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2.  Can intraoperative processed EEG predict postoperative cognitive dysfunction in the elderly? 
Clinical therapeutics  2015;37(12):2700-2705.
Postoperative cognitive dysfunction (POCD) is a serious and costly complication of the elderly; even mild impairment has the potential to impact overall well-being. Anesthesiologists continue to search for ways to manipulate intraoperative technique to optimize postoperative cognition in the elderly. Depth of anesthesia during surgery is one area which has shown some promise for short term outcomes such as delirium. However excessive depth has both positive and negative associations with longer term postoperative cognitive dysfunction. We hypothesize that this uncertainty is due to the inability of median depth to capture the amount of burst suppression or electrical silence. In this study our purpose is to identify the intraoperative processed EEG parameters which are most closely correlated with postoperative cognitive function.
To explore the association of several processed EEG parameters with POCD we performed a retrospective analysis of a cohort of 105 patients over age 68 scheduled for major surgery under general anesthesia. Intraoperative medications, hemodynamics, processed electroencephalography (EEG) and cerebral oxygen saturation were recorded. All patients had a cognitive battery before surgery and repeated at 3 months afterwards.
105 patients enrolled, 77 (73.3%) patients completed the 3-month cognitive testing. The incidence of POCD was 27%; the median BIS value for patients who developed POCD was similar to patients who did not (46 vs. 42 minutes). However patients who developed POCD spent less time with BIS < 45 (82.8 vs. 122.5 minutes, p=.01) and burst suppression (35 vs. 96 minutes, p=.04). Hypotension, cerebral desaturation, and use of total intravenous anesthesia were similar between patients with and without POCD.
Patients who developed POCD spent less time in EEG burst suppression and less time in deep states. Burst suppression may be protective for postoperative cognitive dysfunction. Further work is needed to definitively identify the role of burst suppression in context of other patient and intraoperative variables to prevent POCD.
PMCID: PMC4695244  PMID: 26621628
EEG; burst suppression; anesthesia; geriatrics; cognition
3.  Postoperative Delirium in the Geriatric Patient 
Anesthesiology clinics  2015;33(3):505-516.
Postoperative delirium, a common complication in older surgical patients, is independently associated with increased morbidity and mortality. Patients over the age of 65 years receive greater than 1/3 of the over 40 million anesthetics delivered yearly in the United States. This number is expected to increase with the aging of the population. Thus, it is increasingly important that perioperative clinicians who care for geriatric patients have an understanding of the complex syndrome of postoperative delirium.
PMCID: PMC4555984  PMID: 26315635
Postoperative delirium; geriatric; risk factors; screening; management
4.  Environmental DNA reveals that rivers are conveyer belts of biodiversity information 
Nature Communications  2016;7:12544.
DNA sampled from the environment (eDNA) is a useful way to uncover biodiversity patterns. By combining a conceptual model and empirical data, we test whether eDNA transported in river networks can be used as an integrative way to assess eukaryotic biodiversity for broad spatial scales and across the land–water interface. Using an eDNA metabarcode approach, we detect 296 families of eukaryotes, spanning 19 phyla across the catchment of a river. We show for a subset of these families that eDNA samples overcome spatial autocorrelation biases associated with the classical community assessments by integrating biodiversity information over space. In addition, we demonstrate that many terrestrial species are detected; thus suggesting eDNA in river water also incorporates biodiversity information across terrestrial and aquatic biomes. Environmental DNA transported in river networks offers a novel and spatially integrated way to assess the total biodiversity for whole landscapes and will transform biodiversity data acquisition in ecology.
DNA of a given organism can be detected from its surroundings. Here, Deiner and colleagues use so-called environmental DNA to estimate biodiversity of both aquatic and terrestrial organisms in and near river.
PMCID: PMC5013555  PMID: 27572523
6.  GABA selectively increases mucin-1 expression in isolated pig jejunum 
Genes & Nutrition  2015;10(6):47.
The inhibitory neurotransmitter GABA (γ-aminobutyric acid) is synthesized by glutamic acid decarboxylase, which is expressed in the central nervous system and in various other tissues including the intestine. Moreover, GABA can be ingested in vegetarian diets or produced by bacterial commensals in the gastrointestinal tract. As previous studies in lung have suggested a link between locally increased GABA availability and mucin 5AC production, the present study sought to test whether the presence or lack of GABA (and its precursor glutamine) has an effect on intestinal mucin expression. Porcine jejunum epithelial preparations were incubated with two different amounts of GABA or glutamine on the mucosal side for 4 h, and changes in the relative gene expression of seven different mucins, enzymes involved in mucin shedding, GABA B receptor, enzymes involved in glutamine/GABA metabolism, glutathione peroxidase 2, and interleukin 10 were examined by quantitative PCR (TaqMan® assays). Protein expression of mucin-1 (MUC1) was analyzed by Western blot. On the RNA level, only MUC1 was significantly up-regulated by both GABA concentrations compared with the control. Glutamine-treated groups showed the same trend. On the protein level, all treatment groups showed a significantly higher MUC1 expression than the control group. We conclude that GABA selectively increases the expression of MUC1, a cell surface mucin that prevents the adhesion of microorganisms, because of its size and negative charge, and therefore propose that the well-described positive effects of glutamine on enterocytes and intestinal integrity are partly attributable to effects of its metabolite GABA.
Electronic supplementary material
The online version of this article (doi:10.1007/s12263-015-0497-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4607675  PMID: 26471792
GABA; Glutamine; Glutamic acid decarboxylase; Mucin; Gut health
7.  Evaluating Subcriticality during the Ebola Epidemic in West Africa 
PLoS ONE  2015;10(10):e0140651.
The 2014–2015 Ebola outbreak is the largest and most widespread to date. In order to estimate ongoing transmission in the affected countries, we estimated the weekly average number of secondary cases caused by one individual infected with Ebola throughout the infectious period for each affected West African country using a stochastic hidden Markov model fitted to case data from the World Health Organization. If the average number of infections caused by one Ebola infection is less than 1.0, the epidemic is subcritical and cannot sustain itself. The epidemics in Liberia and Sierra Leone have approached subcriticality at some point during the epidemic; the epidemic in Guinea is ongoing with no evidence that it is subcritical. Response efforts to control the epidemic should continue in order to eliminate Ebola cases in West Africa.
PMCID: PMC4618845  PMID: 26484544
8.  Perioperative Frailty 
PMCID: PMC4182861  PMID: 25268862
9.  Can Routine Preoperative Data Predict Adverse Outcomes in the Elderly? Development and Validation of a Simple Risk Model Incorporating a Chart-Derived Frailty Score 
Frailty has emerged as an important predictor of operative risk among elderly surgical patients. However, the complexity of prospective frailty scores has limited their widespread use. Our goal was to develop two frailty-based surgical risk models employing only routine preoperative data. Our hypothesis was these models could easily integrate into an electronic medical record (EMR) to predict 30-day morbidity and mortality.
Study Design
ACS-NSQIP participant use files from 2005–2010 were reviewed, and patients ≥65 years old who underwent elective lower gastrointestinal surgery were identified. Two multivariate logistic regression models were constructed and internally cross-validated. The first included simple functional data, a comorbidity index based on the Charlson Comorbidity Index, demographics, BMI, and laboratory data (albumin <3.4g/dL, hematocrit<35%, creatinine>2mg/dL). The second model contained only parameters that can directly auto-populate from an EMR: demographics, laboratory data, BMI, and ASA score. To further assess diagnostic accuracy, receiver operating characteristic (ROC) curves were constructed.
76,106 patients met criteria for inclusion. 30-day mortality was seen in 2,853 patients or 3.7% of the study population. 18,436 patients (24.2%) experienced major complication. The c-statistic of the first expanded model was 0.813 for mortality and 0.629 for morbidity. The second simplified model had a c-statistic of 0.795 for mortality and 0.621 for morbidity. Both models were well calibrated per the Hosmer-Lemeshow test.
Our work demonstrates that routine preoperative data can approximate frailty and predict geriatric-specific surgical risk. The models’ predicative power was comparable to that of established prospective frailty scores. Our calculator could be used as a low cost simple screen for high-risk individuals who may require further evaluation or specialized services.
PMCID: PMC4171218  PMID: 25154667
10.  Do stress markers and anesthetic technique predict delirium in the elderly? 
Postoperative delirium (PD) is a prevalent complication of elderly surgical patients which predisposes toward worsened cognitive recovery and dementia. Risk of PD has been associated with increasing magnitude of the hypothalamic-pituitary-adrenal stress response (serum cortisol, epinephrine, norepinephrine) to surgery. Anesthetics suppress this response, some (total intravenous anesthesia, TIVA) more than others (anesthetic gases). Prior comparisons of anesthetics have been equivocal but have not included stress markers. We hypothesized that TIVA would decrease serum stress markers and the incidence of PD.
We performed a prospective cohort study of 76 elderly major surgical patients. Patients received TIVA or sevoflurane gas, blood was drawn for serum markers pre-, intra-, and postoperatively. PD was assessed with the Confusion Assessment Method. We compared stress markers and PD between patients who had TIVA vs. sevoflurane, then modeled PD including stress and anesthetic.
The group that received TIVA during surgery demonstrated lower levels of all stress markers compared to the gas group, but no difference in PD. However, across groups, postoperative norepinephrine was much higher in patients who developed PD. Other markers and other times had no effect.
The development of PD depends more on postoperative stress than intraoperative stress or anesthetic.
PMCID: PMC4201865  PMID: 25171689
11.  Assessing Measles Transmission in the United States Following a Large Outbreak in California 
PLoS Currents  2015;7:ecurrents.outbreaks.b497624d7043b1aecfbfd3dfda3e344a.
The recent increase in measles cases in California may raise questions regarding the continuing success of measles control. To determine whether the dynamics of measles is qualitatively different in comparison to previous years, we assess whether the 2014-2015 measles outbreak associated with an Anaheim theme park is consistent with subcriticality by calculating maximum-likelihood estimates for the effective reproduction numbe given this year’s outbreak, using the Galton-Watson branching process model. We find that the dynamics after the initial transmission event are consistent with prior transmission, but does not exclude the possibilty that the effective reproduction number has increased.
PMCID: PMC4455058  PMID: 26052471
effective reproduction number; infectious diseases; Measles; transmission chain
12.  The Implication of Frailty on Preoperative Risk Assessment 
Purpose of Review
Frailty, a state of decreased homeostatic reserve, is characterized by dysregulation across multiple physiologic and molecular pathways. It is particularly relevant to the perioperative period, during which patients are subject to high levels of stress and inflammation. This review aims to familiarize the anesthesiologist with the most current concepts regarding frailty and its emerging role in preoperative assessment and risk stratification.
Recent findings
Current literature has established frailty as a significant predictor of operative complications, institutionalization, and death among elderly surgical patients. A variety of scoring systems have been proposed to preoperatively identify and assess frail patients, though they differ in their clinical utility and prognostic ability. Additionally, evidence suggests an evolving potential for preoperative intervention and modification of the frailty syndrome.
The elderly are medically complex and heterogeneous with respect to operative risk. Recent advances in the concept of frailty provide an evidence-based framework to guide the anesthesiologist in the perioperative management, evaluation, and risk stratification of older surgical patients.
PMCID: PMC4076287  PMID: 24566452
Frailty; Elderly; Risk Stratification
13.  Patterns of Surgical Care and Complications in the Elderly 
Elderly surgical patients have an increased risk for complications and mortality, however, the “big picture” of their surgical care and complications has not been well described. In this study of the National Anesthesia Clinical Outcomes Registry, our hypothesis was that procedures, hospitals visited, and complications would differ by decade in the elderly and in comparison to younger adults.
Retrospective cohort study
Anesthesia Quality Institute’s National Anesthesia Clinical Outcomes Registry (NACOR) is the largest repository of anesthesia cases from academic and community hospitals and includes all insurance and facility types across the United States.
8,632,979 cases from January 2010 to March 2013 were acquired. After exclusion of age<18, non-applicable locations, and brain death, 2,851,114 remained and were placed into age categories: 18–64, 65–69, 70–79, 80–89, and 90+years old.
Patient, surgical, anesthetic and hospital descriptors, short-term outcomes (major complications, mortality at <48 hours)
The largest number of seniors had surgery in medium-sized community hospitals. The oldest age group (90+) underwent the smallest range of procedures; hip fracture, hip replacement, and cataract procedures comprised greater than 35% of all surgeries. Younger old patients underwent these procedures plus a significant proportion of spinal fusions, cholecystectomy, and knee surgery. Mortality and complications was increased in the geriatric groups relative to younger adults. Exploratory laparotomy had the highest proportion of death in any age category except 90+, where small bowel resection predominated. The proportion of emergency surgery and the amount of mortality associated with emergency surgery was 30% higher in the oldest (90+ group) compared to adults age 18–64.
This paper reports the pattern of surgical procedures, complications and mortality found in NACOR which one of the few datasets which has both community hospitals and all insurance types. Because the outcomes portion is under development it is not currently possible to investigate the relationship between hospital type and complications or mortality. However, this study underscores the magnitude of geriatric surgery which occurs in community hospitals and points to the need for future investigation in this area.
PMCID: PMC4024102  PMID: 24731176
surgery; outcomes; anesthesia; mortality
14.  The Effect of H-bonding and Proton Transfer on the Voltammetry of 2,3,5,6-Tetramethyl-p-phenylenediamine in Acetonitrile. An Unexpectedly Complex Mechanism for a Simple Redox Couple 
The voltammetry of 2,3,5,6-tetramethyl-p-phenylenediamine, H2PD, has been studied and compared to that of its isomer N,N,N’N’-tetramethyl-p-phenylenediamine, Me2PD. Both undergo two reversible electron transfer processes in acetonitrile that nominally correspond to 1e- oxidation to the radical cations, Me2PD+ and H2PD+, and a second 1e- oxidation at more positive potentials to the quinonediimine dications, Me2PD2+ and H2PD2+. While the voltammetry of Me2PD agrees with this simple mechanism, that of H2PD does not. The second voltammetric wave is too small. UV/Vis spectroelectrochemical experiments indicate that the second wave does correspond to oxidation of H2PD+ to H2PD2+ in solution. The fact that the second wave is not present at all at the lowest concentrations (5 µM), and that it increases at longer times and higher concentrations, indicates that H2PD+ is not the initial solution product of the first oxidation. A number of lines of evidence suggest instead that the initial product is a mixed valent, H-bonded dimer between one H2PD in the the full reduced, fully protonated state, H4PD2+, and another in the fully oxidized, fully deprotonated state, PD. A mechanism is proposed in which this dimer is formed on the electrode surface through proton transfer and H-bonding. Once desorbed into solution, it breaks apart via reaction with other H2PD’s, to give 2 H2PD+, which is the thermodynamically favored species in solution.
PMCID: PMC4416659  PMID: 25937857
15.  Prone Position Is Associated with Mild Cerebral Oxygen Desaturation in Elderly Surgical Patients 
PLoS ONE  2014;9(9):e106387.
A variety of hemodynamic and respiratory alterations accompany patients in the prone position; however the effect of the prone position on intraoperative cerebral saturation has not been studied. We sought to examine whether the incidence of cerebral oxygen desaturation in elderly patients (≥68 years of age) undergoing spine surgery in the prone position was more common than patients undergoing major surgery in the supine position.
We performed a retrospective cohort study of 205 patients; 63 patients underwent surgery in the prone position and 142 in the supine position. Patients were evaluated for cerebral desaturation with bilateral cerebral oximetry. The primary predictor was position, secondary were: length of the surgery, incidence and duration of cerebral desaturation episodes at several thresholds, average time of Bispectral index below threshold of 45 in minutes, average electroencephalogram suppression ratio >0, amount of blood transfused, and the incidence of hypotension and hypertension.
Elderly spine surgery patients in the prone position were more than twice as likely to experience mild cerebral desaturation as patients in the supine position. Patients in the prone position had longer surgeries; however cerebral desaturation in the prone position was significantly more common even when adjusted for surgery time and the occurrence of intraoperative hypotension.
Cerebral desaturation is related to the prone position in elderly surgery patients. Future studies are necessary to determine whether this translates to a higher incidence of postoperative cognitive dysfunction and delirium.
PMCID: PMC4162535  PMID: 25216265
16.  Perioperative delirium and its relationship to dementia 
A number of serious clinical cognitive syndromes occur following surgery and anesthesia. Postoperative delirium is a behavioral syndrome that occurs in the perioperative period. It is diagnosed through observation and characterized by a fluctuating loss of orientation and confusion. A distinct syndrome that requires formalized neurocognitive testing is frequently referred to as postoperative cognitive dysfunction (POCD). There are serious concerns as to whether either postoperative delirium or postoperative cognitive dysfunction lead to dementia. These concerns are reviewed in this article.
PMCID: PMC3612127  PMID: 23220565
Postoperative Delirium; Postoperative Cognitive Dysfunction; Long term cognitive impairment; Dementia
17.  Transport Distance of Invertebrate Environmental DNA in a Natural River 
PLoS ONE  2014;9(2):e88786.
Environmental DNA (eDNA) monitoring is a novel molecular technique to detect species in natural habitats. Many eDNA studies in aquatic systems have focused on lake or ponds, and/or on large vertebrate species, but applications to invertebrates in river systems are emerging. A challenge in applying eDNA monitoring in flowing waters is that a species' DNA can be transported downstream. Whether and how far eDNA can be detected due to downstream transport remains largely unknown. In this study we tested for downstream detection of eDNA for two invertebrate species, Daphnia longispina and Unio tumidus, which are lake dwelling species in our study area. The goal was to determine how far away from the source population in a lake their eDNA could be detected in an outflowing river. We sampled water from eleven river sites in regular intervals up to 12.3 km downstream of the lake, developed new eDNA probes for both species, and used a standard PCR and Sanger sequencing detection method to confirm presence of each species' eDNA in the river. We detected D. longispina at all locations and across two time points (July and October); whereas with U. tumidus, we observed a decreased detection rate and did not detect its eDNA after 9.1 km. We also observed a difference in detection for this species at different times of year. The observed movement of eDNA from the source amounting to nearly 10 km for these species indicates that the resolution of an eDNA sample can be large in river systems. Our results indicate that there may be species' specific transport distances for eDNA and demonstrate for the first time that invertebrate eDNA can persist over relatively large distances in a natural river system.
PMCID: PMC3921251  PMID: 24523940
Anesthesia has developed to the point where long term outcomes are important endpoints. Elderly patients are becoming an increasingly large part of most surgical practices, consistent with demographic shifts. Long term outcomes are particularly important for this group. In this review, we discuss functional outcomes in the elderly. We describe the areas of cognitive change and frailty, both of which are specific to the elderly. We also discuss prevention of surgical infections and emerging evidence around hemodynamic alterations in the operating room and their impact on long term outcomes.
PMCID: PMC3261586  PMID: 22238042
Geriatrics; Long term outcomes; Delirium; Postoperative Cognitive Dysfunction; Surgical Site Infection
19.  A Passerine Bird's Evolution Corroborates the Geologic History of the Island of New Guinea 
PLoS ONE  2011;6(5):e19479.
New Guinea is a biologically diverse island, with a unique geologic history and topography that has likely played a role in the evolution of species. Few island-wide studies, however, have examined the phylogeographic history of lowland species. The objective of this study was to examine patterns of phylogeographic variation of a common and widespread New Guinean bird species (Colluricincla megarhyncha). Specifically, we test the mechanisms hypothesized to cause geographic and genetic variation (e.g., vicariance, isolation by distance and founder-effect with dispersal). To accomplish this, we surveyed three regions of the mitochondrial genome and a nuclear intron and assessed differences among 23 of the 30 described subspecies from throughout their range. We found support for eight highly divergent lineages within C. megarhyncha. Genetic lineages were found within continuous lowland habitat or on smaller islands, but all individuals within clades were not necessarily structured by predicted biogeographic barriers. There was some evidence of isolation by distance and potential founder-effects. Mitochondrial DNA sequence divergence among lineages was at a level often observed among different species or even genera of birds (5–11%), suggesting lineages within regions have been isolated for long periods of time. When topographical barriers were associated with divergence patterns, the estimated divergence date for the clade coincided with the estimated time of barrier formation. We also found that dispersal distance and range size are positively correlated across lineages. Evidence from this research suggests that different phylogeographic mechanisms concurrently structure lineages of C. megarhyncha and are not mutually exclusive. These lineages are a result of evolutionary forces acting at different temporal and spatial scales concordant with New Guinea's geological history.
PMCID: PMC3089620  PMID: 21573115
20.  Is Postoperative Cognitive Decline Clinically Relevant? 
Anesthesiology  2010;112(5):1280-1285.
PMCID: PMC2871108  PMID: 20418703
21.  Erythroid progenitor renewal versus differentiation: genetic evidence for cell autonomous, essential functions of EpoR, Stat5 and the GR 
Oncogene  2006;25(20):2890-2900.
The balance between hematopoietic progenitor commitment and self-renewal versus differentiation is controlled by various transcriptional regulators cooperating with cytokine receptors. Disruption of this balance is increasingly recognized as important in the development of leukemia,by causing enhanced renewal and differentiation arrest. We studied regulation of renewal versus differentiation in primary murine erythroid progenitors that require cooperation of erythropoietin receptor (EpoR),the receptor tyrosine kinase c-Kit and a transcriptional regulator (glucocorticoid receptor (GR)) for sustained renewal. However, mice defective for GR- (GRdim/dim), EpoR- (EpoRH) or STAT5ab function (Stat5ab−/−) show no severe erythropoiesis defects in vivo. Using primary erythroblast cultures from these mutants, we present genetic evidence that functional GR, EpoR, and Stat5 are essential for erythroblast renewal in vitro. Cells from GRdim/dim, EpoRH, and Stat5ab−/− mice showed enhanced differentiation instead of renewal, causing accumulation of mature cells and gradual proliferation arrest. Stat5ab was additionally required for Epo-induced terminal differentiation: differentiating Stat5ab−/− erythroblasts underwent apoptosis instead of erythrocyte maturation, due to absent induction of the antiapoptotic protein Bcl-XL. This defect could be fully rescued by exogenous Bcl-XL. These data suggest that signaling molecules driving leukemic proliferation may also be essential for prolonged self-renewal of normal erythroid progenitors.
PMCID: PMC3035873  PMID: 16407844
erythroid progenitor self-renewal; terminal erythropoiesis; Stat5; glucocorticoid receptor; erythropoietin receptor; Bcl-XL
22.  Postoperative delirium and cognitive dysfunction 
BJA: British Journal of Anaesthesia  2009;103(Suppl 1):i41-i46.
Postoperative delirium and cognitive dysfunction (POCD) are topics of special importance in the geriatric surgical population. They are separate entities, whose relationship has yet to be fully elucidated. Although not limited to geriatric patients, the incidence and impact of both are more profound in geriatric patients. Delirium has been shown to be associated with longer and more costly hospital course and higher likelihood of death within 6 months or postoperative institutionalization. POCD has been associated with increased mortality, risk of leaving the labour market prematurely, and dependency on social transfer payments. Here, we review their definitions and aetiology, and discuss treatment and prevention in elderly patients undergoing major non-cardiac surgery. Good basic care demands identification of at-risk patients, awareness of common perioperative aggravating factors, simple prevention interventions, recognition of the disease states, and basic treatments for patients with severe hyperactive manifestations.
PMCID: PMC2791855  PMID: 20007989
age factors; anaesthesia, geriatric; brain; complications
23.  Anesthesia for Pediatric Deep Brain Stimulation 
In patients refractory to medical therapy, deep brain stimulations (DBSs) have emerged as the treatment of movement disorders particularly Parkinson's disease. Their use has also been extended in pediatric and adult patients to treat epileptogenic foci. We here performed a retrospective chart review of anesthesia records from 28 pediatric cases of patients who underwent DBS implantation for dystonia using combinations of dexmedetomidine and propofol-based anesthesia. Complications with anesthetic techniques including airway and cardiovascular difficulties were analyzed.
PMCID: PMC2931390  PMID: 20814550
24.  Complex porcine model of atherosclerosis: Induction of early coronary lesions after long-term hyperlipidemia without sustained hyperglycemia 
The Canadian Journal of Cardiology  2009;25(4):e109-e114.
The incidence of coronary artery disease (CAD) is still increasing in industrialized countries and it is even higher in diabetic patients. For experimental studies investigating the pathophysiology of CAD, the use of an animal model comparable with the pathological situation in patients is crucial.
To develop a model of advanced coronary atherosclerosis with induction of hyperlipidemia and hyperglycemia in domestic pigs.
Six pigs were fed a standard pig chow (controls), two were fed a 2% cholesterol and 17% coconut fat diet (Chol group), and two pigs received a 4% cholesterol and 17% coconut fat diet combined with streptozotocin (STZ) injections to induce diabetes (High Chol+STZ group). Serum lipid and plasma glucose values were analyzed, and histochemical staining for morphometric analysis and immunohistochemistry were performed.
Pigs on the hyperlipidemic diet had elevated mean (± SD) serum lipid levels (total cholesterol 5.05±1.45 mmol/L [Chol] and 5.03±2.41 mmol/L [High Chol+STZ] versus 2.09±0.23 mmol/L [controls]). Histopathological evaluation revealed an initial stage of coronary atherosclerosis. None of the STZ-treated pigs showed a sustained elevation of plasma glucose (mean glucose before STZ injection was 5.11±0.94 mmol/L and thereafter was 6.03±2.39 mmol/L) or a decline in pancreatic beta cells.
The current data suggest that the domestic porcine model is not suitable to create severe CAD using an atherogenic diet in combination with STZ injections for experimental interventional vascular research. This may be due to different STZ sensitivities among species. However, hyperlipidemia induced early pathological lesions in coronary arteries resembling initial stages of atherosclerosis without severe luminal narrowing.
PMCID: PMC2706769  PMID: 19340354
Atherosclerosis; Coronary disease; Diabetes mellitus; Hyperlipoproteinemia
25.  Raf-1 Antagonizes Erythroid Differentiation by Restraining Caspase Activation 
The Journal of Experimental Medicine  2002;196(10):1347-1353.
The Raf kinases are key signal transducers activated by mitogens or oncogenes. The best studied Raf isoform, Raf-1, was identified as an inhibitor of apoptosis by conventional and conditional gene ablation in mice. c-raf-1−/− embryos are growth retarded and anemic, and die at midgestation with anomalies in the placenta and fetal liver. Here, we show that Raf-1–deficient primary erythroblasts cannot be expanded in culture due to their accelerated differentiation into mature erythrocytes. In addition, Raf-1 expression is down-regulated in differentiating wild-type cells, whereas overexpression of activated Raf-1 delays differentiation. As recently described for human erythroid precursors, we find that caspase activation is necessary for the differentiation of murine fetal liver erythroblasts. Differentiation-associated caspase activation is accelerated in erythroid progenitors lacking Raf-1 and delayed by overexpression of the activated kinase. These results reveal an essential function of Raf-1 in erythropoiesis and demonstrate that the ability of Raf-1 to restrict caspase activation is biologically relevant in a context distinct from apoptosis.
PMCID: PMC2193984  PMID: 12438425
kinase; gene inactivation; erythropoiesis; fetal liver; apoptosis

Results 1-25 (26)