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1.  Comparative promoter region analysis powered by CORG 
BMC Genomics  2005;6:24.
Promoters are key players in gene regulation. They receive signals from various sources (e.g. cell surface receptors) and control the level of transcription initiation, which largely determines gene expression. In vertebrates, transcription start sites and surrounding regulatory elements are often poorly defined. To support promoter analysis, we present CORG , a framework for studying upstream regions including untranslated exons (5' UTR).
The automated annotation of promoter regions integrates information of two kinds. First, statistically significant cross-species conservation within upstream regions of orthologous genes is detected. Pairwise as well as multiple sequence comparisons are computed. Second, binding site descriptions (position-weight matrices) are employed to predict conserved regulatory elements with a novel approach. Assembled EST sequences and verified transcription start sites are incorporated to distinguish exonic from other sequences.
As of now, we have included 5 species in our analysis pipeline (man, mouse, rat, fugu and zebrafish). We characterized promoter regions of 16,127 groups of orthologous genes. All data are presented in an intuitive way via our web site. Users are free to export data for single genes or access larger data sets via our DAS server . The benefits of our framework are exemplarily shown in the context of phylogenetic profiling of transcription factor binding sites and detection of microRNAs close to transcription start sites of our gene set.
The CORG platform is a versatile tool to support analyses of gene regulation in vertebrate promoter regions. Applications for CORG cover a broad range from studying evolution of DNA binding sites and promoter constitution to the discovery of new regulatory sequence elements (e.g. microRNAs and binding sites).
PMCID: PMC555765  PMID: 15723697
2.  Interleukin 22 Inhibits Intracellular Growth of Mycobacterium tuberculosis by Enhancing Calgranulin A Expression 
The Journal of Infectious Diseases  2013;209(4):578-587.
Previously, we found that interleukin 22 (IL-22) inhibits intracellular growth of Mycobacterium tuberculosis in human monocyte–derived macrophages (MDMs). In the current study, we determined the mechanisms underlying these effects. We found that W7, a phagolysosomal fusion inhibitor, abrogates IL-22–dependent M. tuberculosis growth inhibition in MDMs, suggesting that IL-22 acts through enhanced phagolysosomal fusion. Our microarray analysis indicated that recombinant IL-22 (rIL-22) enhances the expression of an intracellular signaling molecule, calgranulin A. This was confirmed by real-time polymerase chain reaction, Western blot, and confocal microscopy. Calgranulin A small interfering RNA (siRNA) abrogated rIL-22–dependent growth inhibition of M. tuberculosis in MDMs. IL-22 enhanced Rab7 expression and downregulated Rab14 expression of M. tuberculosis–infected MDMs, and these effects were reversed by calgranulin A siRNA. These results suggest that M. tuberculosis growth inhibition by IL-22 depends on calgranulin A and enhanced phagolysosomal fusion, which is associated with increased Rab7 and reduced Rab14 expression.
PMCID: PMC3903372  PMID: 24041785
tuberculosis; Human; Cytokine; IL-22
3.  High Risk of Graft Failure in Patients with Anti-HLA Antibodies Undergoing Haploidentical Stem Cell Transplantation 
Transplantation  2009;88(8):1019-1024.
While donor-specific anti-HLA antibodies (DSA) have been implicated in graft rejection in solid organ transplantation, their role in hematopoietic stem cell transplantation (HSCT) remains unclear.
To address the hypothesis that the presence of DSA contributes to the development graft failure, we tested 24 consecutive patients for the presence of anti-HLA antibodies determined by a highly sensitive and specific solid-phase/single-antigen assay. The study included a total of 28 haploidentical transplants, each with 2–5 HLA allele mismatches, at a single institution, from 9/2005 to 8/2008.
DSA were detected in five patients (21%). Three out of 4 (75%) patients with DSA prior to the first transplant failed to engraft, compared with 1 out of 20 (5%) without DSA (p=0.008). All 4 patients who experienced primary graft failure had second haploidentical transplants. One patient developed a second graft failure with persistent high DSA levels, while 3 engrafted, 2 of them in the absence of DSA. No other known factors that could negatively influence engraftment were associated with the development of graft failure in these patients.
These results suggest that donor-specific anti-HLA antibodies are associated with a high rate of graft rejection in patients undergoing haploidentical stem cell transplantation. Anti-HLA sensitization should be evaluated routinely in hematopoietic stem cell transplantation with HLA mismatched donors.
PMCID: PMC4324621  PMID: 19855248
Donor-specific anti-HLA antibodies; primary graft failure; haploidentical stem cell transplantation
4.  Do LQTS Gene Single Nucleotide Polymorphisms Alter QTc Intervals at Rest and During Exercise Stress Testing? 
The impact of harboring, genetic variants or single nucleotide polymorphisms (LQT-PM) on the repolarization response during exercise and recovery is unknown.
To assess the QTc interval adaptation during exercise stress testing (EST) in children with LQT polymorphisms compared to a group of age and gender matched normal controls.
One-hundred and forty-eight patients were age and gender matched into two groups: LQT-PM and control. Each patient underwent a uniform exercise protocol employing a cycle ergometer followed by a 9 minute recovery phase with continuous 12-lead electrocardiogram (ECG) monitoring. Intervals (RR, QT and QTc) at rest (supine), peak exercise and in recovery (1, 3, 5, 7, and 9 minutes) were measured.
Forty three patients were positive for LQT-PM and the control group consisted of 105 patients. A total of 83 SNPs were identified: SCN5A n=31 (37%), KCNE1 n=29 (35%), KCNH2 n=20 (24%), KCNQ1 n=2 (2%) and KCNE2 n=1 (1%). The QTc interval measurements of the LQT-PM were longer at rest, peak exercise and all phases of recovery when compared to the control group. Neither group demonstrated abnormal QTc interval adaptation in response to exercise. Patients with homozygous SNPs had longer resting QTc intervals when compared to patients with only heterozygous SNPs (435±23 ms vs 415±20 ms respectively, P-value <0.006).
Individuals with LQT-PM may have longer QTc intervals at rest as well as at peak exercise and all phases of the recovery period compared to normal controls. Additionally, subjects with homozygous SNPs had longer resting QTc intervals when compared to those with only heterozygous SNPs.
PMCID: PMC4317726  PMID: 23714088
5.  Use of Corticosteroids After Hepatoportoenterostomy for Bile Drainage in Infants With Biliary Atresia 
JAMA  2014;311(17):1750-1759.
Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome.
To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver.
The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013.
Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy.
The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events.
The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, −10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P= .008).
Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia.
PMCID: PMC4303045  PMID: 24794368
6.  Pharmacological Inhibition of Glucosylceramide Synthase Enhances Insulin Sensitivity 
Diabetes  2007;56(5):1341-1349.
A growing body of evidence implicates ceramide and/or its glycosphingolipid metabolites in the pathogenesis of insulin resistance. We have developed a highly specific small molecule inhibitor of glucosylceramide synthase, an enzyme that catalyzes a necessary step in the conversion of ceramide to glycosphingolipids. In cultured 3T3-L1 adipocytes, the iminosugar derivative N-(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM) counteracted tumor necrosis factor-α-induced abnormalities in glycosphingo-lipid concentrations and concomitantly reversed abnormalities in insulin signal transduction. When administered to mice and rats, AMP-DNM significantly reduced glycosphin-golipid but not ceramide concentrations in various tissues. Treatment of ob/ob mice with AMP-DNM normalized their elevated tissue glucosylceramide levels, markedly lowered circulating glucose levels, improved oral glucose tolerance, reduced A1C, and improved insulin sensitivity in muscle and liver. Similarly beneficial metabolic effects were seen in high fat-fed mice and ZDF rats. These findings provide further evidence that glycosphingolipid metabolites of ceramide may be involved in mediating the link between obesity and insulin resistance and that interference with glycosphingolipid biosynthesis might present a novel approach to the therapy of states of impaired insulin action such as type 2 diabetes.
PMCID: PMC4298701  PMID: 17287460
7.  Elective Change of Surgeon During the OR Day Has an Operationally Negligible Impact on Turnover Time 
Journal of clinical anesthesia  2014;26(5):343-349.
Study Objective
To compare turnover times for a series of elective cases with surgeons following themselves to turnover times for a series of previously scheduled, elective procedures where the following surgeon differed from the preceding surgeon. We also considered the effect of changing procedure types and the time of day on turnover time.
Retrospective, cohort study.
University-affiliated teaching hospital.
We used the operating room statistical database to gather 32 months of turnover data from a large academic institution. Turnover time data for the same-surgeon and surgeon-swap groups were batched by month to minimize autocorrelation and achieve data normalization. A two-way ANOVA using the monthly batched data was performed with surgeon swapping and changes in procedure category as variables of turnover time. Similar analyses were performed using individual surgical services and using hourly time intervals during the surgical day as additional covariates to surgeon swapping.
Main Results
The mean (95% confidence interval) same-surgeon turnover time was 43.6 (43.2 – 44.0) min versus 51.0 (50.5 – 51.6) min for a planned surgeon swap (p < 0.0001). This resulted in a difference (95% confidence interval) of 7.4 (6.8 – 8.1) min. The exact increase in turnover time was dependent on surgical service, change in subsequent procedure type, time of day when the turnover occurred, and turnover frequency per OR.
The investigated institution averages 2.5 cases per OR per day. The cumulative additional turnover time (far less than one hour per operating room per day) for switching surgeons definitely does not allow the addition of another elective procedure if the difference could be eliminated. A flexible scheduling policy allowing surgeon swapping rather than requiring full blocks incurs minimal additional staffed time during the OR day while allowing the schedule to be filled with available elective cases.
PMCID: PMC4283491  PMID: 25074630
Surgeon swapping; Turnover times; Operating room efficiency
8.  Effects of Biologic Scaffolds on Human Stem Cells and Implications for CNS Tissue Engineering 
Tissue Engineering. Part A  2013;20(1-2):313-323.
Biologic scaffolds composed of mammalian extracellular matrix (ECM) promote constructive remodeling of tissues via mechanisms that include the recruitment of endogenous stem/progenitor cells, modulation of the host innate immune response, and influence of cell fate differentiation. Such scaffold materials are typically prepared by decellularization of source tissues and are prepared as sheets, powder, or hydrogels. It is plausible that ECM derived from an anatomically distinct tissue would have unique or specific effects on cells that naturally reside in this same tissue. The present study investigated the in vitro effect of a soluble form of ECM derived from central nervous system (CNS) tissue, specifically the spinal cord or brain, versus ECM derived from a non-CNS tissue; specifically, the urinary bladder on the behavior of neural stem cells (NSCs) and perivascular stem cells. All forms of ECM induce positive, mitogenic, and chemotactic effects at concentrations of approximately 100 μg/mL without affecting stem cell viability. CNS-derived ECMs also showed the ability to differentiate NSCs into neurons as indicted by βIII-tubulin expression in two-dimensional culture and neurite extension on the millimeter scale after 24 days of three-dimensional cultures in an ECM hydrogel. These results suggest that solubilized forms of ECM scaffold materials may facilitate the postinjury healing response in CNS tissues.
PMCID: PMC3875189  PMID: 24004192
9.  Tissue Penetration of Antifungal Agents 
Clinical Microbiology Reviews  2014;27(1):68-88.
Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection.
PMCID: PMC3910906  PMID: 24396137
10.  Evaluation of Amphotericin B and Chloramphenicol as Alternative Drugs for Treatment of Chytridiomycosis and Their Impacts on Innate Skin Defenses 
Applied and Environmental Microbiology  2014;80(13):4034-4041.
Chytridiomycosis, an amphibian skin disease caused by the emerging fungal pathogen Batrachochytrium dendrobatidis, has been implicated in catastrophic global amphibian declines. The result is an alarming decrease in amphibian diversity that is a great concern for the scientific community. Clinical trials testing potential antifungal drugs are needed to identify alternative treatments for amphibians infected with this pathogen. In this study, we quantified the MICs of chloramphenicol (800 μg/ml), amphotericin B (0.8 to 1.6 μg/ml), and itraconazole (Sporanox) (20 ng/ml) against B. dendrobatidis. Both chloramphenicol and amphotericin B significantly reduced B. dendrobatidis infection in naturally infected southern leopard frogs (Rana [Lithobates] sphenocephala), although neither drug was capable of complete fungal clearance. Long-term exposure of R. sphenocephala to these drugs did not inhibit antimicrobial peptide (AMP) synthesis, indicating that neither drug is detrimental to this important innate skin defense. However, we observed that chloramphenicol, but not amphotericin B or itraconazole, inhibited the growth of multiple R. sphenocephala skin bacterial isolates in vitro at concentrations below the MIC against B. dendrobatidis. These results indicate that treatment with chloramphenicol might dramatically alter the protective natural skin microbiome when used as an antifungal agent. This study represents the first examination of the effects of alternative antifungal drug treatments on amphibian innate skin defenses, a crucial step to validating these treatments for practical applications.
PMCID: PMC4054225  PMID: 24771024
11.  Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor 
Biomaterials  2013;35(2):699-710.
Traditional stem cell differentiation protocols make use of a variety of cytokines including growth factors (GFs) and inhibitors in an effort to provide appropriate signals for tissue specific differentiation. In this study, iPSC-derived type II pneumocytes (iPSC-ATII) as well as native isolated human type II pneumocytes (hATII) were differentiated toward a type I phenotype using a unique air–liquid interface (ALI) system that relies on a rotating apparatus that mimics in vivo respiratory conditions. A relatively homogenous population of alveolar type II-like cells from iPSC was first generated (iPSC-ATII cells), which had phenotypic properties similar to mature human alveolar type II cells. iPSC-ATII cells were then cultured in a specially designed rotating culture apparatus. The effectiveness of the ALI bioreactor was compared with the effectiveness of small molecule-based differentiation of type II pneumocytes toward type 1 pneumocytes. The dynamics of differentiation were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), flow cytometry and immunocytochemistry. iPSC-ATII and hATII cells cultured in the ALI bioreactor had higher levels of type I markers, including aquaporin-5(AQ5), caveolin-1, and T1α, at both the RNA and protein levels as compared with the flask-grown iPSC-ATII and hATII that had been treated with small molecules to induce differentiation. In summary, this study demonstrates that a rotating bioreactor culture system that provides an air–liquid interface is a potent inducer of type I epithelial differentiation for both iPS-ATII cells and hATII cells, and provides a method for large-scale production of alveolar epithelium for tissue engineering and drug discovery.
PMCID: PMC3897000  PMID: 24144903
Induced pluripotent stem (iPS); Alveolar epithelium; Bioreactor; Air—liquid interface
12.  Bridging the divide 
Fly  2013;8(1):13-18.
Ring canals are made from arrested cleavage furrows, and provide direct cytoplasmic connections among sibling cells. They are well documented for their participation in Drosophila oogenesis, but little is known about their role in several somatic tissues in which they are also found. Using a variety of genetic tools in live and fixed tissue, we recently demonstrated that rapid intercellular exchange occurs through somatic ring canals by diffusion, and presented evidence that ring canals permit equilibration of protein among transcriptionally mosaic cells. We also used a novel combination of markers to evaluate the extent of protein movement within and across mitotic clones in follicle cells and imaginal discs, providing evidence of robust movement of GFP between the 2 sides of mitotic clones and frequently into non-recombined cells. These data suggest that, depending on the experimental setup and proteins of interest, inter-clonal diffusion of protein may alter the interpretation of clonal data in follicle cells. Here, we discuss these results and provide additional insight into the impact of ring canals in Drosophila somatic tissues.
PMCID: PMC3974888  PMID: 24406334
Drosophila; egg chamber; follicle cells; intercellular bridge; ring canal; imaginal discs
13.  Evaluating controlled human malaria infection in Kenyan adults with varying degrees of prior exposure to Plasmodium falciparum using sporozoites administered by intramuscular injection 
Background: Controlled human malaria infection (CHMI) studies are a vital tool to accelerate vaccine and drug development. As CHMI trials are performed in a controlled environment, they allow unprecedented, detailed evaluation of parasite growth dynamics (PGD) and immunological responses. However, CHMI studies have not been routinely performed in malaria-endemic countries or used to investigate mechanisms of naturally-acquired immunity (NAI) to Plasmodium falciparum.
Methods: We conducted an open-label, randomized CHMI pilot-study using aseptic, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) to evaluate safety, infectivity and PGD in Kenyan adults with low to moderate prior exposure to P. falciparum (Pan African Clinical Trial Registry: PACTR20121100033272).
Results: All participants developed blood-stage infection confirmed by quantitative polymerase chain reaction (qPCR). However one volunteer (110) remained asymptomatic and blood-film negative until day 21 post-injection of PfSPZ Challenge. This volunteer had a reduced parasite multiplication rate (PMR) (1.3) in comparison to the other 27 volunteers (median 11.1). A significant correlation was seen between PMR and screening anti-schizont Enzyme Linked Immunosorbent Assays (ELISA) OD (p = 0.044, R = −0.384) but not when volunteer 110 was excluded from the analysis (p = 0.112, R = −0.313).
Conclusions: PfSPZ Challenge is safe and infectious in malaria-endemic populations and could be used to assess the efficacy of malaria vaccines and drugs in African populations. Whilst our findings are limited by sample size, our pilot study has demonstrated for the first time that NAI may impact on PMR post-CHMI in a detectable fashion, an important finding that should be evaluated in further CHMI studies.
PMCID: PMC4264479  PMID: 25566206
malaria; challenge; falciparum; immunity; CHMI
14.  18FDG-PET/CT Definition of Clinical Target Volume for Robotic Stereotactic Body Radiosurgery Treatment of Metastatic Gynecologic Malignancies 
The objective of the current article was to evaluate 2-[18F]fluoro-2-deoxy-D-glucose 18F-FDG) as measured by positron emission tomography for delineation of abdominopelvic gross tumor volumes (GTV) for stereotactic body radiosurgery treatment (SBRT) of metastatic gynecologic cancers. A retrospective review of SBRT was conducted in 27 women with stage IV gynecologic cancers recurring in para-aortic lymph nodes. Robotic SBRT involved 2400 cGy in 3 consecutive 800 cGy daily fractions prescribed to a 3.0 mm expanded planning tumor volume (PTV) defined by both CT-based and 18F-FDG-based GTVs. In this study, 18F-FDG-based GTVs led to significantly larger PTVs in all 27 women, than if they had been based on CT GTVs alone (P < 0.001). Enlarged PTVs may have resulted from the breathing-induced target motion during the time of 18F-FDG image acquisition smearing 18F-FDG signal over a greater anatomic dimension. Ultimately, SBRT-target local control, based on the RECIST 1.1 criteria, was 96% (26 of 27), and associated with minor reversible toxicity. The use of 18F-FDG to define SBRT target volumes warrants further interrogation in SBRT clinical trials.
PMCID: PMC4260799  PMID: 25506042
16.  Adapting and Implementing a Community Program to Improve Retention in Care among Patients with HIV in Southern Haiti: “Group of 6” 
AIDS Research and Treatment  2014;2014:137545.
Objective. In Mozambique, a patient-led Community ART Group model developed by Médecins Sans Frontières improved retention in care and adherence to antiretroviral therapy (ART) among persons with HIV. We describe the adaptation and implementation of this model within the HIV clinic located in the largest public hospital in Haiti's Southern Department. Methods. Our adapted model was named Group of 6. Hospital staff enabled stable patients with HIV receiving ART to form community groups with 4–6 members to facilitate monthly ART distribution, track progress and adherence, and provide support. Implementation outcomes included recruitment success, participant retention, group completion of monthly monitoring forms, and satisfaction surveys. Results. Over one year, 80 patients from nine communities enrolled into 15 groups. Six participants left to receive HIV care elsewhere, two moved away, and one died of a non-HIV condition. Group members successfully completed monthly ART distribution and returned 85.6% of the monthly monitoring forms. Members reported that Group of 6 made their HIV management easier and hospital staff reported that it reduced their workload. Conclusions. We report successful adaptation and implementation of a validated community HIV-care model in Southern Haiti. Group of 6 can reduce barriers to ART adherence, and will be integrated as a routine care option.
PMCID: PMC4274858  PMID: 25548659
17.  Does the surgical approach in one stage bilateral total hip arthroplasty affect blood loss? 
International Orthopaedics  2013;37(12):2357-2362.
It is not clear whether type of surgical approach affects the amount of blood loss in one-stage bilateral total hip arthroplasty (THA). This study therefore aims to examine if type of surgical approach can affect peri-operative blood loss and allogeneic blood transfusion in patients undergoing one-stage bilateral THA.
Records of 319 patients who underwent one-stage bilateral THA from January 2004 to June 2011 were retrospectively reviewed. Patients were divided into two groups: direct anterior (DA) approach (75 patients) and direct lateral (DL) approach (244 patients). Blood loss was calculated using a previously validated formula. Blood loss and need for allogeneic blood transfusion were compared between the two groups. Additionally, the effects of using cell saver and surgical approach were evaluated in a multivariate analysis.
Compared to the DL approach, calculated blood loss was significantly lower in the DA group (2,813.90 ± 804.13 ml vs 3,617.03 ± 1,148.47 ml) and a significantly lower per cent of patients needed allogeneic blood transfusion in the DA group (26.6 vs 52.4 %). Intra-operative cell saver was used in 36 patients. Compared to the non-cell saver group, mean blood loss was significantly higher in the cell saver group (4,061.0 ± 1,285.55 ml vs 3,347.71 ± 1,083.85 ml), whereas the difference between the two groups regarding allogeneic blood transfusion was not statistically significant. The DA approach was an independent predictor of lower peri-operative blood loss and allogeneic blood transfusion while using cell saver was not.
Our results may be explained by the lower extent of muscular dissection performed in the DA approach. Our findings also indicate that intra-operative cell salvage might not be justified in bilateral THA performed expeditiously.
PMCID: PMC3843217  PMID: 24068441
Bilateral total hip arthroplasty; Direct anterior approach; Cell salvage; Blood loss; Transfusion
18.  Atom mapping with constraint programming 
Chemical reactions are rearrangements of chemical bonds. Each atom in an educt molecule thus appears again in a specific position of one of the reaction products. This bijection between educt and product atoms is not reported by chemical reaction databases, however, so that the “Atom Mapping Problem” of finding this bijection is left as an important computational task for many practical applications in computational chemistry and systems biology. Elementary chemical reactions feature a cyclic imaginary transition state (ITS) that imposes additional restrictions on the bijection between educt and product atoms that are not taken into account by previous approaches. We demonstrate that Constraint Programming is well-suited to solving the Atom Mapping Problem in this setting. The performance of our approach is evaluated for a manually curated subset of chemical reactions from the KEGG database featuring various ITS cycle layouts and reaction mechanisms.
Electronic supplementary material
The online version of this article (doi:10.1186/s13015-014-0023-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4256833  PMID: 25484913
Atom-atom mapping; Constraint programming; Chemical reaction; Imaginary transition state
19.  Ten-year experience with testicular cancer at a tertiary care hospital in a resource-limited setting: a single centre experience in Tanzania 
Testicular cancers constitute major therapeutic challenges in resource-limited countries and still carry poor outcomes. There is a paucity of published data regarding testicular cancer in Tanzania, and Bugando Medical Centre in particular. This study describes the clinicopathological pattern, treatment outcome and challenges in the management of testicular cancer in our local setting.
This was a retrospective study including all patients who had had histopathologically confirmed testicular cancer at Bugando Medical Centre between February 2004 and January 2014.
A total of 56 testicular cancer patients were enrolled in the study, representing 0.9% of all malignancies. The median age of patients at presentation was 28 years, with a peak incidence in the 21-to-30-year age group. A family history of testicular cancer was reported in four (5.4%) patients. A history of cryptorchidism was reported in six (10.7%) patients. Most patients (57.1%) presented late with an advanced stage of cancer. Testicular swelling was the main complaint in 48 (85.7%) patients. The right testis was involved in 67.9% of cases. Lymph node and distant metastases were documented in 10 (17.9%) and 12 (21.4%) patients, respectively. Histologically, 80.4% of patients had germ cell cancers, with seminoma accounting for 62.2% of cases. The most common surgical procedure was inguinal orchidectomy (77.4%). Adjuvant chemotherapy and radiotherapy were used in six (11.1%) and four (7.4%) patients, respectively. Eight (14.3%) patients died. The main predictors of mortality (P < 0.001) were patient’s age (>65 years), late presentation (>6 months), stage of disease, and presence of metastasis at time of diagnosis. The mean follow-up period was 22 months. At the end of five years, only 18 (37.5%) patients were available for follow-up and the overall 5-year survival rate was 22.2%. The main predictors of 5-year survival rate (P < 0.001) were patients’ age, stage of disease, and presence of lymph node and distant metastases.
Testicular cancers, though rare in our setting, still carries a poor prognosis. Late presentation, poverty, paucity of resources and the high cost of newer imaging and treatment modalities are major challenges to management. Better health funding and education regarding testicular self-examination is essential.
PMCID: PMC4258266  PMID: 25418694
Challenges; clinicopathological pattern; incidence; management; Tanzania; testicular cancers
20.  Effectiveness of Paliperidone Palmitate vs. Haloperidol Decanoate for Maintenance Treatment of Schizophrenia: A Randomized Clinical Trial 
Long-acting injectable (LAI) antipsychotics are used to reduce medication non-adherence and subsequent relapse in schizophrenia-spectrum disorders. The relative effectiveness of LAI versions of second-generation (atypical) and older antipsychotics has not been assessed.
To compare the effectiveness of the second-generation LAI antipsychotic paliperidone palmitate (PP) to the older LAI antipsychotic haloperidol decanoate (HD).
Design, Setting, and Participants
Multisite, double-blind, randomized clinical trial conducted at 22 clinical research sites in the U.S. The 311 randomized patients (PP=157, HD=154) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a LAI antipsychotic.
Intramuscular injections of HD 25–200 mg or PP 39–234 mg every month for up to 24 months.
Main Outcome Measures
Efficacy failure, which reflected inadequate control of psychopathology by the study medication, as determined by a blinded adjudication committee. Key secondary outcomes were common adverse effects of antipsychotic medications.
There was no statistically significant difference in the rate of efficacy failure for PP compared to HD (adjusted hazard ratio 0.98, 95% confidence interval [CI] 0.65–1.47). On average, patients on PP gained and those on HD lost weight; after six months the least squares mean weight change on PP was +2.17 kg (1.25 to 3.09) and on HD was −0.96 kg (−1.88 to −0.04). Patients taking PP had significantly greater increases in serum prolactin (men 34.56 µg/L (29.75 to 39.37) vs. 15.41 (10.73 to 20.08), p<0.001; women 75.19 (63.03 to 87.36) vs. 26.84 (13.29 to 40.40), p<0.001). Patients taking HD had significantly larger increases in global ratings of akathisia (0.73 [0.59 to 0.87] vs. 0.45 [0.31 to 0.59], p=0.006).
Conclusions and Relevance
Among adults with schizophrenia or schizoaffective disorder, treatment with paliperidone palmitate compared with haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol was associated with more akathisia. However, based on the 95% confidence limits, a clinically meaningful difference in efficacy failure between treatments cannot be ruled out.
Trial Registration identifier NCT01136772
PMCID: PMC4101890  PMID: 24846035
21.  The live attenuated chimeric vaccine rWN/DEN4Δ30 is well-tolerated and immunogenic in healthy flavivirus-naïve adult volunteers 
Vaccine  2013;31(48):10.1016/j.vaccine.2013.07.064.
WNV has become the leading vector-borne cause of meningoencephalitis in the United States. Although the majority of WNV infections result in asymptomatic illness, approximately 20% of infections result in West Nile fever and 1% in West Nile neuroinvasive disease (WNND), which causes encephalitis, meningitis, or flaccid paralysis. The elderly are at particular risk for WNND, with more than half the cases occurring in persons older than sixty years of age. There is no licensed treatment for WNND nor is there any licensed vaccine for humans for the prevention of WNV infection. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a recombinant live attenuated WNV vaccine based on chimerization of the wild-type WNV NY99 genome with that of the live attenuated DENV-4 candidate vaccine rDEN430. The genes encoding the prM and envelope proteins of DENV-4 were replaced with those of WNV NY99 and the resultant virus was designated rWN/DEN4Δ30. The vaccine was evaluated in healthy flavivirus-naïve adult volunteers age 18 – 50 years in two separate studies, both of which are reported here. The first study evaluated 103 or 104 PFU of the vaccine given as a single dose; the second study evaluated 105 PFU of the vaccine given as two doses 6 months apart. The vaccine was well-tolerated and immunogenic at all three doses, inducing seroconversion to WNV NY99 in 74% (103 PFU), 75% (104 PFU), and 55% (105 PFU) of subjects after a single dose. A second 105 PFU dose of rWN/DEN4Δ30 given 6 months after the first dose increased the seroconversion rate 89%. Based on the encouraging results from these studies, further evaluation of the candidate vaccine in adults older than 50 years of age is planned.
PMCID: PMC3833717  PMID: 23968769
West Nile virus (WNV); live attenuated WNV vaccine; clinical trial
22.  Passive sampling methods for contaminated sediments: State of the science for organic contaminants 
This manuscript surveys the literature on passive sampler methods (PSMs) used in contaminated sediments to assess the chemical activity of organic contaminants. The chemical activity in turn dictates the reactivity and bioavailability of contaminants in sediment. Approaches to measure specific binding of compounds to sediment components, for example, amorphous carbon or specific types of reduced carbon, and the associated partition coefficients are difficult to determine, particularly for native sediment. Thus, the development of PSMs that represent the chemical activity of complex compound–sediment interactions, expressed as the freely dissolved contaminant concentration in porewater (Cfree), offer a better proxy for endpoints of concern, such as reactivity, bioaccumulation, and toxicity. Passive sampling methods have estimated Cfree using both kinetic and equilibrium operating modes and used various polymers as the sorbing phase, for example, polydimethylsiloxane, polyethylene, and polyoxymethylene in various configurations, such as sheets, coated fibers, or vials containing thin films. These PSMs have been applied in laboratory exposures and field deployments covering a variety of spatial and temporal scales. A wide range of calibration conditions exist in the literature to estimate Cfree, but consensus values have not been established. The most critical criteria are the partition coefficient between water and the polymer phase and the equilibrium status of the sampler. In addition, the PSM must not appreciably deplete Cfree in the porewater. Some of the future challenges include establishing a standard approach for PSM measurements, correcting for nonequilibrium conditions, establishing guidance for selection and implementation of PSMs, and translating and applying data collected by PSMs. Integr Environ Assess Manag 2014;10:167–178. © 2014 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of SETAC.
PMCID: PMC4235472  PMID: 24307344
Passive sampling methods; Organic contaminants; Freely dissolved aqueous concentration; Bioavailability; Sediment-associated contaminants
23.  Once Daily IV Busulfan and Fludarabine (IV Bu-Flu) Compares Favorably with IV Busulfan and Cyclophosphamide (IV BuCy2) as Pretransplant Conditioning Therapy in AML/MDS 
We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with IV busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. 67 patients received BuCy2 and subsequently 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these non-randomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 vs. 39 years, p< 0.01), more often had unrelated donors (47.3% vs. 20.9%, p< 0.0003), and had shorter median follow-up (39.7 vs. 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome (“period” effects), 78 AML patients receiving Melphalan-Flu (“MF”), treated in parallel during this time (1997 to 2004) were used to estimate the period effect; The MF patients’ outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in CR1 had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, while CR1 patients younger than age 41 had a 3-year EFS of 89%. These results support replacing BuCy±ATG with Bu-Flu±rabbit-ATG, and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1.
PMCID: PMC4230823  PMID: 18489993
IV Busulfan; Fludarabine; Cyclophosphamide; AML; MDS; Allogeneic Stem Cell Transplantation
24.  Historical factors that have shaped the evolution of tropical reef fishes: a review of phylogenies, biogeography, and remaining questions 
Frontiers in Genetics  2014;5:394.
Biodiversity patterns across the marine tropics have intrigued evolutionary biologists and ecologists alike. Tropical coral reefs host 1/3 of all marine species of fish on 0.1% of the ocean’s surface. Yet our understanding of how mechanistic processes have underpinned the generation of this diversity is limited. However, it has become clear that the biogeographic history of the marine tropics has played an important role in shaping the diversity of tropical reef fishes we see today. In the last decade, molecular phylogenies and age estimation techniques have provided a temporal framework in which the ancestral biogeographic origins of reef fish lineages have been inferred, but few have included fully sampled phylogenies or made inferences at a global scale. We are currently at a point where new sequencing technologies are accelerating the reconstruction and the resolution of the Fish Tree of Life. How will a complete phylogeny of fishes benefit the study of biodiversity in the tropics? Here, I review the literature concerning the evolutionary history of reef-associated fishes from a biogeographic perspective. I summarize the major biogeographic and climatic events over the last 65 million years that have regionalized the tropical marine belt and what effect they have had on the molecular record of fishes and global biodiversity patterns. By examining recent phylogenetic trees of major reef associated groups, I identify gaps to be filled in order to obtain a clearer picture of the origins of coral reef fish assemblages. Finally, I discuss questions that remain to be answered and new approaches to uncover the mechanistic processes that underpin the evolution of biodiversity on coral reefs.
PMCID: PMC4230204  PMID: 25431581
coral reef fishes; ancestral biogeography; marine tropics; phylogeny; diversification
25.  How Evolution of Genomes Is Reflected in Exact DNA Sequence Match Statistics 
Molecular Biology and Evolution  2014;32(2):524-535.
Genome evolution is shaped by a multitude of mutational processes, including point mutations, insertions, and deletions of DNA sequences, as well as segmental duplications. These mutational processes can leave distinctive qualitative marks in the statistical features of genomic DNA sequences. One such feature is the match length distribution (MLD) of exactly matching sequence segments within an individual genome or between the genomes of related species. These have been observed to exhibit characteristic power law decays in many species. Here, we show that simple dynamical models consisting solely of duplication and mutation processes can already explain the characteristic features of MLDs observed in genomic sequences. Surprisingly, we find that these features are largely insensitive to details of the underlying mutational processes and do not necessarily rely on the action of natural selection. Our results demonstrate how analyzing statistical features of DNA sequences can help us reveal and quantify the different mutational processes that underlie genome evolution.
PMCID: PMC4298173  PMID: 25398628
genome evolution; sequence similarities; segmental duplication; comparative genomics

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