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1.  Outcomes of high volume cataract surgeries in a developing country 
The British Journal of Ophthalmology  2005;89(9):1079-1083.
Aim: To analyse the outcome of high volume cataract surgery in a developing country, community based, high volume eye hospital.
Methods: In a non-comparative interventional case series, the authors reviewed the surgical outcomes of 593 patients with cataract operated upon by three high volume surgeons on six randomly selected days. There were 318 female (54%) and 275 male (46%) patients. Their mean age was 59.57 (SD 10.13) years. The majority of the patients underwent manual small incision cataract surgery (manual SICS). Extracapsular cataract extraction with posterior chamber intraocular lens (ECCE-PCIOL) and intracapsular cataract extraction (ICCE) were also done on a few patients as clinically indicated.
Results: Best corrected visual acuity of ⩾6/18 was achieved in 94% of the 520 patients who could be followed up on the 40th postoperative day (88% follow up rate). Intraoperative and immediate postoperative complications as defined by OCTET occurred in 11 (1.9%) and 75 (12.6%) patients, respectively. Average surgical time of 3.75 minutes per case (16–18 cases per hour) was achieved. Statistically significant risk factors for outcomes were found to be age >60, sex, and surgeon.
Conclusion: High volume surgery using appropriate techniques and standardised protocols does not compromise quality of outcomes.
PMCID: PMC1772816  PMID: 16113352
cataract surgery; developing country
2.  Runx Family Genes in a Cartilaginous Fish, the Elephant Shark (Callorhinchus milii) 
PLoS ONE  2014;9(4):e93816.
The Runx family genes encode transcription factors that play key roles in hematopoiesis, skeletogenesis and neurogenesis and are often implicated in diseases. We describe here the cloning and characterization of Runx1, Runx2, Runx3 and Runxb genes in the elephant shark (Callorhinchus milii), a member of Chondrichthyes, the oldest living group of jawed vertebrates. Through the use of alternative promoters and/or alternative splicing, each of the elephant shark Runx genes expresses multiple isoforms similar to their orthologs in human and other bony vertebrates. The expression profiles of elephant shark Runx genes are similar to those of mammalian Runx genes. The syntenic blocks of genes at the elephant shark Runx gene loci are highly conserved in human, but represented by shorter conserved blocks in zebrafish indicating a higher degree of rearrangements in this teleost fish. Analysis of promoter regions revealed conservation of binding sites for transcription factors, including two tandem binding sites for Runx that are totally conserved in the distal promoter regions of elephant shark Runx1-3. Several conserved noncoding elements (CNEs), which are putative cis-regulatory elements, and miRNA binding sites were identified in the elephant shark and human Runx gene loci. Some of these CNEs and miRNA binding sites are absent in teleost fishes such as zebrafish and fugu. In summary, our analysis reveals that the genomic organization and expression profiles of Runx genes were already complex in the common ancestor of jawed vertebrates.
PMCID: PMC3974841  PMID: 24699678
3.  Characterizing Long-Term Land Use/Cover Change in the United States from 1850 to 2000 Using a Nonlinear Bi-analytical Model 
Ambio  2012;42(3):285-297.
We relate the historical (1850–2000) spatial and temporal changes in cropland cover in the conterminous United States to several socio-economic and biophysical determinants using an eco-region based spatial framework. Results show population density as a major determinant during the nineteenth century, and biophysical suitability as the major determinant during the twentieth century. We further examine the role of technological innovations, socio-economic and socio-ecological feedbacks that have either sustained or altered the cropland trajectories in different eco-regions. The cropland trajectories for each of the 84 level-III eco-regions were analyzed using a nonlinear bi-analytical model. In the Eastern United States, low biophysically suitable eco-regions, e.g., New England, have shown continual decline in the cropland after reaching peak levels. The cropland trajectories in high biophysically suitable regions, e.g., Corn Belt, have stabilized after reaching peak levels. In the Western United States, low-intensity crop cover (<10 %) is sustained with irrigation support. A slower rate of land conversion was found in the industrial period. Significant effect of Conservation Reserve Program on planted crop area is found in last two decades (1990–2010).
Electronic supplementary material
The online version of this article (doi:10.1007/s13280-012-0354-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3606703  PMID: 23151939
Land cover change; Cropland change; Spatial determinants; United States
4.  Persistent Genital Tract HIV-1 RNA Shedding After Change in Treatment Regimens in Antiretroviral-Experienced Women with Detectable Plasma Viral Load 
Journal of Women's Health  2013;22(4):330-338.
To longitudinally assess the association between plasma viral load (PVL) and genital tract human immunodeficiency virus (GT HIV) RNA among HIV-1 infected women changing highly active antiretroviral therapy (HAART) because of detectable PVL on current treatment.
Women were eligible for the study if they had detectable PVL (defined as two consecutive samples with PVL>1000 copies/mL) and intended to change their current HAART regimen at the time of enrollment. Paired plasma and GT HIV-1 RNA were measured prospectively over 3 years. Longitudinal analyses examined rates of GT HIV-1 RNA shedding and the association with PVL.
Sixteen women were followed for a median of 11 visits contributing a total of 205 study visits. At study enrollment, all had detectable PVL and 69% had detectable GT HIV-1 RNA. Half of the women changed to a new HAART regimen with ≥3 active antiretroviral drugs. The probability of having detectable PVL ≥30 days after changing HAART was 0.56 (95% CI: 0.37 to 0.74). Fourteen women (88%) had detectable PVL on a follow-up visit ≥30 or 60 days after changing HAART; and 12 women (75%) had detectable GT HIV-1 RNA on a follow-up visit ≥30 or 60 days after changing HAART. When PVL was undetectable, GT shedding occurred at 11% of visits, and when PVL was detectable, GT shedding occurred at 47% of visits.
Some treatment-experienced HIV-infected women continue to have detectable virus in both the plasma and GT following a change in HAART, highlighting the difficulty of viral suppression in this patient population.
PMCID: PMC3627435  PMID: 23531097
5.  Relationship between particulate matter exposure and atherogenic profile in “Ground Zero” workers as shown by dynamic contrast enhanced MR imaging 
In this pilot study, we hypothesize that dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has the potential to evaluate differences in atherosclerosis profiles in patients subjected to high (initial dust cloud) and low (after 13 September 2001) particulate matter (PM) exposure. Exposure to PM may be associated with adverse health effects leading to increased morbidity. Law enforcement workers were exposed to high levels of particulate pollution after working at “Ground Zero” and may exhibit accelerated atherosclerosis. 31 subjects (28 male) with high (n = 19) or low (n = 12) exposure to PM underwent DCE-MRI. Demographics (age, gender, family history, hypertension, diabetes, BMI, and smoking status), biomarkers (lipid profiles, hs-CRP, BP) and ankle-brachial index (ABI) measures (left and right) were obtained from all subjects. Differences between the high and low exposures were compared using independent samples t test. Using linear forward stepwise regression with information criteria model, independent predictors of increased area under curve (AUC) from DCE-MRI were determined using all variables as input. Confidence interval of 95 % was used and variables with p > 0.1 were eliminated. p < 0.05 was considered significant. Subjects with high exposure (HE) had significantly higher DCE-MRI AUC uptake (increased neovascularization) compared to subjects with lower exposure (LE). (AUC: 2.65 ± 0.63 HE vs. 1.88 ± 0.69 LE, p = 0.016). Except for right leg ABI, none of the other parameters were significantly different between the two groups. Regression model indicated that only HE to PM, CRP > 3.0 and total cholesterol were independently associated with increased neovascularization (in decreasing order of importance, all p < 0.026). HE to PM may increase plaque neovascularization, and thereby potentially indicate worsening atherogenic profile of “Ground Zero” workers.
PMCID: PMC3647018  PMID: 23179748
DCE-MRI; Particulate matter; Atherosclerosis; Plaque neovascularization
6.  Morphological Differences between Ruptured and Unruptured Basilar Bifurcation Aneurysms 
Background Aspect ratio (AP), daughter artery ratio (DA), and lateral angle ratio (LA) have been reported in middle cerebral artery bifurcation aneurysms to correlate with rupture status.
Objective To study the differences in AP, DA, LA, and aneurysm orientation between ruptured and unruptured basilar bifurcation aneurysms.
Methods Three-dimensional (3D) angiograms of patients with basilar bifurcation aneurysms were analyzed for AP, DA, and LA. Aneurysm projection was classified as type A if the long axis of aneurysm was along basilar artery and type-B if otherwise.
Results Thirty-one ruptured and 17 unruptured aneurysms were analyzed. The APs were significantly different (p = 0.008), 2.63 ± 1.1 for ruptured aneurysms and 1.7 ± 0.55 for unruptured aneurysms. AP ≥ 1.9 correlated with rupture status with 68% sensitivity and 70% specificity. Type-A configuration was significantly associated with ruptured aneurysms with an odds ratio (OR) of 5.9. LAs were 0.9 ± 0.4 and 1.4 ± 0.8 for ruptured and unruptured aneurysms, respectively, and the difference tended to be significant (p = 0.56). DAs were 1.25 ± 0.22 and 1.21 ± 0.19 for ruptured and unruptured aneurysms without any statistical difference.
Conclusion AP > 1.9, type-A configuration, and lower LA is associated with ruptured basilar bifurcation aneurysms. DA did not differ between ruptured and unruptured aneurysms
PMCID: PMC3699210  PMID: 24436894
rupture; aspect ratio; lateral angle ratio; daughter artery ratio; aneurysm
7.  Synapse Maturation by Activity-Dependent Ectodomain Shedding of SIRPα 
Nature neuroscience  2013;16(10):10.1038/nn.3516.
Formation of appropriate synaptic connections is critical for proper functioning of the brain. After initial synaptic differentiation, active synapses are stabilized by neural activity-dependent signals to establish functional synaptic connections. However, the molecular mechanisms underlying activity-dependent synapse maturation remain to be elucidated. Here we show that activity-dependent ectodomain shedding of SIRPα mediates presynaptic maturation. Two target-derived molecules, FGF22 and SIRPα, sequentially organize the glutamatergic presynaptic terminals during the initial synaptic differentiation and synapse maturation stages, respectively, in the mouse hippocampus. SIRPα drives presynaptic maturation in an activity-dependent fashion. Remarkably, neural activity cleaves the extracellular domain of SIRPα, and the shed ectodomain, in turn, promotes the maturation of the presynaptic terminal. This process involves CaM kinase, matrix metalloproteinases, and the presynaptic receptor CD47. Finally, SIRPα-dependent synapse maturation has significant impacts on synaptic function and plasticity. Thus, ectodomain shedding of SIRPα is an activity-dependent trans-synaptic mechanism for the maturation of functional synapses.
PMCID: PMC3820962  PMID: 24036914
8.  A comparative analysis of trypanosomatid SNARE proteins☆ 
Parasitology International  2014;63(2):341-348.
The Kinetoplastida are flagellated protozoa evolutionary distant and divergent from yeast and humans. Kinetoplastida include trypanosomatids, and a number of important pathogens. Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. inflict significant morbidity and mortality on humans and livestock as the etiological agents of human African trypanosomiasis, Chagas' disease and leishmaniasis respectively. For all of these organisms, intracellular trafficking is vital for maintenance of the host–pathogen interface, modulation/evasion of host immune system responses and nutrient uptake. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are critical components of the intracellular trafficking machinery in eukaryotes, mediating membrane fusion and contributing to organelle specificity. We asked how the SNARE complement evolved across the trypanosomatids. An in silico search of the predicted proteomes of T. b. brucei and T. cruzi was used to identify candidate SNARE sequences. Phylogenetic analysis, including comparisons with yeast and human SNAREs, allowed assignment of trypanosomatid SNAREs to the Q or R subclass, as well as identification of several SNAREs orthologous with those of opisthokonts. Only limited variation in number and identity of SNAREs was found, with Leishmania major having 27 and T. brucei 26, suggesting a stable SNARE complement post-speciation. Expression analysis of T. brucei SNAREs revealed significant differential expression between mammalian and insect infective forms, especially within R and Qb-SNARE subclasses, suggesting possible roles in adaptation to different environments. For trypanosome SNAREs with clear orthologs in opisthokonts, the subcellular localization of TbVAMP7C is endosomal while both TbSyn5 and TbSyn16B are at the Golgi complex, which suggests conservation of localization and possibly also function. Despite highly distinct life styles, the complement of trypanosomatid SNAREs is quite stable between the three pathogenic lineages, suggesting establishment in the last common ancestor of trypanosomes and Leishmania. Developmental changes to SNARE mRNA levels between blood steam and procyclic life stages suggest that trypanosomes modulate SNARE functions via expression. Finally, the locations of some conserved SNAREs have been retained across the eukaryotic lineage.
Graphical abstract
•SNARE proteins are essential components of intracellular transport.•These proteins exhibit considerable conservation across pathogenic trypanosomes.•Some trypanosome SNARE families are expanded or lost.•Developmental changes in trypanosome SNARE expression are apparent.•Orthologous SNAREs demonstrate conserved locations and hence function.
PMCID: PMC3979113  PMID: 24269876
Trypanosoma; SNARE; Molecular evolution; Vesicle trafficking
9.  Preserved Coronary Flow Reserve Effectively Excludes High-Risk Coronary Artery Disease on Angiography 
Myocardial perfusion imaging has limited sensitivity for the detection of high-risk coronary artery disease (CAD). We tested the hypothesis that a normal coronary flow reserve (CFR) would be helpful for excluding the presence of high-risk CAD on angiography.
We studied 290 consecutive patients undergoing 82Rb PET within 180 d of invasive coronary angiography. High-risk CAD on angiography was defined as 2-vessel disease (≥70% stenosis), including the proximal left anterior descending artery; 3-vessel disease; or left main CAD (≥50% stenosis). Patients with prior Q wave myocardial infarction, elevated troponin levels between studies, prior coronary artery bypass grafting, a left ventricular ejection fraction of less than 40%, or severe valvular heart disease were excluded.
Fifty-five patients (19%) had high-risk CAD on angiography. As expected, the trade-off between the sensitivity and the specificity of the CFR for identifying high-risk CAD varied substantially depending on the cutoff selected. In multivariable analysis, a binary CFR of less than or equal to 1.93 provided incremental diagnostic information for the identification of high-risk CAD beyond the model with the Duke clinical risk score (>25%), percentage of left ventricular ischemia (>10%), transient ischemic dilation index (>1.07), and change in the left ventricular ejection fraction during stress (<2) (P = 0.0009). In patients with normal or slightly to moderately abnormal results on perfusion scans (<10% of left ventricular mass) during stress (n = 136), a preserved CFR (>1.93) excluded high-risk CAD with a high sensitivity (86%) and a high negative predictive value (97%).
A normal CFR has a high negative predictive value for excluding high-risk CAD on angiography. Although an abnormal CFR increases the probability of significant obstructive CAD, it cannot reliably distinguish significant epicardial stenosis from nonobstructive, diffuse atherosclerosis or microvascular dysfunction.
PMCID: PMC3962818  PMID: 24408896
coronary flow reserve; 82Rb PET; coronary artery disease
10.  Mucus and adiponectin deficiency: role in chronic inflammation-induced colon cancer 
This study aims to define the role of adiponectin (APN) in preventing goblet cell apoptosis and in differentiation of epithelial cells to goblet cell lineage resulting in greater mucus production and hence greater protection from chronic inflammation-induced colon cancer (CICC).
Six- to eight-week-old male APNKO and C57BL/6 (WT) mice were randomly distributed to three treatment groups: DSS, DMH, DSS+DMH and control. Chronic inflammation was induced in DSS and DSS+ DMH group by administrating 2 % DSS in drinking water for 5 days followed by 5 days of normal drinking water and this constitutes one DSS cycle. Three cycles of DSS were administered to induce chronic inflammation. Cancer was induced in both APNKO and WT mice in DMH and DSS+ DMH groups by intraperitoneal injections of DMH (20 mg/kg body weight) once for DSS+DMH group and once per week for 12 weeks for DMH group. On day 129, the colon tissue was dissected for mucus thickness measurements and for genomic studies. HT29-Cl.16E and Ls174T cells were used for several genomic and siRNA studies.
APNKO mice have more tumors and tumor area in DSS+DMH group than WT mice. APN deficiency down-regulated goblet to epithelial cell ratio and enhanced the colonic mucosal erosion with reduced mucus thickness. APN increases Muc2 production with no affect on Muc1 production. APN abated goblet cell apoptosis, while APN deficiency reduced epithelial to goblet cell differentiation.
APN may be involved in reducing the severity of CICC by preventing goblet cell apoptosis and increasing epithelial to goblet cell differentiation.
PMCID: PMC3961717  PMID: 23474825
Mucus; Adiponectin; Colon cancer; Inflammation; Goblet cells
11.  Evaluation of Dietary Effects on Hepatic Lipids in High Fat and Placebo Diet Fed Rats by In Vivo MRS and LC-MS Techniques 
PLoS ONE  2014;9(3):e91436.
Background & Aims
Dietary saturated fatty acids contribute to the development of fatty liver and have pathogenic link to systemic inflammation. We investigated the effects of dietary fat towards the pathogenesis of non-alcoholic fatty liver disease by longitudinal in vivo magnetic resonance spectroscopy (MRS) and in vitro liquid chromatography coupled with mass spectrometry (LC-MS).
All measurements were performed on rats fed with high fat diet (HFD) and chow diet for twenty four weeks. Longitudinal MRS measurements were performed at the 12th, 18th and 24th weeks. Liver tissues were analyzed by LC-MS, histology and gene transcription studies after terminal in vivo experiments.
Liver fat content of HFD rats for all ages was significantly (P<0.05) higher compared to their respective chow diet fed rats. Unsaturation indices estimated from MRS and LC-MS data of chow diet fed rats were significantly higher (P<0.05) than HFD fed rats. The concentration of triglycerides 48∶1, 48∶2, 50∶1, 50∶2, 50∶3, 52∶1, 52∶2, 52∶3, 54∶3 and 54∶2 was significantly higher (P<0.05) in HFD rats. The concentration for some polyunsaturated triglycerides 54∶7, 56∶8, 56∶7, 58∶11, 58∶10, 58∶9, 58∶8 and 60∶10 was significantly higher (P<0.05) in chow diet fed rats compared to HFD rats. Lysophospholipid concentrations including LPC and LPE were higher in HFD rats at 24 weeks indicating the increased risk of diabetes. The expression of CD36, PPARα, SCD1, SREBF1 and UCP2 were significantly upregulated in HFD rats.
We demonstrated the early changes in saturated and unsaturated lipid composition in fatty liver by in vivo MRS and ex vivo LC-MS. The higher LPC concentration in HFD rats indicated a higher risk of developing diabetes. Early metabolic perturbations causing changes in lipid composition can be evaluated by the unsaturation index and correlated to the non alcoholic fatty liver disease.
PMCID: PMC3956606  PMID: 24638096
12.  Factors predicting adverse short-term outcomes in patients with acute cholangitis undergoing ERCP: A single center experience 
AIM: To identify potential factors that can predict adverse short-term outcomes in patients with acute cholangitis undergoing endoscopic retrograde cholangiopancreatography (ERCP).
METHODS: Retrospective analysis of consecutive patients admitted to our center for acute cholangitis and underwent ERCP from 2001 to 2012. Involvement of two or more organ systems was termed as organ failure (OF). Cardiovascular failure was defined based on a systolic blood pressure of < 90 mmHg despite fluid replacement and/or requiring vasopressor treatment; respiratory failure if the Pa02/Fi02 ratio was < 300 mmHg and/or required mechanical ventilation; coagulopathy if the platelet count was < 80; and renal insufficiency if serum creatinine was > 1.9 mg/dL. Variables associated with short term adverse clinical outcomes defined as persistent OF and/or 30-d mortality was determined.
RESULTS: A total of 172 patients (median age 62 years, 56.4% female) were included. The median door to ERCP time was 17 h. Bile duct stones were the most common etiology (n = 67, 39.2%). In multivariate analysis, factors that were independently associated with persistent OF and/or 30-d mortality included American Society of Anesthesiology (ASA) physical classification score > 3 (OR = 7.70; 95%CI: 2.73-24.40), presence of systemic inflammatory response syndrome (OR = 3.67; 95%CI: 1.34-10.3) and door to ERCP time greater than 72 h (OR = 3.36; 95%CI: 1.12-10.20). Door to ERCP time greater than 72 h was also associated with 70% increase in the mean length of stay (P < 0.001). Every one point increase in the ASA physical classification and every 1 mg/dL increase in the pre-ERCP bilirubin level was associated with a 34% and 2% increase in the mean length of hospital stay, respectively. Transfer status did not impact clinical outcomes.
CONCLUSION: Higher ASA physical classification and delays in ERCP are associated with adverse clinical outcomes and prolonged length of hospital stay in patients with acute cholangitis undergoing ERCP.
PMCID: PMC3952163  PMID: 24634711
Endoscopic retrograde cholangiopancreatography; Cholangitis; Outcomes
13.  Machine-learning prediction of cancer survival: a retrospective study using electronic administrative records and a cancer registry 
BMJ Open  2014;4(3):e004007.
Using the prediction of cancer outcome as a model, we have tested the hypothesis that through analysing routinely collected digital data contained in an electronic administrative record (EAR), using machine-learning techniques, we could enhance conventional methods in predicting clinical outcomes.
A regional cancer centre in Australia.
Disease-specific data from a purpose-built cancer registry (Evaluation of Cancer Outcomes (ECO)) from 869 patients were used to predict survival at 6, 12 and 24 months. The model was validated with data from a further 94 patients, and results compared to the assessment of five specialist oncologists. Machine-learning prediction using ECO data was compared with that using EAR and a model combining ECO and EAR data.
Primary and secondary outcome measures
Survival prediction accuracy in terms of the area under the receiver operating characteristic curve (AUC).
The ECO model yielded AUCs of 0.87 (95% CI 0.848 to 0.890) at 6 months, 0.796 (95% CI 0.774 to 0.823) at 12 months and 0.764 (95% CI 0.737 to 0.789) at 24 months. Each was slightly better than the performance of the clinician panel. The model performed consistently across a range of cancers, including rare cancers. Combining ECO and EAR data yielded better prediction than the ECO-based model (AUCs ranging from 0.757 to 0.997 for 6 months, AUCs from 0.689 to 0.988 for 12 months and AUCs from 0.713 to 0.973 for 24 months). The best prediction was for genitourinary, head and neck, lung, skin, and upper gastrointestinal tumours.
Machine learning applied to information from a disease-specific (cancer) database and the EAR can be used to predict clinical outcomes. Importantly, the approach described made use of digital data that is already routinely collected but underexploited by clinical health systems.
PMCID: PMC3963101  PMID: 24643167
Cancer; Survival; Prediction; Machine Learning; Electronic Medical Record
14.  Risk stratification using data from electronic medical records better predicts suicide risks than clinician assessments 
BMC Psychiatry  2014;14:76.
To date, our ability to accurately identify patients at high risk from suicidal behaviour, and thus to target interventions, has been fairly limited. This study examined a large pool of factors that are potentially associated with suicide risk from the comprehensive electronic medical record (EMR) and to derive a predictive model for 1–6 month risk.
7,399 patients undergoing suicide risk assessment were followed up for 180 days. The dataset was divided into a derivation and validation cohorts of 4,911 and 2,488 respectively. Clinicians used an 18-point checklist of known risk factors to divide patients into low, medium, or high risk. Their predictive ability was compared with a risk stratification model derived from the EMR data. The model was based on the continuation-ratio ordinal regression method coupled with lasso (which stands for least absolute shrinkage and selection operator).
In the year prior to suicide assessment, 66.8% of patients attended the emergency department (ED) and 41.8% had at least one hospital admission. Administrative and demographic data, along with information on prior self-harm episodes, as well as mental and physical health diagnoses were predictive of high-risk suicidal behaviour. Clinicians using the 18-point checklist were relatively poor in predicting patients at high-risk in 3 months (AUC 0.58, 95% CIs: 0.50 – 0.66). The model derived EMR was superior (AUC 0.79, 95% CIs: 0.72 – 0.84). At specificity of 0.72 (95% CIs: 0.70-0.73) the EMR model had sensitivity of 0.70 (95% CIs: 0.56-0.83).
Predictive models applied to data from the EMR could improve risk stratification of patients presenting with potential suicidal behaviour. The predictive factors include known risks for suicide, but also other information relating to general health and health service utilisation.
PMCID: PMC3984680  PMID: 24628849
Suicide risk; Electronic medical record; Predictive models
15.  Quantification of Myocardial Perfusion Reserve Using Dynamic SPECT Imaging in Humans: A Feasibility Study 
Myocardial perfusion imaging (MPI) is well established in the diagnosis and workup of patients with known or suspected coronary artery disease (CAD); however, it can underestimate the extent of obstructive CAD. Quantification of myocardial perfusion reserve with PET can assist in the diagnosis of multivessel CAD. We evaluated the feasibility of dynamic tomographic SPECT imaging and quantification of a retention index to describe global and regional myocardial perfusion reserve using a dedicated solid-state cardiac camera.
Ninety-five consecutive patients (64 men and 31 women; median age, 67 y) underwent dynamic SPECT imaging with 99mTc-sestamibi at rest and at peak vasodilator stress, followed by standard gated MPI. The dynamic images were reconstructed into 60–70 frames, 3–6 s/frame, using ordered-subsets expectation maximization with 4 iterations and 32 subsets. Factor analysis was used to estimate blood-pool time–activity curves, used as input functions in a 2-compartment kinetic model. K1 values (99mTc-sestamibi uptake) were calculated for the stress and rest images, and K2 values (99mTc-sestamibi washout) were set to zero. Myocardial perfusion reserve (MPR) index was calculated as the ratio of the stress and rest K1 values. Standard MPI was evaluated semiquantitatively, and total perfusion deficit (TPD) of at least 5% was defined as abnormal.
Global MPR index was higher in patients with normal MPI (n = 51) than in patients with abnormal MPI (1.61 [interquartile range (IQR), 1.33–2.03] vs. 1.27 [IQR, 1.12–1.61], P = 0.0002). By multivariable regression analysis, global MPR index was associated with global stress TPD, age, and smoking. Regional MPR index was associated with the same variables and with regional stress TPD. Sixteen patients undergoing invasive coronary angiography had 20 vessels with stenosis of at least 50%. The MPR index was 1.11 (IQR, 1.01–1.21) versus 1.30 (IQR, 1.12–1.67) in territories supplied by obstructed and nonobstructed arteries, respectively (P = 0.02). MPR index showed a stepwise reduction with increasing extent of obstructive CAD (P = 0.02).
Dynamic tomographic imaging and quantification of a retention index describing global and regional perfusion reserve are feasible using a solid-state camera. Preliminary results show that the MPR index is lower in patients with perfusion defects and in regions supplied by obstructed coronary arteries. Further studies are needed to establish the clinical role of this technique as an aid to semiquantitative analysis of MPI.
PMCID: PMC3951831  PMID: 23578996
dynamic SPECT; myocardial perfusion imaging; quantification; solid-state camera; coronary artery disease
16.  Quantitative Relationship Between the Extent and Morphology of Coronary Atherosclerotic Plaque and Downstream Myocardial Perfusion 
The purpose of this study was to quantify the effects of coronary atherosclerosis morphology and extent on myocardial flow reserve (MFR).
Although the relationship between coronary stenosis and myocardial perfusion is well established, little is known about the contribution of other anatomic descriptors of atherosclerosis burden to this relationship.
We evaluated the relationship between atherosclerosis plaque burden, morphology, and composition and regional MFR (MFRregional) in 73 consecutive patients undergoing Rubidium-82 positron emission tomography and coronary computed tomography angiography for the evaluation of known or suspected coronary artery disease.
Atherosclerosis was seen in 51 of 73 patients and in 107 of 209 assessable coronary arteries. On a per-vessel basis, the percentage diameter stenosis (p = 0.02) or summed stenosis score (p = 0.002), integrating stenoses in series, was the best predictor of MFRregional. Importantly, MFRregional varied widely within each coronary stenosis category, even in vessels with nonobstructive plaques (n = 169), 38% of which had abnormal MFRregional (<2.0). Total plaque length, composition, and remodeling index were not associated with lower MFR. On a per-patient basis, the modified Duke CAD (coronary artery disease) index (p = 0.04) and the number of segments with mixed plaque (p = 0.01) were the best predictors of low MFRglobal.
Computed tomography angiography descriptors of atherosclerosis had only a modest effect on downstream MFR. On a per-patient basis, the extent and severity of atherosclerosis as assessed by the modified Duke CAD index and the number of coronary segments with mixed plaque were associated with decreased MFR.
PMCID: PMC3951833  PMID: 21996395
atherosclerosis; coronary computed tomography angiography; myocardial flow reserve; positron emission tomography
17.  Polymorphisms in Radio-Responsive Genes and Its Association with Acute Toxicity among Head and Neck Cancer Patients 
PLoS ONE  2014;9(3):e89079.
Cellular and molecular approaches are being explored to find a biomarker which can predict the development of radiation induced acute toxicity prior to radiation therapy. SNPs in radiation responsive genes may be considered as an approach to develop tools for finding the inherited basis of clinical radiosensitivity. The current study attempts to screen single nucleotide polymorphisms/deletions in DNA damage response, DNA repair, profibrotic cytokine as well as antioxidant response genes and its predictive potential with the normal tissue adverse reactions from 183 head and neck cancer patients undergoing platinum based chemoradiotherapy or radiotherapy alone. We analysed 22 polymorphisms in 17 genes having functional relevance to radiation response. Radiation therapy induced oral mucositis and skin erythema was considered as end point for clinical radiosensitivity. Direct correlation of heterozygous and mutant alleles with acute reactions as well as haplotype correlation revealed NBN variants to be of predictive significance in analysing oral mucositis prior to radiotherapy. In addition, genetic linkage disequilibrium existed in XRCC1 polymorphisms for >grade 2 oral mucositis and skin reaction indicating the complex inheritance pattern. The current study indicates an association for polymorphism in NBN with normal tissue radiosensitivity and further warrants the replication of such studies in a large set of samples.
PMCID: PMC3942321  PMID: 24594932
18.  Magnetic Resonance Elastography of Liver: Technique, Analysis and Clinical Applications 
Many pathological processes cause marked changes in the mechanical properties of tissue. Magnetic Resonance Elastography (MRE) is a non-invasive MRI based technique for quantitatively assessing the mechanical properties of tissues in vivo. MRE is performed by using a vibration source to generate low frequency mechanical waves in tissue, imaging the propagating waves using a phase contrast MRI technique, and then processing the wave information to generate quantitative images showing mechanical properties such as tissue stiffness. Since its first description in 1995, published studies have explored many potential clinical applications including brain, thyroid, lung, heart, breast, and skeletal muscle imaging. However, the best-documented application to emerge has been the use of MRE to assess liver disease. Multiple studies have demonstrated that there is a strong correlation between MRE-measured hepatic stiffness and the stage of fibrosis at histology. The emerging literature indicates that MRE can serve as a safer, less expensive, and potentially more accurate alternative to invasive liver biopsy which is currently the gold standard for diagnosis and staging of liver fibrosis. This review describes the basic principles, technique of performing a liver MRE, analysis and calculation of stiffness, clinical applications, limitations, and potential future applications.
PMCID: PMC3579218  PMID: 23423795
Magnetic Resonance Elastography (MRE); Liver; Fibrosis; Technique; Analysis; Clinical applications
19.  Genome-Wide Association Study for Type 2 Diabetes in Indians Identifies a New Susceptibility Locus at 2q21 
Diabetes  2013;62(3):977-986.
Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes–associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10−9). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10−12) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.
PMCID: PMC3581193  PMID: 23209189
20.  Non-coding transcription SETs up regulation 
Cell Research  2012;23(3):311-313.
An abundance of long non-coding RNA (lncRNA) present in most species from yeast to human are involved in transcriptional regulation, dosage compensation and imprinting. This underscores the importance of lncRNA as functional RNA despite the fact that they do not produce proteins. Two recent papers in Cell have demonstrated that transcription of the non-conserved lncRNAs, but not the RNAs themselves, is necessary to introduce co-transcriptional regulatory histone marks to regulate gene expression.
PMCID: PMC3587699  PMID: 23147798
21.  Pentoxifylline: A New Armamentarium in Diabetic Foot Ulcers 
Background: Diabetic foot ulcers are estimated to affect 15% of all diabetics and precede almost 85% of foot amputations. Pentoxyfylline a substituted xanthenes’ derivative has been reported to increase the blood flow to the microcirculation and enhances tissue oxygenation. It has been widely used in the treatment of intermittent claudication.
Materials and Methods: Pentoxyfylline is known to decrease the rouleaux formation of RBC and hence helps in improving the microcirculation. Out of 67 patients 30 received pentoxyfylline and 32 were on traditional treatment and there was loss of follow-up in five cases.
The response was observed subjectively, histologically and by Doppler studies.
Results: It was observed that the patients on pentoxyfylline had early healing as compared to patients receiving only conventional treatment as evident on biopsy and Doppler.
Conclusion: Here in this research our objective was to determine whether pentoxyfylline (trental 400 mg) taken orally TDS in addition to ambulatory compression bandages and dressings improves the healing rates of diabetic ulcers.
PMCID: PMC3939596  PMID: 24596731
Pentoxyfylline; Doppler study; Diabetic foot ulcers ligament
22.  Water Filtration Using Plant Xylem 
PLoS ONE  2014;9(2):e89934.
Effective point-of-use devices for providing safe drinking water are urgently needed to reduce the global burden of waterborne disease. Here we show that plant xylem from the sapwood of coniferous trees – a readily available, inexpensive, biodegradable, and disposable material – can remove bacteria from water by simple pressure-driven filtration. Approximately 3 cm3 of sapwood can filter water at the rate of several liters per day, sufficient to meet the clean drinking water needs of one person. The results demonstrate the potential of plant xylem to address the need for pathogen-free drinking water in developing countries and resource-limited settings.
PMCID: PMC3935949  PMID: 24587134
23.  MR Imaging-Verified Plaque Delipidation With Lipid-Lowering Therapy 
JACC. Cardiovascular imaging  2011;4(9):987-989.
PMCID: PMC3916136  PMID: 21920336
atherosclerotic plaque; carotid artery; lipid lowering; magnetic resonance imaging
Immunity  2012;37(3):399-411.
Viral infections are often detrimental to host survival and reproduction. Consequently, hosts have evolved a variety of mechanisms to defend themselves against viruses. A component of this arsenal is a set of proteins, termed restriction factors, which exhibit direct antiviral activity. Among these are several classes of proteins (APOBEC3, TRIM5, Tetherin and SAMHD1) that inhibit the replication of human and simian immunodeficiency viruses. Here, we outline the features, mechanisms, and evolution of these defense mechanisms. We also speculate on how restriction factors arose, how they might interact with the conventional innate and adaptive immune systems and how an understanding of these intrinsic cellular defenses might be usefully exploited.
PMCID: PMC3912573  PMID: 22999946
25.  Gadolinium-Based Contrast Agents for Vessel Wall Magnetic Resonance Imaging (MRI) of Atherosclerosis 
Cardiovascular disease due to atherosclerosis is the number one killer in the Western world, and threatens to become the major cause of morbidity and mortality worldwide. It is therefore paramount to develop non-invasive methods for the detection of high-risk, asymptomatic individuals before the onset of clinical symptoms or events. In the recent past, great strides have been made in the understanding of the pathological mechanisms involved in the atherosclerotic cascade down to the molecular details. This has allowed the development of contrast agents that can aid in the in vivo characterization of these processes. Gadolinium chelates are among the contrast media most commonly used in MR imaging. Originally used for MR angiography for the detection and quantification of vascular stenosis, more recently they have been applied to improve characterization of atherosclerotic plaques. In this manuscript, we will briefly review gadolinium-chelates (Gd) based contrast agents for non-invasive MR imaging of atherosclerosis. We will first describe Gd-based non-targeted FDA approved agents, used routinely in clinical practice for the evaluation of neovascularization in other diseases. Secondly, we will describe non-specific and specific targeted contrast agents, which have great potential for dissecting specific biological processes in the atherosclerotic cascade. Lastly, we will briefly compare Gd-based agents to others commonly used in MRI and to other imaging modalities.
PMCID: PMC3607396  PMID: 23539505
Atherosclerosis; Imaging; Gadolinium; Gd; Contrast agent; Magnetic resonance imaging; MRI; CE-MRI; DCE-MRI; Non-specific contrast agents; Specific non-targeted contrast agents; Specific targeted contrast agents

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