Strategic faculty recruitment increases research productivity within an academic university division.

BACKGROUND: Research is an important mandate for academic surgical divisions. However, there is widespread concern that the current health care climate is leading to a decline in research activity. A University of British Columbia (UBC) academic surgical division attempted to address this concern by strategically recruiting PhD research scientists to prioritize research and develop collaborative research programs. The objective of our study was to determine whether this strategy resulted in increased research productivity. METHODS: We reviewed the UBC Department of Surgery database to assess research funding obtained by the Division of General Surgery for the years 1994-2004. We searched MEDLINE for peer-reviewed publications by faculty members during this period. RESULTS: Research funding increased from a mean of Can$417,292 per year in the 5 years (1994/95-1998/99) before the recruitment of dedicated PhD scientists to a mean of Can$1.3 million per year in the 5 years following the recruitment strategy (1999/2000-2003/04; p = 0.012). Funding for the initial 5 years was Can$2.1 million, including 1 Canadian Institutes of Health Research (CIHR) grant. Funding increased to Can$6.8 million, including 22 CIHR grants over the subsequent 5 years (p < 0.001). Collaborative research led to the awarding of multidisciplinary grants exceeding Can$4 million with divisional members as principle or coprinciple investigators. From 1994/05 to 1998/99, the total number of peer-reviewed publications was 116 (mean 23.2, standard deviation [SD] 7 per year), increasing to 144 from 1999/2000 to 2003/04 (mean 28.8, SD 13 per year). The trend was for publications in journals with higher impact factors in the latter 5-year period. CONCLUSION: Strategic recruitment resulted in increased and sustained research productivity. Interactions between research scientists and clinicians resulted in successful program grant funding support. These results have implications for sustaining the research mission within academic departments of surgery.

Perioperative analysis of laparoscopic versus open liver resection.

BACKGROUND: Over the past decade there has been an increasing trend toward minimally invasive liver surgery. Initially limited by technical challenges, advances in laparoscopic techniques have rendered this approach safe and feasible. However, as health care costs approach 50% of some provincial budgets, surgical innovation must be justifiable in costs and patient outcomes. With introduction of standardized postoperative liver resection guidelines to optimize patient hospital length of stay, the advantages of laparoscopic liver resection (LLR) compared with open liver resection (OLR) measured by perioperative outcomes and resource utilization are not well defined. It remains to be established whether LLR is superior to OLR by these measurements. METHODS: Eighteen LLRs performed at the Vancouver General Hospital from 2005 to 2007 were prospectively analyzed. These data were compared with an equivalent group of 12 consecutive OLRs undertaken immediately prior to the introduction of LLR. Outcomes were evaluated for differences in perioperative morbidity, hospital length of stay, and operative costs. RESULTS: There were no differences between LLRs and OLRs in demographics, pathology, cirrhosis, tumour location or extent of resection. There were no deaths. LLRs had significantly decreased intraoperative blood loss (287 ml versus 473 ml, p = 0.03), postoperative complications (6% versus 42%, p = 0.03), and length of stay (4.3 versus 5.8 days, p = 0.01) compared with OLRs. There were no differences in operating time for LLRs compared to OLRs (135 min versus 138 min, respectively), total time in the operating theatre (214 min versus 224 min), or costs related to stapler/trocar devices (CA $1267 versus CA $1007). CONCLUSIONS: LLR is associated with decreased morbidity and decreased resource utilization compared with OLR. Perioperative patient outcomes and cost-effectiveness justify LLR despite introduction of standardized postoperative liver resection guidelines and decreased length of stay for OLR.

Murine hepatitis virus strain 1 produces a clinically relevant model of severe acute respiratory syndrome in A/J mice.

Severe acute respiratory syndrome (SARS) is a life-threatening infectious disease which has been difficult to study and treat because of the lack of a readily available animal model. Intranasal infection of A/J mice with the coronavirus murine hepatitis virus strain 1 (MHV-1) produced pulmonary pathological features of SARS. All MHV-1-infected A/J mice developed progressive interstitial pneumonitis, including dense macrophage infiltrates, giant cells, and hyaline membranes, resulting in death of all animals. In contrast, other mouse strains developed only mild transitory disease. Infected A/J mice had significantly higher cytokine levels, particularly macrophage chemoattractant protein 1 (MCP-1/CCL-2), gamma interferon, and tumor necrosis factor alpha. Furthermore, FGL2/fibroleukin mRNA transcripts and protein and fibrin deposits were markedly increased in the lungs of infected A/J mice. These animals developed a less robust type I interferon response to MHV-1 infection than resistant C57BL/6J mice, and treatment with recombinant beta interferon improved survival. This study describes a potentially useful small animal model of human SARS, defines its pathogenesis, and suggests treatment strategies.

Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity.

Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203-treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro.

Outcomes and DNA analysis of ex vivo expanded stem cell allograft for ocular surface reconstruction.

PURPOSE: To investigate the outcome of a new technique of ex vivo expanded stem cell allograft for limbal stem cell deficiency (LSCD), and to characterize the ocular surface genotype after surgery. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Ten eyes of 10 patients with profound LSCD arising from ectodermal dysplasia (3 eyes), Stevens-Johnson syndrome (3 eyes), chemical injury (2 eyes), thermal injury (1 eye), and rosacea blepharoconjunctivitis (1 eye). INTERVENTION: Allogeneic corneal limbal stem cells were cultured on plastic and transplanted to the recipient eye after removal of conjunctival pannus. Amniotic membrane was applied in a bandage capacity. The procedure was combined with other reconstructive surgery in 2 cases. Nine patients received systemic cyclosporin A immunosuppression, and the DNA genotype was investigated with surface impression cytology. MAIN OUTCOME MEASURES: Parameters of LSCD, including vascularization, conjunctivalization, inflammation, epithelial defect, photophobia, and pain. RESULTS: The mean follow-up period was 28 months (range, 12-50). Seven of 10 eyes (70%) had improved parameters of LSCD at final follow-up and were considered successes. Four (40%) had improved visual acuity, including 3 having had further procedures for visual rehabilitation. Three patients failed to improve-1 with a thermal burn and lid deformity, 1 with Stevens-Johnson syndrome and severe dry eye, and 1 with ectodermal dysplasia who developed an epithelial defect at 26 months. DNA analysis of the first 7 cases showed no ex vivo donor stem cell DNA present beyond 9 months. CONCLUSIONS: Ex vivo expanded stem cell allograft is a useful technique for restoring the ocular surface in profound LSCD. The absence of donor DNA beyond 9 months suggests that ongoing immunosuppression may be unnecessary and raises questions regarding the origin of the host corneal epithelium.

Enhanced synthesis of the oxysterol 24(S),25-epoxycholesterol in macrophages by inhibitors of 2,3-oxidosqualene:lanosterol cyclase: a novel mechanism for the attenuation of foam cell formation.

Oxysterols are key regulators of lipid metabolism and regulate gene expression by activating the liver X receptor (LXR). LXR plays a vital role in macrophage foam cell formation, a central event in atherosclerosis. It is known that addition of exogenous oxysterols to cultured macrophages activates LXR, leading to increased expression of ABCA1 and cholesterol efflux. In this study, we tested the novel hypothesis that stimulation of endogenous oxysterol synthesis would block foam cell formation induced by atherogenic lipoproteins. Macrophage synthesis of 24(S),25-epoxycholesterol, a potent LXR ligand, increased 60-fold by partial inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC), a microsomal enzyme in both the cholesterol biosynthetic pathway and the alternative oxysterol synthetic pathway. When macrophages were challenged with human hypertriglyceridemic VLDL (HTG-VLDL), cellular cholesteryl ester accumulation increased 12-fold. This was reduced dramatically, by 65%, after preincubation with an OSC inhibitor (OSCi). The HTG-VLDL-induced accumulation of macrophage TG (70-fold) was unaffected by the OSCi or exogenous 24(S),25-epoxycholesterol, an effect associated with suppression of SREBP-1 processing. By contrast, TO901317, a synthetic LXR agonist, increased cellular TG significantly and markedly increased SREBP-1 processing. OSC inhibition decreased HTG-VLDL uptake through downregulation of LDL-receptor expression, despite substantial inhibition of cholesterol synthesis. Furthermore, OSC inhibition significantly upregulated ABCA1 and ABCG1 expression, which led to enhanced macrophage cholesterol efflux, an effect mediated through LXR activation. Therefore, increased macrophage synthesis of endogenous oxysterols represents a new mechanism for the dual regulation of LXR- and SREBP-responsive genes, an approach that inhibits foam cell formation without detrimental effect on TG synthesis.

Collagen biomechanics in cerebral arteries and bifurcations assessed by polarizing microscopy.

Collagen is the main matrix protein of the artery wall. We have used the known correlation between collagen birefringence and its mechanical properties to assess the wall structural integrity in brain arteries and their bifurcation regions, which are the sites of formation of saccular aneurysms. Segments of 28 brain arteries, including bifurcations, were pressure fixed and sectioned in one of three orthogonal planes. Measurements were taken by polarizing microscopy of the birefringence of collagen fibers at the apex of bifurcations and in the main layers of the artery wall - adventitia, media and intima. Dimensional data were obtained of the layers in order to estimate wall properties. Along the apex of the flow divider we measured a narrow band of collagen (birefringence 30% higher than the adjacent adventitia) providing strength and stiffness in that region. There is a thin cell-free outer layer of the tunica media (mean thickness 11 microm) comprised of densely packed coaligned collagen with high birefringence. From the fiber birefringence and directional alignment of the individual layers we calculated that the adventitia contributes about one third of circumferential and almost all of longitudinal strength of intracranial arteries.

Impaired olfactory identification in Asperger's syndrome.

The authors measured odor detection threshold and odor identification in 12 males with Asperger's syndrome and 12 matched control subjects. Relative to control subjects, Asperger's syndrome subjects were not impaired at odor detection but were significantly impaired at olfactory identification.

Asperger syndrome: a proton magnetic resonance spectroscopy study of brain.

BACKGROUND: Asperger syndrome (AS; an autistic disorder) is associated with impaired social skills and obsessional/repetitive behavior. Patients with autism have significant abnormalities in the frontal lobe and frontoparietal connectivity. Nobody has examined the relationship between abnormalities in the frontal and parietal lobes and clinical symptoms in people with AS. METHODS: We used in vivo proton magnetic resonance spectroscopy to examine neuronal integrity of the medial prefrontal and parietal lobes in 14 non-learning-disabled adults with AS and 18 control subjects (of similar sex, age, and IQ). We obtained measures of the prefrontal lobe in 11, the parietal lobe in 13, and both lobes in 10 subjects with AS. We measured concentrations and ratios of N-acetylaspartate (NAA), creatine and phosphocreatine (Cr + PCr), and choline (Cho). Levels of NAA, Cr + PCr, and Cho are indicators of neuronal density and mitochondrial metabolism, phosphate metabolism, and membrane turnover. Frontal metabolite levels were correlated with scores on the Yale-Brown Obsessive Compulsive Scale and the Autism Diagnostic Interview. RESULTS: Subjects with AS had a significantly higher prefrontal lobe concentration of NAA (z = -3.1; P =.002), Cr + PCr (z = -2.2; P =.03), and Cho (z = -2.9; P =.003). Increased prefrontal NAA concentration was significantly correlated with obsessional behavior (tau = 0.67; P =.005); increased prefrontal concentration of Cho, with social function (tau = 0.72; P =.02). We found no significant differences in parietal lobe metabolite concentrations. CONCLUSION: Subjects with AS have abnormalities in neuronal integrity of the prefrontal lobe, which is related to severity of clinical symptoms.