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1.  MR-Tandem: parallel X!Tandem using Hadoop MapReduce on Amazon Web Services 
Bioinformatics  2011;28(1):136-137.
Summary: MR-Tandem adapts the popular X!Tandem peptide search engine to work with Hadoop MapReduce for reliable parallel execution of large searches. MR-Tandem runs on any Hadoop cluster but offers special support for Amazon Web Services for creating inexpensive on-demand Hadoop clusters, enabling search volumes that might not otherwise be feasible with the compute resources a researcher has at hand. MR-Tandem is designed to drop in wherever X!Tandem is already in use and requires no modification to existing X!Tandem parameter files, and only minimal modification to X!Tandem-based workflows.
Availability and implementation: MR-Tandem is implemented as a lightly modified X!Tandem C++ executable and a Python script that drives Hadoop clusters including Amazon Web Services (AWS) Elastic Map Reduce (EMR), using the modified X!Tandem program as a Hadoop Streaming mapper and reducer. The modified X!Tandem C++ source code is Artistic licensed, supports pluggable scoring, and is available as part of the Sashimi project at The MR-Tandem Python script is Apache licensed and available as part of the Insilicos Cloud Army project at Full documentation and a windows installer that configures MR-Tandem, Python and all necessary packages are available at this same URL.
PMCID: PMC3244769  PMID: 22072385
2.  Small molecule screening platform for assessment of cardiovascular toxicity on adult zebrafish heart 
BMC Physiology  2012;12:3.
Cardiovascular toxicity is a major limiting factor in drug development and requires multiple cost-effective models to perform toxicological evaluation. Zebrafish is an excellent model for many developmental, toxicological and regenerative studies. Using approaches like morpholino knockdown and electrocardiogram, researchers have demonstrated physiological and functional similarities between zebrafish heart and human heart. The close resemblance of the genetic cascade governing heart development in zebrafish to that of humans has propelled the zebrafish system as a cost-effective model to conduct various genetic and pharmacological screens on developing embryos and larvae. The current report describes a methodology for rapid isolation of adult zebrafish heart, maintenance ex vivo, and a setup to perform quick small molecule throughput screening, including an in-house implemented analysis script.
Adult zebrafish were anesthetized and after rapid decapitation the hearts were isolated. The short time required for isolation of hearts allows dissection of multiple fishes, thereby obtaining a large sample size. The simple protocol for ex vivo culture allowed maintaining the beating heart for several days. The in-house developed script and spectral analyses allowed the readouts to be presented either in time domain or in frequency domain. Taken together, the current report offers an efficient platform for performing cardiac drug testing and pharmacological screens.
The new methodology presents a fast, cost-effective, sensitive and reliable method for performing small molecule screening. The variety of readouts that can be obtained along with the in-house developed analyses script offers a powerful setup for performing cardiac toxicity evaluation by researchers from both academics and industry.
PMCID: PMC3334682  PMID: 22449203
Heart; Screening; Zebrafish; Small molecule; Ex vivo; Ca2+ signaling
3.  HDL in humans with cardiovascular disease exhibits a proteomic signature 
Alterations in protein composition and oxidative damage of high-density lipoprotein (HDL) have been proposed to impair the cardioprotective properties of HDL. We tested whether relative levels of proteins in HDL2 could be used as biomarkers for coronary artery disease (CAD).
Twenty control and eighteen CAD subjects matched for HDL-cholesterol, age, and sex were studied. HDL2 isolated from plasma was digested with trypsin and analyzed by high-resolution matrix-assisted laser desorption ionization mass spectrometry (MALDI- MS) and pattern recognition analysis.
Partial least squares discriminant analysis (PLS-DA) of mass spectra clearly differentiated CAD from control subjects with area under the Receiver operating characteristic curve (ROCAUC) 0.94. Targeted tandem mass spectrometric analysis of the model's significant features revealed that HDL2 of CAD subjects contained oxidized methionine residues of apolipoprotein A-I and elevated levels of apolipoprotein C-III. A proteomic signature composed of MALDI-MS signals from apoA-I, apoC-III, Lp(a) and apoC-I accurately classified CAD and control subjects (ROCAUC = 0.82).
HDL2 of CAD subjects carries a distinct protein cargo and that protein oxidation helps generate dysfunctional HDL. Moreover, models based on selected identified peptides in MALDI-TOF mass spectra of the HDL may have diagnostic potential.
PMCID: PMC2862883  PMID: 20307520
Cardiovascular risk score; inflammation; mass spectrometry; oxidized HDL; partial least squares discriminant analysis
4.  A Guided Tour of the Trans-Proteomic Pipeline 
Proteomics  2010;10(6):1150-1159.
The Trans-Proteomic Pipeline (TPP) is a suite of software tools for the analysis of tandem mass spectrometry datasets. The tools encompass most of the steps in a proteomic data analysis workflow in a single, integrated software system. Specifically, the TPP supports all steps from spectrometer output file conversion to protein-level statistical validation, including quantification by stable isotope ratios. We describe here the full workflow of the TPP and the tools therein, along with an example on a sample dataset, demonstrating that the set up and use of the tools is straightforward and well supported and does not require specialized informatics resources or knowledge.
PMCID: PMC3017125  PMID: 20101611
5.  Downsizing Treatment with Tyrosine Kinase Inhibitors in Patients with Advanced Gastrointestinal Stromal Tumors Improved Resectability 
World Journal of Surgery  2010;34(9):2090-2097.
Gastrointestinal stromal tumors (GISTs) express the receptor tyrosine kinase KIT. Most GISTs have mutations in the KIT or PDGFRA gene, causing activation of tyrosine kinase. Imatinib, a tyrosine kinase inhibitor (TKI), is the first-line palliative treatment for advanced GISTs. Sunitinib was introduced for patients with mutations not responsive to imatinib. The aim was to compare the survival of patients with high-risk resected GISTs treated with TKI prior to surgery with historical controls and to determine if organ-preserving surgery was facilitated.
Ten high-risk GIST-patients had downsizing/adjuvant TKI treatment: nine with imatinib and one with sunitinib. The patients were matched with historical controls (n = 89) treated with surgery alone, from our population-based series (n = 259). Mutational analysis of KIT and PDGFRA was performed in all cases. The progression-free survival was calculated.
The primary tumors decreased in mean diameter from 20.4 cm to 10.5 cm on downsizing imatinib. Four patients with R0 resection and a period of adjuvant imatinib had no recurrences versus 67% in the historical control group. Four patients with residual liver metastases have stable disease on continuous imatinib treatment after surgery. One patient has undergone reoperation with liver resection. The downsizing treatment led to organ-preserving surgery in nine patients and improved preoperative nutritional status in one patient.
Downsizing TKI is recommended for patients with bulky tumors with invasion of adjacent organs. Sunitinib can be used for patients in case of imatinib resistance (e.g., wild-type GISTs), underlining the importance of mutational analysis for optimal surgical planning.
PMCID: PMC2917560  PMID: 20512492
6.  Cholecystectomy and sphincterotomy in patients with mild acute biliary pancreatitis in Sweden 1988 - 2003: a nationwide register study 
BMC Gastroenterology  2009;9:80.
Gallstones represent the most common cause of acute pancreatitis in Sweden. Epidemiological data concerning timing of cholecystectomy and sphincterotomy in patients with first attack of mild acute biliary pancreatitis (MABP) are scarce. Our aim was to analyse readmissions for biliary disease, cholecystectomy within one year, and mortality within 90 days of index admission for MABP.
Hospital discharge and death certificate data were linked for patients with first attack acute pancreatitis in Sweden 1988-2003. Mortality was calculated as case fatality rate (CFR) and standardized mortality ratio (SMR). MABP was defined as acute pancreatitis of biliary aetiology without mortality during an index stay of 10 days or shorter. Patients were analysed according to four different treatment policies: Cholecystectomy during index stay (group 1), no cholecystectomy during index stay but within 30 days of index admission (group 2), sphincterotomy but not cholecystectomy within 30 days of index admission (group 3), and neither cholecystectomy nor sphincterotomy within 30 days of index admission (group 4).
Of 11636 patients with acute biliary pancreatitis, 8631 patients (74%) met the criteria for MABP. After exclusion of those with cholecystectomy or sphincterotomy during the year before index admission (N = 212), 8419 patients with MABP remained for analysis. Patients in group 1 and 2 were significantly younger than patients in group 3 and 4. Length of index stay differed significantly between the groups, from 4 (3-6) days, (representing median, 25 and 75 percentiles) in group 2 to 7 (5-8) days in groups 1. In group 1, 4.9% of patients were readmitted at least once for biliary disease within one year after index admission, compared to 100% in group 2, 62.5% in group 3, and 76.3% in group 4. One year after index admission, 30.8% of patients in group 3 and 47.7% of patients in group 4 had undergone cholecystectomy. SMR did not differ between the four groups.
Cholecystectomy during index stay slightly prolongs this stay, but drastically reduces readmissions for biliary indications.
PMCID: PMC2770478  PMID: 19852782
7.  A Method to Quantify Mouse Coat-Color Proportions 
PLoS ONE  2009;4(4):e5414.
Coat-color proportions and patterns in mice are used as assays for many processes such as transgene expression, chimerism, and epigenetics. In many studies, coat-color readouts are estimated from subjective scoring of individual mice. Here we show a method by which mouse coat color is quantified as the proportion of coat shown in one or more digital images. We use the yellow-agouti mouse model of epigenetic variegation to demonstrate this method. We apply this method to live mice using a conventional digital camera for data collection. We use a raster graphics editing program to convert agouti regions of the coat to a standard, uniform, brown color and the yellow regions of the coat to a standard, uniform, yellow color. We use a second program to quantify the proportions of these standard colors. This method provides quantification that relates directly to the visual appearance of the live animal. It also provides an objective analysis with a traceable record, and it should allow for precise comparisons of mouse coats and mouse cohorts within and between studies.
PMCID: PMC2671165  PMID: 19404391
8.  First attack of acute pancreatitis in Sweden 1988 – 2003: incidence, aetiological classification, procedures and mortality – a register study 
BMC Gastroenterology  2009;9:18.
Population-based studies suggest that the incidence of first attack of acute pancreatitis (FAAP) is increasing and that old age is associated with increased mortality. Beacuse nationwide data are limited and information on standardized mortality ratio (SMR) versus age is lacking, we wanted to describe incidence and mortality of first attack acute pancreatitis (FAAP) in Sweden.
Hospital discharge data concerning diagnoses and surgical procedures and death certificate data were linked for patients with FAAP in Sweden. Mortality was calculated as case fatality rate (CFR), i.e. deaths per 1000 patients and SMR using age-, gender- and calendar year-specific expected survival estimates, and is given as mean with 95% confidence intervals. Data are presented as median values with 25% and 75% percentiles, means and standard deviations, or proportions. Proportions have been compared using the chi square test, Poisson-regression test or Fisher exact test. Location of two groups of ratio scale variables were compared using independent samples t-test or Mann-Whitney U-test.
From 1988 through 2003, 43415 patients (23801 men and 19614 women) were admitted for FAAP. Age adjusted incidence rose from 27.0 to 32.0 per 100000 individuals and year. Incidence increased with age for both men and women. At index stay 19.7% of men and 35.4% of women had biliary diagnoses, and 7.1% of men and 2.1% of women alcohol-related diagnoses. Of 10072 patients who underwent cholecystectomy, 7521 (74.7%) did so after index stay within the audit period. With increasing age CFR increased and SMR decreased. For the whole period studied SMR was 11.75 (11.34–12.17) within 90 days of index admission and 2.03 (1.93–2.13) from 91 to 365 days. Alcohol-related diagnoses and young age was associated with increased SMR. Length of stay and SMR decreased significantly during the audit period.
Incidence of FAAP increased slightly from 1988 to 2003. Incidence increased and SMR declined with increasing patient age. Although the prognosis for patients with FAAP has improved it remains an important health problem. Aetiological classification at index stay and timing of cholecystectomy should be improved.
PMCID: PMC2669478  PMID: 19265519
9.  Rectal cancer treatment and outcome in the elderly: an audit based on the Swedish rectal cancer registry 1995–2004 
BMC Cancer  2009;9:68.
Limited information is available regarding the effect of age on choice of surgical and oncological treatment for rectal cancer. The objective of this study was to assess the influence of age on treatment and outcome of rectal cancer.
We utilized data in the Swedish Rectal Cancer Registry (SRCR) from patients treated for rectal cancer in Sweden in 1995–2004.
A total of 15,104 patients with rectal cancer were identified, 42.4% of whom were 75 years or older. Patients ≥75 years were less likely to have distant metastases than younger patients (14.8% vs. 17.8%, P < 0.001), and underwent abdominal tumor resection less frequently (68.5% vs. 84.4%, P < 0.001). Of 11,725 patients with abdominal tumor resection (anterior resection [AR], abdominoperineal excision [APE], and Hartmann's procedure [HA]), 37.4% were ≥75 years. Curative surgery was registered for 85.0% of patients ≥ 75 years and for 83.9% of patients < 75 years, P = 0.11. Choice of abdominal operation differed significantly between the two age groups for both curative and non-curative surgery, The frequency of APE was similar in both age groups (29.5% vs. 28.6%), but patients ≥75 years were more likely to have HA (16.9% vs. 4.9%) and less likely to have preoperative radiotherapy (34.3vs. 67.2%, P < 0.001). The relative survival rate at five years for all patients treated with curative intent was 73% (70–75%) for patients ≥75 years and 78% (77–79%) for patients < 75 years of age. Local recurrence rate was 9% (8–11%) for older and 8% (7–9%) for younger patients.
Treatment of rectal cancer is influenced by patient's age. Future studies should include younger and older patients alike to reveal whether or not age-related differences are purposive. Local recurrence following surgery for low tumors and quality of life aspects deserve particular attention.
PMCID: PMC2653041  PMID: 19245701
10.  Cholecystectomy in Sweden 2000 – 2003: a nationwide study on procedures, patient characteristics, and mortality 
BMC Gastroenterology  2007;7:35.
Epidemiological data on characteristics of patients undergoing open or laparoscopic cholecystectomy are limited. In this register study we examined characteristics and mortality of patients who underwent cholecystectomy during hospital stay in Sweden 2000 – 2003.
Hospital discharge and death certificate data were linked for all patients undergoing cholecystectomy in Sweden from January 1st 2000 through December 31st 2003. Mortality risk was calculated as standardised mortality ratio (SMR) i.e. observed over expected deaths considering age and gender of the background population.
During the four years of the study 43072 patients underwent cholecystectomy for benign biliary disease, 31144 (72%) using a laparoscopic technique and 11928 patients (28%) an open procedure (including conversion from laparoscopy). Patients with open cholecystectomy were older than patients with laparoscopic cholecystectomy (59 vs 49 years, p < 0.001), they were more likely to have been admitted to hospital during the year preceding cholecystectomy, and they had more frequently been admitted acutely for cholecystectomy (57% Vs 21%, p < 0.001). The proportion of women was lower in the open cholecystectomy group compared to the laparoscopic group (57% vs 73%, p < 0.001). Hospital stay was 7.9 (8.9) days, mean (SD), for patients with open cholecystectomy and 2.6 (3.3) days for patients with laparoscopic cholecystectomy, p < 0.001. SMR within 90 days of index admission was 3.89 (3.41–4.41) (mean and 95% CI), for patients with open cholecystectomy and 0.73 (0.52–1.01) for patients with laparoscopic cholecystectomy. During this period biliary disease accounted for one third of all deaths in both groups. From 91 to 365 days after index admission, SMR for patients in the open group was 1.01 (0.87–1.16) and for patients in the laparoscopic group 0.56 (0.44–0.69).
Laparoscopic cholecystectomy is performed on patients having a lower mortality risk than the general Swedish population. Patients with open cholecystectomy are more sick than patients with laparoscopic cholecystectomy, and they have a mortality risk within 90 days of admission for cholecystectomy, which is four times that of the general population. Further efforts to reduce surgical trauma in open biliary surgery are motivated.
PMCID: PMC2040147  PMID: 17705871
11.  Preoperative mechanical preparation of the colon: the patient's experience 
BMC Surgery  2007;7:5.
Preoperative mechanical bowel preparation can be questioned as standard procedure in colon surgery, based on the result from several randomised trials.
As part of a large multicenter trial, 105 patients planned for elective colon surgery for cancer, adenoma, or diverticulitis in three hospitals were asked to complete a questionnaire regarding perceived health including experience with bowel preparation. There were 39 questions, each having 3 – 10 answer alternatives, dealing with food intake, pain, discomfort, nausea/vomiting, gas distension, anxiety, tiredness, need of assistance with bowel preparation, and willingness to undergo the procedure again if necessary.
60 patients received mechanical bowel preparation (MBP) and 45 patients did not (No-MBP). In the MBP group 52% needed assistance with bowel preparation and 30% would consider undergoing the same preoperative procedure again. In the No-MBP group 65 % of the patients were positive to no bowel preparation. There was no significant difference between the two groups with respect to postoperative pain and nausea. On Day 4 (but not on Days 1 and 7 postoperatively) patients in the No-MBP group perceived more discomfort than patients in the MBP group, p = 0.02. Time to intake of fluid and solid food did not differ between the two groups. Bowel emptying occurred significantly earlier in the No-MBP group than in the MBP group, p = 0.03.
Mechanical bowel preparation is distressing for the patient and associated with a prolonged time to first bowel emptying.
PMCID: PMC1884131  PMID: 17480223
12.  Non-randomised patients in a cholecystectomy trial: characteristics, procedures, and outcomes 
BMC Surgery  2006;6:17.
Laparoscopic cholecystectomy is now considered the first option for gallbladder surgery. However, 20% to 30% of cholecystectomies are completed as open operations often on elderly and fragile patients. The external validity of randomised trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy has not been studied. The aim of this study is to analyse characteristics, procedures, and outcomes for all patients who underwent cholecystectomy without being included in such a trial.
Characteristics (age, sex, co-morbidity, and ASA-score), operation time, hospital stay, and mortality were compared for patients who underwent cholecystectomy outside and within a randomised controlled trial comparing mini-laparotomy and laparoscopic cholecystectomy.
During the inclusion period 1719 patients underwent cholecystectomy. 726 patients were randomised and 724 of them completed the trial; 993 patients underwent cholecystectomy outside the trial. The non-randomised patients were older – and had more complications from gallstone disease, higher co-morbidity, and higher ASA – score when compared with trial patients. They were also more likely to undergo acute surgery and they had a longer postoperative hospital stay, with a median 3 versus 2 days (p < 0.001 for all comparisons). Standardised mortality ratio within 90 days of operation was 3.42 (mean) (95% CI 2.17 to 5.13) for non-randomised patients and 1.61 (mean) (95%CI 0.02 to 3.46) for trial patients. For non-randomised patients, operation time did not differ significantly between mini-laparotomy and open cholecystectomy in multivariate analysis. However, the operation for laparoscopic cholecystectomy lasted 20 minutes longer than open cholecystectomy. Hospital stay was significantly shorter for both mini-laparotomy and laparoscopic cholecystectomy compared to open cholecystectomy.
Non-randomised patients were older and more sick than trial patients. The assignment of healthier patients to trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy limits the external validity of conclusions reached in such trials.
PMCID: PMC1769514  PMID: 17190587
13.  Open cholecystectomy for all patients in the era of laparoscopic surgery – a prospective cohort study 
BMC Surgery  2006;6:5.
Open cholecystectomy through a small incision is an alternative to laparoscopic cholecystectomy.
From 1 January 2002 through 31 December 2003, all operations upon the gallbladder in a district hospital with emergency admission and responsibility for surgical training were done as intended small-incision open cholecystectomy.
182 women and 90 men with a median age of 56 (interquartile range 45 to 68 years) underwent cholecystectomy for symptomatic gallbladder disease, 170 as elective and 102 as emergency cases. Trainee surgeons assisted by consultants or registrars having passed an examination for open cholecystectomy performed surgery in 194 cases (71%). The common bile duct was explored in 52 patients. Total postoperative morbidity was six percent. Median postoperative stay was one day and mean total (pre- and postoperative) hospital stay 3.1 days. 32 operations (12%) were done as day surgery procedures. Nationally in Sweden in 2002, mean total hospital stay was 4.4 days, and 13% of all cholecystectomies were performed on an outpatient basis.
Open, small-incision cholecystectomy for all patients is compatible with short hospital stay, evidence-based gall-bladder surgery, and training of surgical residents.
PMCID: PMC1450318  PMID: 16584556

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