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1.  Prevention of Arteriovenous Shunt Occlusion Using Microbubble and Ultrasound Mediated Thromboprophylaxis 
Palliative shunts in congenital heart disease patients are vulnerable to thrombotic occlusion. High mechanical index (MI) impulses from a modified diagnostic ultrasound (US) transducer during a systemic microbubble (MB) infusion have been used to dissolve intravascular thrombi without anticoagulation, and we sought to determine whether this technique could be used prophylactically to reduce thrombus burden and prevent occlusion of surgically placed extracardiac shunts.
Methods and Results
Heparin‐bonded ePTFE tubular vascular shunts of 4 mm×2.5 cm (Propaten; W.L Gore) were surgically placed in 18 pigs: a right‐sided side‐to‐side arteriovenous (AV, carotid‐jugular) shunt, and a left‐sided arterio‐arterial (AA, carotid‐carotid) interposition shunt in each animal. After shunt implantation, animals were randomly assigned to one of 3 groups. Transcutaneous, weekly 30‐minute treatments (total of 4 treatments) of either guided high MI US+MB (Group 1; n=6) using a 3% MRX‐801 MB infusion, or US alone (Group 2; n=6) were given separately to each shunt. The third group of 6 pigs received no treatments. The shunts were explanted after 4 weeks and analyzed by histopathology to quantify luminal thrombus area (mm2) for the length of each shunt. No pigs received antiplatelet agents or anticoagulants during the treatment period. The median overall thrombus burden in the 3 groups for AV shunts was 5.10 mm2 compared with 4.05 mm2 in AA (P=0.199). Group 1 pigs had significantly less thrombus burden in the AV shunts (median 2.5 mm2) compared with Group 2 (median 5.6 mm2) and Group 3 (median 7.5 mm2) pigs (P=0.006). No difference in thrombus burden was seen between groups for AA shunts.
Transcutaneous US with intravenous MB is capable of preventing thrombus accumulation in arteriovenous shunts without the need for antiplatelet agents, and may be a method of preventing progressive occlusion of palliative shunts.
PMCID: PMC3959668  PMID: 24518555
pediatric; shunt thrombosis; sonothrombolysis; therapeutic ultrasound
2.  Use of the Word “Cure” in Oncology 
Journal of Oncology Practice  2013;9(4):e136-e140.
Oncology clinicians say patients are hesitant to ask whether they are cured, and clinicians are hesitant to tell them they are cured. Annual oncology follow-up was frequently endorsed, even after 20 years of remission.
Use of the word “cure” in cancer care reflects a balance of physician and patient optimism, realism, medico-legal concerns, and even superstition. This study surveyed a group of oncology specialists regarding the frequency and determinants of using the word cure.
Oncology clinicians at the Dana-Farber Cancer Institute (n = 180) were invited to complete a survey regarding the word cure in cancer care. Participants completed a 19-question survey regarding how commonly their patients are cured, how often they use the word cure in their practice, and details about its use. Three case scenarios were presented to elicit participants' views.
Of the 117 participants (65%) who provided responses, 81% were hesitant to tell a patient that they are cured, and 63% would never tell a patient that they are cured. Only 7% felt that greater than 75% of their patients are, or will be, cured. The participating clinicians reported that only 34% of patients ask if they are cured. For 20-year survivors of testicular cancer, large-cell lymphoma, and estrogen receptor–positive breast cancer, 84%, 76%, and 48% of clinicians, respectively, believed that the patients were cured, and 35%, 43%, and 56% recommended annual oncology follow-up of the patients. Twenty-three percent of oncology clinicians believed that patients should never be discharged from the cancer center.
Oncology clinicians report that patients are hesitant to ask whether they are cured, and the clinicians are hesitant to tell patients they are cured. Annual oncology follow-up was frequently endorsed, even after 20 years in remission.
PMCID: PMC3710180  PMID: 23942930
3.  Gluten-free diet does not appear to induce endoscopic remission of eosinophilic esophagitis in children with coexistent celiac disease 
Celiac disease and eosinophilic esophagitis are usually considered to be separate gastrointestinal diseases; however, it appears that they may coexist more often than would be expected. It is unknown whether eosinophilic esophagitis in patients with celiac disease responds to a gluten-free diet.
To examine the clinical, endoscopic and histological features of children with both conditions to evaluate whether eosinophilic esophagitis responds to a gluten-free diet.
From January 1, 2009, to June 30, 2011, the medical records of children <18 years of age diagnosed with eosinophilic esophagitis and/or celiac disease were reviewed. Patients with clinical, endoscopic and histological diagnoses of both diseases were identified and included. These findings were analyzed, as were laboratory results, treatment and follow-up.
During the study period, there were 206 celiac disease patients, 86 eosinophilic esophagitis patients and nine (4.4% of total celiac) patients with both diagnoses. Gluten-free diet was the primary treatment for both conditions in seven of nine (78%) cases. In six of these seven (86%) patients, no endoscopic or histological improvement of eosinophilic esophagitis was observed, while in one patient, histological remission of esophageal eosinophilia occurred while on a gluten-free diet.
The prevalence of eosinophilic esophagitis in patients with celiac disease was 4.4%, confirming a higher than expected prevalence of eosinophilic esophagitis compared with the general population. In patients with celiac disease, a gluten-free diet did not appear to induce remission of coexistent endoscopic and histological features of eosinophilic esophagitis.
PMCID: PMC3414473  PMID: 22891176
Case series; Celiac disease; Eosinophilic esophagitis; Gluten-free diet
4.  Towards a System Level Understanding of Non-Model Organisms Sampled from the Environment: A Network Biology Approach 
PLoS Computational Biology  2011;7(8):e1002126.
The acquisition and analysis of datasets including multi-level omics and physiology from non-model species, sampled from field populations, is a formidable challenge, which so far has prevented the application of systems biology approaches. If successful, these could contribute enormously to improving our understanding of how populations of living organisms adapt to environmental stressors relating to, for example, pollution and climate. Here we describe the first application of a network inference approach integrating transcriptional, metabolic and phenotypic information representative of wild populations of the European flounder fish, sampled at seven estuarine locations in northern Europe with different degrees and profiles of chemical contaminants. We identified network modules, whose activity was predictive of environmental exposure and represented a link between molecular and morphometric indices. These sub-networks represented both known and candidate novel adverse outcome pathways representative of several aspects of human liver pathophysiology such as liver hyperplasia, fibrosis, and hepatocellular carcinoma. At the molecular level these pathways were linked to TNF alpha, TGF beta, PDGF, AGT and VEGF signalling. More generally, this pioneering study has important implications as it can be applied to model molecular mechanisms of compensatory adaptation to a wide range of scenarios in wild populations.
Author Summary
Understanding how living organisms adapt to changes in their natural habitats is of paramount importance particularly in respect to environmental stressors, such as pollution or climate. Computational models integrating the multi-level molecular responses with organism physiology are likely to be indispensable tools to address this challenge. However, because of the difficulties in acquiring and integrating data from non-model species and because of the intrinsic complexity of field studies, such an approach has not yet been attempted. Here we describe the first example of a global network reconstruction linking transcriptional and metabolic responses to physiology in the flatfish, European flounder, a species currently used to monitor coastal waters around Northern Europe. The model we developed has revealed a remarkable similarity between network modules predictive of chemical exposure in the environment and pathways involved in relevant aspects of human pathophysiology. Generally, the approach we have pioneered has important implications as it can be applied to model molecular mechanisms of compensatory adaptation to a wide range of scenarios in wild populations.
PMCID: PMC3161900  PMID: 21901081
5.  A method to correct for population structure using a segregation model 
BMC Proceedings  2009;3(Suppl 7):S104.
To overcome the "spurious" association caused by population stratification in population-based association studies, we propose a principal-component based method that can use both family and unrelated samples at the same time. More specifically, we adapt the multivariate logistic model, which is often used in segregation analysis and can allow for the family correlation structure, for association analysis. To correct the effect of hidden population structure, the first ten principal-components calculated from the matrix of marker genotype data are incorporated as covariates in the model. To test for the association, the marker of interest is also incorporated as a covariate in the model. We applied the proposed method to the second generation (i.e., the Offspring Cohort), in the Genetic Analysis Workshop 16 Framingham Heart Study 50 k data set to evaluate the performance of the method. Although there may have been difficulty in the convergence while maximizing the likelihood function as indicated by a flat likelihood, the distribution of the empirical p-values for the test statistic does show that the method has a correct type I error rate whenever the variance-covariance matrix of the estimates can be computed.
PMCID: PMC2795875  PMID: 20017968
6.  An efficient algorithm to compute marginal posterior genotype probabilities for every member of a pedigree with loops 
Marginal posterior genotype probabilities need to be computed for genetic analyses such as geneticcounseling in humans and selective breeding in animal and plant species.
In this paper, we describe a peeling based, deterministic, exact algorithm to compute efficiently genotype probabilities for every member of a pedigree with loops without recourse to junction-tree methods from graph theory. The efficiency in computing the likelihood by peeling comes from storing intermediate results in multidimensional tables called cutsets. Computing marginal genotype probabilities for individual i requires recomputing the likelihood for each of the possible genotypes of individual i. This can be done efficiently by storing intermediate results in two types of cutsets called anterior and posterior cutsets and reusing these intermediate results to compute the likelihood.
A small example is used to illustrate the theoretical concepts discussed in this paper, and marginal genotype probabilities are computed at a monogenic disease locus for every member in a real cattle pedigree.
PMCID: PMC2801663  PMID: 19958551
7.  Amino acid sequence divergence of Tat protein (exon1)of subtype B and C HIV-1 strains: Does it have implications for vaccine development? 
Bioinformation  2009;4(6):237-241.
Functional genes of HIV-1 like the tat express proteins essential for viral survival and propagation. There are variations reported in levels of Tat transactivation among the different subtypes of HIV-1. This study looked at the amino acid differences in the different regions of Tat protein (exon 1) of subtype B and C strains of HIV-1 and tried to observe a molecular basis for protein function. HIV-1 sequences of subtype B (n=30) and C (n=60) strains were downloaded from HIV-1 Los Alamos data base. Among the 60 subtype C strain sequences, 30 each were from India and Africa. A HIV-1 Tat protein (exon 1) sequence, the consensus B and C sequence was obtained from the ’sequence search interface‘ in the Los Alamos HIV-1 sequence data. The sequences were visualized using Weblogo and the RNA binding regions of the three consensus sequences were also determined using BindN software program. Compared to subtype B, there was a high level of divergence in the auxiliary domain of tat exon 1 (amino acid positions 58- 69). The net charge of the subtype C (Indian) Tat protein (exon 1) auxiliary domain was -1.9 at pH 7 and it had an isoelectric point of 4.1. The net charge of the subtype C (African) auxiliary domain was -2.9 at pH 7 and it had an isoelectric point of 3.7 while the net charge of same region in subtype B was -0.9 at pH 7 with an isoelectric point of 4.9. The ratio of the hydrophilic residues to the total number of residues was 60% in the in both the Indian and African subtype C in the auxiliary domain while this was 50% in subtype B. The consensus subtype B sequence was found to have 36 RNA binding sites while subtype C (India) had 33 and subtype C (Africa) had 32 RNA binding sites. The HIV-1 Tat-TAR interaction is a potential target for inhibitors and being considered for its potential use in HIV-1 vaccines. Development of such inhibitor/vaccines would have to take into consideration the variation in amino acid sequence analyzed in this study as this could determine epitope presentation on MHC class I antigen for afferent immune response.
PMCID: PMC2951709  PMID: 20975916
HIV-1; Subtype C; India; tat
8.  HIV reverse transcriptase: Structural interpretation of drug resistant genetic variants from India 
Bioinformation  2009;4(1):36-45.
The reverse transcriptase (RT) enzyme is the prime target of nucleoside/ nucleotide (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors. Here we investigate the structural basis of effects of drug-resistance mutations in clade C RT using three-dimensional structural modeling. Apropos the expectation was for unique mechanisms in clade C based on interactions with amino acids of p66 subunit in RT molecule. 3-D structures of RT with mutations found in sequences from 2 treatment naïve, 8 failed and one reference clade C have been modeled and analyzed. Models were generated by computational mutation of available crystal structures of drug bound homologous RT. Energy minimization of the models and the structural analyses were carried out using standard methods. Mutations at positions 75,101,118,190,230,238 and 318 known to confer drug resistance were investigated. Different mutations produced different effects such as alteration of geometry of the drugbinding pocket, structural changes at the site of entry of the drug (into the active site), repositioning the template bases or by discriminating the inhibitors from their natural substrates. For the mutations analyzed, NRTI resistance was mediated mainly by the ability to discriminate between inhibitors and natural substrate, whereas, NNRTI resistance affected either the drug entry or the geometry of the active site. Our analysis suggests that different mutations result in different structural effects affecting the ability of a given drug to bind to the RT. Our studies will help in the development of newer drugs taking into account the presence of these mutations and the structural basis of drug resistance.
PMCID: PMC2770369  PMID: 20011151
Drug resistance; Genetic mutations; HIV-1; Reverse transcriptase; Structural modeling
9.  Within-Home versus Between-Home Variability of House Dust Endotoxin in a Birth Cohort 
Environmental Health Perspectives  2005;113(11):1516-1521.
Endotoxin exposure has been proposed as an environmental determinant of allergen responses in children. To better understand the implications of using a single measurement of house dust endotoxin to characterize exposure in the first year of life, we evaluated room-specific within-home and between-home variability in dust endotoxin obtained from 470 households in Boston, Massachusetts. Homes were sampled up to two times over 5–11 months. We analyzed 1,287 dust samples from the kitchen, family room, and baby’s bedroom for endotoxin. We fit a mixed-effects model to estimate mean levels and the variation of endotoxin between homes, between rooms, and between sampling times. Endotoxin ranged from 2 to 1,945 units per milligram of dust. Levels were highest during summer and lowest in the winter. Mean endotoxin levels varied significantly from room to room. Cross-sectionally, endotoxin was moderately correlated between family room and bedroom floor (r = 0.30), between family room and kitchen (r = 0.32), and between kitchen and bedroom (r = 0.42). Adjusting for season, the correlation of endotoxin levels within homes over time was 0.65 for both the bedroom and kitchen and 0.54 for the family room. The temporal within-home variance of endotoxin was lowest for bedroom floor samples and highest for kitchen samples. Between-home variance was lowest in the family room and highest for kitchen samples. Adjusting for season, within-home variation was less than between-home variation for all three rooms. These results suggest that room-to-room and home-to-home differences in endotoxin influence the total variability more than factors affecting endotoxin levels within a room over time.
PMCID: PMC1310912  PMID: 16263505
dust endotoxin; endotoxin; intraclass correlation; variance components
10.  Fitzgerald Trait 
Journal of Clinical Investigation  1975;55(5):1082-1089.
The prolonged partial thromboplastin time observed in the plasma of a 71-yr-old asymptomatic man was related to the deficiency of a hitherto unrecognized agent. The patient's plasma also exhibited impaired surface-mediated fibrinolysis and esterolytic activity and impaired generation of kinins and of the property enhancing vascular permeability designated PF/Dil. The patient's plasma contained normal amounts of all known clotting factors except Fletcher factor (a plasma prekallikrein) which was present at a concentration of 10-15% of pooled normal plasma. Fletcher trait plasma, however, contained normal amounts of the agent missing from the patient's plasma and corrected the defects in clotting, fibrinolysis, and vascular permeability. Fletcher trait plasma was less effective in correcting generation of kinins and esterolytic activity, presumably because of the patient's partial deficiency of prekallikrein. The site of action of the factor deficient in the patient's plasma appeared to be subsequent to the activation of Hageman factor and plasma prekallikrein. A fraction of normal plasma, devoid of other clotting factors, corrected the defect in clotting in the patient's plasma; a similar fraction of the patient's plasma did not correct this abnormality. No evidence yet exists pointing to the familial nature of the patient's defect. Tentatively, the patient's disorder may be referred to by his surname as Fitzgerald trait, and the agent apparently deficient in his plasma as Fitzgerald factor.
PMCID: PMC301855  PMID: 16695963

Results 1-10 (10)