Faculty Bibliography

We evaluate the effects of adjuvant treatment with the angiogenesis inhibitor Avastin (bevacizumab) on pathological tissue specimens of high-grade glioma. Tissue from five patients before and after treatment with Avastin was subjected to histological evaluation and compared to four control cases of glioma before and after similar treatment protocols not including bevacizumab. Clinical and radiographic data were reviewed. Histological analysis focused on microvessel density and vascular morphology, and expression patterns of vascular endothelial growth factor-A (VEGF-A) and the hematopoietic stem cell, mesenchymal, and cell motility markers CD34, smooth muscle actin, D2-40, and fascin. All patients with a decrease in microvessel density had a radiographic response, whereas no response was seen in the patients with increased microvessel density. Vascular morphology showed apparent 'normalization' after Avastin treatment in two cases, with thin-walled and evenly distributed vessels. VEGF-A expression in tumor cells was increased in two cases and decreased in three and did not correlate with treatment response. There was a trend toward a relative increase of CD34, smooth muscle actin, D2-40, and fascin immunostaining following treatment with Avastin. Specimens from four patients with recurrent malignant gliomas before and after adjuvant treatment (not including bevacizumab) had features dissimilar from our study cases. We conclude that a change in vascular morphology can be observed following antiangiogenic treatment. There seems to be no correlation between VEGF-A expression and clinical parameters. While the phenomena we describe may not be specific to Avastin, they demonstrate the potential of tissue-based analysis for the discovery of clinically relevant treatment response biomarkers

BACKGROUND: The perioperative course of patients undergoing intracranial surgery is frequently complicated by hypertensive episodes. Dexmedetomidine (DEX), an alpha-2 adrenoreceptor agonist, is gaining popularity in neuroanesthesia, because its sympatholytic and antinociceptive properties may improve hemodynamic stability at critical moments of surgery. We designed this study to assess the efficacy of DEX in controlling hypertensive responses in patients undergoing intracranial surgery. METHODS: Patients scheduled for elective craniotomy were randomly assigned to receive either sevoflurane-opioid or sevoflurane-opioid-DEX anesthesia. Bispectral index was used to maintain a similar level of hypnosis in both groups (40-50). Opioids, sevoflurane, and vasoactive medications were titrated in a routine manner, at the discretion of the blinded anesthesiologist managing the case, to maintain systolic blood pressure (SBP) targeted within 90-130 mm Hg and heart rate (HR) between 50 and 90 bpm. Hemodynamic variables were continuously recorded and stored on a computer for analysis. Efficacy of the anesthetic technique in controlling SBP or HR is inversely proportional to the area under the curve (AUC) outside the targeted range. Areas under the curves above and below targeted ranges for SBP-time (AUCsbp mm Hg*min/h) and HR-time (bpm*min/h) were compared. Coefficient of variation was used to assess hemodynamic stability. RESULTS: Seventy-two patients were recruited for the study. Computerized records of 56 patients only were analyzed because of technical problems with data collection in 14 cases. AUCsbp for above the targeted range was significantly lower for patients in the DEX group (P=0.044). The coefficient of variation for SBP or HR did not differ between groups. A significantly smaller proportion of patients in the DEX group required treatment with antihypertensive medications (12 of 28, 42% vs 24 of 28, 86%, P=0.0008). The DEX group required fewer opioids in the intraoperative period, but there were no differences in the use of sevoflurane. In the postanesthesia care unit, patients in the DEX group had fewer hypertensive episodes (1.25+/-1.55 vs 2.50+/-2.00, P=0.0114) and were discharged earlier (91+/-17 vs 130+/-27 min, P<0.0001). There were no differences in the requirement for postoperative opioids or antiemetics. CONCLUSIONS: By using indices, which assess a global hemodynamic stability of the anesthetic, we determined that intraoperative DEX infusion was effective for blunting the increases in SBP perioperatively. The use of DEX did not increase the incidence of hypotension or bradycardia, common side effects of the drug

This article describes results on using steered molecular dynamics (SMD) simulations and experimental single molecule force spectroscopy (SMFS) to investigate the relationship between hydrogen bonding and mechanical stability of a series of homodimeric beta-sheet mimics. The dimers consisting of 4, 6, and 8 H-bonding sites were modeled in explicit chloroform solvent and the rupture force was studied using constant velocity SMD. The role of solvent structuring on the conformation of the dimers was analyzed and showed no significant contribution of chloroform molecules in the rupture event. The simulated stability of the dimers was validated by force data obtained with atomic force microscopy (AFM)-based SMFS in toluene. The computational model for the 8H dimer also offered insight into a possible mismatched dimer intermediate that may contribute to the lower than expected mechanical stability observed by single molecule AFM force studies. In addition, atomic level analysis of the rupture mechanism verified the dependence of mechanical strength on pulling trajectory due to the directional nature of chemical bonding under an applied force. The knowledge gained from this basic study will be used to guide further design of modular polymers having folded nanostructures through strategic programming of weak, non-covalent interactions into polymer backbones

OBJECTIVE: To determine the applicability and external validity of randomized control studies (RCTs) in the light of patient susceptibilities and vulnerabilities to the sequelae of otitis media with effusion (OME) and tonsillar pharyngitis (T&A) and the composition of their cohorts. STUDY DESIGN: RCTs for OME and T&A were analyzed to determine which intrinsic and extrinsic susceptibilities to the otolaryngic disease and its sequelae were included or excluded and the composition of the cohort. METHODS: A Medline and a Science Direct search were performed for all RCTs concerning OME and T&A through 2007. The articles selected to be included in this study are the OME RCTs that reported language and/or hearing outcomes and the T&A RCT studies in which the outcome measure was infection, alleviation of airway obstruction, and/or quality of life. These were analyzed for their inclusion or exclusion of intrinsic and extrinsic susceptibilities to the otolaryngic disease and their sequelae and the composition of the cohort. The pertinent otolaryngologic literature was assessed to determine applicable risk factors. RESULTS: The analysis of the inclusion or exclusion of risk factors showed that for OME 0 percent were included and 16 percent were excluded, and there were no data for 84 percent. The T&A findings were similar in that 1 percent of risk factors were included, 8 percent excluded, and there were no data for 92 percent. Both the OME and the T&A cohorts data were similar in that approximately half of the suitable candidates completed the study; 25 percent of the OME and 13 percent of the T&A enrolled subjects were either withdrawn or placed into a different experimental group. On the average, with data available, it took 4.6 years to recruit the OME sample and 5.5 years to recruit the T&A sample. CONCLUSION: The results of RCTs for these conditions are only applicable to narrowly defined and highly circumscribed populations. They cannot be generalized to the entire patient population because of their limited external validity. Future RCT protocols should be designed to control for the intrinsic and extrinsic susceptibilities that result in a propensity to acquire the disease and/or an exacerbation of the disease's sequelae. These studies would determine the most effective strategies for preventing disorders and/or their deleterious sequelae.

An important topic in the evolution of language is the kinds of grammars that can be computed by humans and other animals. Fitch and Hauser (F&H; 2004) approached this question by assessing the ability of different species to learn 2 grammars, (AB)(n) and A(n) B(n) . A(n) B(n) was taken to indicate a phrase structure grammar, eliciting a center-embedded pattern. (AB)(n) indicates a grammar whose strings entail only local relations between the categories of constituents. F&H's data suggest that humans, but not tamarin monkeys, learn an A(n) B(n) grammar, whereas both learn a simpler (AB)(n) grammar (Fitch & Hauser, 2004). In their experiments, the A constituents were syllables pronounced by a female voice, whereas the B constituents were syllables pronounced by a male voice. This study proposes that what characterizes the A(n) B(n) exemplars is the distributional regularities of the syllables pronounced by either a male or a female rather than the underlying, more abstract patterns. This article replicates F&H's data and reports new controls using either categories similar to those in F&H or less salient ones. This article shows that distributional regularities explain the data better than grammar learning. Indeed, when familiarized with A(n) B(n) exemplars, participants failed to discriminate A(3) B(2) and A(2) B(3) from A(n) B(n) items, missing the crucial feature that the number of As must equal the number of Bs. Therefore, contrary to F&H, this study concludes that no syntactic rules implementing embedded nonadjacent dependencies were learned in these experiments. The difference between human linguistic abilities and the putative precursors in monkeys deserves further exploration.

PURPOSE: Head and neck neoplasms requiring surgical resection of the mandible can have negative consequences on patient quality of life. For patients with segmental resections, the vascularized fibular free flap and nonvascularized iliac crest are frequently used. The fibula has surpassed the iliac crest in popularity due to the success associated with a vascularized graft; however, there still remain significant advantages with the nonvascularized graft. There has not been a study comparing the quality of life associated with these two methods of mandibular reconstruction. We carried out the following study to compare quality of life of both grafts in an attempt to help guide therapeutic decisions. PATIENTS AND METHODS: Twenty-nine patients at the University of California, San Francisco undergoing mandibular resection with subsequent reconstruction with either a vascularized fibular free flap or nonvascularized iliac crest bone graft were identified. Patient quality of life was assessed with a modified version of the University of Washington Quality of Life Questionnaire, version 4. RESULTS: Eighteen patients responded (10 reconstructed previously with a fibula, 8 with iliac crest reconstructions). Patients with an iliac crest bone graft had significantly better chewing and swallowing scores (P = .04, P = .049 respectively). There was also a trend for better taste (P = .067). When patients with a history of radiation therapy were excluded, differences in chewing and swallowing were not significant (P = .26 and P = .31 respectively), whereas taste was (P = .038). CONCLUSIONS: These findings suggest that reconstruction with the iliac crest had benefits in improved function (chewing, swallowing, and taste) rather than esthetics, donor site morbidity, or psychologic discomfort as was anticipated. However, prior radiation, a relatively frequent therapy in this patient population, presents an important confounding factor. Radiation therapy is difficult to control for without limiting an already scarce patient pool, and bears with it significant morbidity that likely influenced these findings. Further study is warranted to confirm the results and further distinguish the 2 groups

Inhibitory neurotransmission is a critical determinant of neuronal network gain and dynamic range, suggesting that network properties are shaped by activity during development. A previous study demonstrated that sensorineural hearing loss (SNHL) in gerbils leads to smaller inhibitory potentials in L2/3 pyramidal neurons in the thalamorecipient auditory cortex, ACx. Here, we explored the mechanisms that account for proper maturation of gamma-amino butyric acid (GABA)ergic transmission. SNHL was induced at postnatal day (P) 10, and whole-cell voltage-clamp recordings were obtained from layer 2/3 pyramidal neurons in thalamocortical slices at P16-19. SNHL led to an increase in the frequency of GABAzine-sensitive (antagonist) spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs), accompanied by diminished amplitudes and longer durations. Consistent with this, the amplitudes of minimum-evoked IPSCs were also reduced while their durations were longer. The alpha1- and beta2/3 subunit-specific agonists zolpidem and loreclezole increased control but not SNHL sIPSC durations. To test whether SNHL affected the maturation of GABAergic transmission, sIPSCs were recorded at P10. These sIPSCs resembled the long SNHL sIPSCs. Furthermore, zolpidem and loreclezole were ineffective in increasing their durations. Together, these data strongly suggest that the presynaptic release properties and expression of key postsynaptic GABA(A) receptor subunits are coregulated by hearing