRH neurons depends on the reproductive status of the male. We found that, irrespective of reproductive status, most GnRH neurons in the preoptic area project to the pituitary and that all of these GnRH neurons show the soma size change that has been associated with reproductive status in Haplochromis burtoni. Based on these data, we propose that there is a single population of GnRH containing cells in the preoptic area that change size as a function of reproductive state and that this entire population projects to the pituitary. This is the first direct demonstration that this essential circuit, linking GnRH neurons in the preoptic area to the pituitary, exists

The effect of diazepam on the trade-off function between current and frequency for stimulation-induced feeding was evaluated in five rats with electrodes implanted in medial forebrain bundle structures. Three of the five exhibited stimulation-induced feeding (SIF) in vehicle tests, while in the remaining two attention to food was interspersed with periods of high activity. In all cases diazepam facilitated stimulation-induced feeding; the expression of stimulation-induced feeding was observed at a dose of 2.5 mg/kg and 5.0 mg/kg, where tested, and frequency threshold shifts ranged from 10% to 25%. The degree of facilitation was consistent across currents in two of the four pairs of trade-off functions examined. The results suggest that diazepam can facilitate stimulation-induced feeding and its expression in feeding sites with a competing arousal component