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author:("ramanis, S.")
1.  Rapid flow cytometric susceptibility testing of Candida albicans. 
Journal of Clinical Microbiology  1997;35(9):2320-2324.
A rapid flow cytometric assay for in vitro antifungal drug susceptibility testing was developed by adapting the proposed reference method for broth macrodilution testing of yeasts. Membrane permeability changes caused by the antifungal agent were measured by flow cytometry using propidium iodide, a nucleic acid-binding fluorochrome largely excluded by the intact cell membrane. We determined the in vitro susceptibility of 31 Candida albicans isolates and two quality control strains (Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258) to amphotericin B and fluconazole. Amphotericin B MICs ranged from 0.03 to 2.0 microg/ml, while fluconazole MICs ranged from 0.125 to 128 microg/ml. This method results in clear-cut endpoints that were reproducible. Four-hour incubation was required for fluconazole, whereas a 2-h incubation was sufficient for amphotericin B to provide MICs comparable to the reference macrodilution method developed by the National Committee for Clinical Laboratory Standards Subcommittee on Antifungal Susceptibility Tests. Results of these studies show that flow cytometry provides a rapid and sensitive in vitro method for antifungal susceptibility testing of C. albicans.
PMCID: PMC229962  PMID: 9276410
2.  Ultrasound-guided needle aspiration of amoebic liver abscess. 
Postgraduate Medical Journal  1993;69(811):381-383.
This prospective study was carried out on 200 patients with clinically, ultrasonographically and serologically confirmed amoebic liver abscess. The role of ultrasound-guided needle aspiration in addition to medications was evaluated compared to drug treatment alone. Both the groups were monitored clinically and sonographically for up to 6 months after diagnosis. The initial response (after 15 days) was better in the aspirated group (P < 0.05) but resolution of abscess after 6 months were similar. There was a more rapid clinical response in the aspirated group, particularly in those with larger (> 6 cm) abscesses and there were no complications. Percutaneous ultrasound-guided needle aspiration is a safe diagnostic and therapeutic approach which enhances clinical recovery, accelerates resolution, especially in large abscesses, and prevents complications.
PMCID: PMC2399819  PMID: 8346134
3.  Heat-Passing Framework for Robust Interpretation of Data in Networks 
PLoS ONE  2015;10(2):e0116121.
Researchers are regularly interested in interpreting the multipartite structure of data entities according to their functional relationships. Data is often heterogeneous with intricately hidden inner structure. With limited prior knowledge, researchers are likely to confront the problem of transforming this data into knowledge. We develop a new framework, called heat-passing, which exploits intrinsic similarity relationships within noisy and incomplete raw data, and constructs a meaningful map of the data. The proposed framework is able to rank, cluster, and visualize the data all at once. The novelty of this framework is derived from an analogy between the process of data interpretation and that of heat transfer, in which all data points contribute simultaneously and globally to reveal intrinsic similarities between regions of data, meaningful coordinates for embedding the data, and exemplar data points that lie at optimal positions for heat transfer. We demonstrate the effectiveness of the heat-passing framework for robustly partitioning the complex networks, analyzing the globin family of proteins and determining conformational states of macromolecules in the presence of high levels of noise. The results indicate that the methodology is able to reveal functionally consistent relationships in a robust fashion with no reference to prior knowledge. The heat-passing framework is very general and has the potential for applications to a broad range of research fields, for example, biological networks, social networks and semantic analysis of documents.
PMCID: PMC4323200  PMID: 25668316
4.  Absence of Genetic Differences among G10P[11] Rotaviruses Associated with Asymptomatic and Symptomatic Neonatal Infections in Vellore, India 
Journal of Virology  2014;88(16):9060-9071.
Rotaviruses (RVs) are leading causes of severe diarrhea and vomiting in infants and young children. RVs with G10P[11] genotype specificity have been associated with symptomatic and asymptomatic neonatal infections in Vellore, India. To identify possible viral genetic determinants responsible for differences in symptomology, the genome sequences of G10P[11] RVs in stool samples of 19 neonates with symptomatic infections and 20 neonates with asymptomatic infections were determined by Sanger and next-generation sequencing. The data showed that all 39 viruses had identical genotype constellations (G10-P[11]-I2-R2-C2-M2-A1-N1-T1-E2-H3), the same as those of the previously characterized symptomatic N155 Vellore isolate. The data also showed that the RNA and deduced protein sequences of all the Vellore G10P[11] viruses were nearly identical; no nucleotide or amino acid differences were found that correlated with symptomatic versus asymptomatic infection. Next-generation sequencing data revealed that some stool samples, both from neonates with symptomatic infections and from neonates with asymptomatic infections, also contained one or more positive-strand RNA viruses (Aichi virus, astrovirus, or salivirus/klassevirus) suspected of being potential causes of pediatric gastroenteritis. However, none of the positive-strand RNA viruses could be causally associated with the development of symptoms. These results indicate that the diversity of clinical symptoms in Vellore neonates does not result from genetic differences among G10P[11] RVs; instead, other undefined factors appear to influence whether neonates develop gastrointestinal disease symptoms.
IMPORTANCE Rotavirus (RV) strains have been identified that preferentially replicate in neonates, in some cases, without causing gastrointestinal disease. Surveillance studies have established that G10P[11] RVs are a major cause of neonatal infection in Vellore, India, with half of infected neonates exhibiting symptoms. We used Sanger and next-generation sequencing technologies to contrast G10P[11] RVs recovered from symptomatic and asymptomatic neonates. Remarkably, the data showed that the RNA genomes of the viruses were virtually indistinguishable and lacked any differences that could explain the diversity of clinical outcomes among infected Vellore neonates. The sequencing results also indicated that some symptomatic and some asymptomatic Vellore neonates were infected with other enteric viruses (Aichi virus, astrovirus, salvirus/klassevirus); however, none could be correlated with the presence of symptoms in neonates. Together, our findings suggest that other poorly defined factors, not connected to the genetic makeup of the Vellore G10P[11] viruses, influence whether neonates develop gastrointestinal disease symptoms.
PMCID: PMC4136299  PMID: 24899175
5.  Amino Acid Profile in Oral Submucous Fibrosis: A High Performance Liquid Chromatography (HPLC) Study 
Background: Collagen is a significant structural protein, the integrity of which is essential to be maintained for proper homeostasis. Oral submucous fibrosis (OSMF), being a collagen metabolic disorder, may be subject to changes in amino acid profiling.
Aim: The present study was attempted to evaluate the amino acid profile to assess its feasibility as a biological marker in OSMF.
Materials and Methods: The study group comprised of 13 patents with OSMF and the normal group comprised of 13 normal patients without associated habits or systemic disorders. Venous blood was collected from the antecubital vein, plasma was separated and the plasma was then subjected to high profile liquid chromatographic analysis.
Results: The assay levels of threonine, alanine and tyrosine did not yield any significant results. The decreased assay levels of valine, Isoleucine and the increased assay level of methionine and glycine observed in group II yielded significant results in correlation with the control group. The decreased assay level seen in phenylalanine in group II and III in correlation with group IV is statistically significant.
Conclusion: A few amino acids have been identified which can be used as biological markers for the severity of the disease such as valine, methionine and phenyl alanine. Large scale studies are required to elucidate the potential of these biological markers.
PMCID: PMC4316336  PMID: 25654030
Amino acids; Collagen; OSMF; Plasma
6.  Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes 
Aging Cell  2014;14(1):35-48.
Age-dependent neurodegenerative diseases progressively form aggregates containing both shared components (e.g., TDP-43, phosphorylated tau) and proteins specific to each disease. We investigated whether diverse neuropathies might have additional aggregation-prone proteins in common, discoverable by proteomics. Caenorhabditis elegans expressing unc-54p/Q40::YFP, a model of polyglutamine array diseases such as Huntington's, accrues aggregates in muscle 2–6 days posthatch. These foci, isolated on antibody-coupled magnetic beads, were characterized by high-resolution mass spectrometry. Three Q40::YFP-associated proteins were inferred to promote aggregation and cytotoxicity, traits reduced or delayed by their RNA interference knockdown. These RNAi treatments also retarded aggregation/cytotoxicity in Alzheimer's disease models, nematodes with muscle or pan-neuronal Aβ1–42 expression and behavioral phenotypes. The most abundant aggregated proteins are glutamine/asparagine-rich, favoring hydrophobic interactions with other random-coil domains. A particularly potent modulator of aggregation, CRAM-1/HYPK, contributed < 1% of protein aggregate peptides, yet its knockdown reduced Q40::YFP aggregates 72–86% (P < 10−6). In worms expressing Aβ1–42, knockdown of cram-1 reduced β-amyloid 60% (P < 0.002) and slowed age-dependent paralysis > 30% (P < 10−6). In wild-type worms, cram-1 knockdown reduced aggregation and extended lifespan, but impaired early reproduction. Protection against seeded aggregates requires proteasome function, implying that normal CRAM-1 levels promote aggregation by interfering with proteasomal degradation of misfolded proteins. Molecular dynamic modeling predicts spontaneous and stable interactions of CRAM-1 (or human orthologs) with ubiquitin, and we verified that CRAM-1 reduces degradation of a tagged-ubiquitin reporter. We propose that CRAM-1 exemplifies a class of primitive chaperones that are initially protective and highly beneficial for early reproduction, but ultimately impair aggregate clearance and limit longevity.
PMCID: PMC4326912  PMID: 25510159
Alzheimer (disease); C. elegans; Huntington (disease); neurodegeneration; (protein) aggregation; proteasome
7.  Seroepidemiology of Norovirus-Associated Travelers’ Diarrhea 
Journal of travel medicine  2014;21(1):6-11.
Noroviruses (NoVs) are the most common cause of epidemic gastroenteritis, responsible for at least 50% of all gastroenteritis outbreaks worldwide and were recently identified as a leading cause of travelers’ diarrhea (TD) in U.S. and European travelers to Mexico, Guatemala and India.
Serum and diarrheic stool samples were collected from 75 US student travelers to Cuernavaca, Mexico, who developed TD. NoV RNA was detected in acute diarrheic stool samples using RT-PCR. Serology assays were performed using GI.1 Norwalk virus (NV) and GII.4 Houston virus (HOV) virus-like particles (VLP) to measure serum levels of IgA and IgG by Dissociation-Enhanced Lanthanide Fluorescent Immunoassay (DELFIA); serum IgM was measured by capture ELISA, and the 50% antibody blocking titer (BT50) was determined by a carbohydrate-blocking assay.
NoV infection was identified in 12 (16%; 9 GI-NoV and 3 GII-NoV) of 75 travelers by either RT-PCR or ≥4-fold rise in antibody titer. Significantly more individuals had detectable pre-existing IgA antibodies against HOV (62/75, 83%) than against NV (49/75, 65%) (p=0.025) VLPs. A significant difference was observed between NV- and HOV-specific preexisting IgA antibody levels (p=0.0037), IgG (p=0.003) and BT50 (p=<0.0001). None of the NoV-infected TD travelers had BT50 >200, a level that has been described previously as a possible correlate of protection.
We found that GI-NoVs are commonly associated with TD cases identified in U.S. adults traveling to Mexico, and seroprevalence rates and geometric mean antibody levels to a GI-NoV were lower than to a GII-NoV strain.
PMCID: PMC3904865  PMID: 24383649
8.  Substance Abuse Treatment in Persons with HIV/AIDS: Challenges in Managing Triple Diagnosis 
This paper provides a review of the current literature addressing substance abuse treatment in persons living with HIV/AIDS. Clinical management of HIV must account for the “triple diagnosis” of HIV, psychiatric diagnosis, and substance use disorders and requires integrated treatment services that focus beyond just mitigation of substance use and psychiatric and medical symptoms but also address other health behaviors. Because clinical management of HIV/AIDS has shifted significantly with the advent of highly active antiretroviral therapies (HAART) in the mid 1990's, a literature review focusing on literature published since 2000, and using relevant key words was conducted using a wide range of literature search databases. This literature review was complemented by studies to expand on specific treatment modalities for which there was a dearth of literature addressing HIV infected cohorts and to provide discussion of issues around substance abuse treatment as an HIV prevention tool. Existing models of substance abuse treatment including cognitive behavioral therapy and motivational interviewing have proven to be useful for enhancing adherence and reducing substance use in outpatient populations, while methadone maintenance and directly observed treatment have been useful with specific subgroups of users. Contextualization of services heightens the likelihood of successful outcomes and relapse prevention.
PMCID: PMC3999248  PMID: 24274175
substance abuse; HIV; psychiatric disorder; triple diagnosis; treatment
9.  Combining Ordered Subsets and Momentum for Accelerated X-ray CT Image Reconstruction 
Statistical X-ray computed tomography (CT) reconstruction can improve image quality from reduced dose scans, but requires very long computation time. Ordered subsets (OS) methods have been widely used for research in X-ray CT statistical image reconstruction (and are used in clinical PET and SPECT reconstruction). In particular, OS methods based on separable quadratic surrogates (OS-SQS) are massively parallelizable and are well suited to modern computing architectures, but the number of iterations required for convergence should be reduced for better practical use. This paper introduces OS-SQS-momentum algorithms that combine Nesterov's momentum techniques with OS-SQS methods, greatly improving convergence speed in early iterations. If the number of subsets is too large, the OS-SQS-momentum methods can be unstable, so we propose diminishing step sizes that stabilize the method while preserving the very fast convergence behavior. Experiments with simulated and real 3D CT scan data illustrate the performance of the proposed algorithms.
PMCID: PMC4280323  PMID: 25163058
Statistical image reconstruction; computed tomography; parallelizable iterative algorithms; ordered subsets; separable quadratic surrogates; momentum; stochastic gradient; relaxation
10.  Bilateral ovarian metastases from ureteric urothelial cancer: Initial case report and distinguishing role of immunohistochemistry 
Urothelial cancers of the upper tract are aggressive malignancies with a propensity for distant metastases. Transitional cell carcinoma can also develop de novo in the ovaries and differentiation between these lesions requires immunohistochemistry. We report a case of right lower ureteric urothelial carcinoma with metastases to both ovaries. To our knowledge, this is the first reported case of bilateral ovarian metastases from an upper tract primary, diagnosed with immunohistochemistry.
PMCID: PMC4301973  PMID: 25624971
11.  Protein expression, characterization and activity comparisons of wild type and mutant DUSP5 proteins 
BMC Biochemistry  2014;15(1):27.
The mitogen-activated protein kinases (MAPKs) pathway is critical for cellular signaling, and proteins such as phosphatases that regulate this pathway are important for normal tissue development. Based on our previous work on dual specificity phosphatase-5 (DUSP5), and its role in embryonic vascular development and disease, we hypothesized that mutations in DUSP5 will affect its function.
In this study, we tested this hypothesis by generating full-length glutathione-S-transferase-tagged DUSP5 and serine 147 proline mutant (S147P) proteins from bacteria. Light scattering analysis, circular dichroism, enzymatic assays and molecular modeling approaches have been performed to extensively characterize the protein form and function. We demonstrate that both proteins are active and, interestingly, the S147P protein is hypoactive as compared to the DUSP5 WT protein in two distinct biochemical substrate assays. Furthermore, due to the novel positioning of the S147P mutation, we utilize computational modeling to reconstruct full-length DUSP5 and S147P to predict a possible mechanism for the reduced activity of S147P.
Taken together, this is the first evidence of the generation and characterization of an active, full-length, mutant DUSP5 protein which will facilitate future structure-function and drug development-based studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12858-014-0027-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4299175  PMID: 25519881
DUSP5; Mutation; Vascular anomalies; Protein purification; Molecular modeling
12.  Genome dynamics and evolution of Salmonella Typhi strains from the typhoid-endemic zones 
Scientific Reports  2014;4:7457.
Typhoid fever poses significant burden on healthcare systems in Southeast Asia and other endemic countries. Several epidemiological and genomic studies have attributed pseudogenisation to be the major driving force for the evolution of Salmonella Typhi although its real potential remains elusive. In the present study, we analyzed genomes of S. Typhi from different parts of Southeast Asia and Oceania, comprising of isolates from outbreak, sporadic and carrier cases. The genomes showed high genetic relatedness with limited opportunity for gene acquisition as evident from pan-genome structure. Given that pseudogenisation is an active process in S. Typhi, we further investigated core and pan-genome profiles of functional and pseudogenes separately. We observed a decline in core functional gene content and a significant increase in accessory pseudogene content. Upon functional classification, genes encoding metabolic functions formed a major constituent of pseudogenes as well as core functional gene clusters with SNPs. Further, an in-depth analysis of accessory pseudogene content revealed the existence of heterogeneous complements of functional and pseudogenes among the strains. In addition, these polymorphic genes were also enriched in metabolism related functions. Thus, the study highlights the existence of heterogeneous strains in a population with varying metabolic potential and that S. Typhi possibly resorts to metabolic fine tuning for its adaptation.
PMCID: PMC4264004  PMID: 25504040
13.  Structural basis of glycan interaction in gastroenteric viral pathogens 
Current opinion in virology  2014;7:119-127.
A critical event in the life cycle of a virus is its initial attachment to host cells. This involves recognition by the viruses of specific receptors on the cell surface, including glycans. Viruses typically exhibit strain-dependent variations in recognizing specific glycan receptors, a feature that contributes significantly to cell tropism, host specificity, host adaptation and interspecies transmission. Examples include influenza viruses, noroviruses, rotaviruses, and parvoviruses. Both rotaviruses and noroviruses are well known gastroenteric pathogens that are of significant global health concern. While rotaviruses, in the family Reoviridae, are the major causative agents of life-threatening diarrhea in children, noroviruses, which belong to Caliciviridae family, cause epidemic and sporadic cases of acute gastroenteritis across all age groups. Both exhibit enormous genotypic and serotypic diversity. Consistent with this diversity each exhibits strain-dependent variations in the types of glycans they recognize for cell attachment. This chapter reviews current status of the structural biology of such strain-dependent glycan specificities in these two families of viruses.
PMCID: PMC4251800  PMID: 25073118
14.  The Impact of NMDA Receptor Blockade on Human Working Memory-Related Prefrontal Function and Connectivity 
Neuropsychopharmacology  2013;38(13):2613-2622.
Preclinical research suggests that N-methyl-D-aspartate glutamate receptors (NMDA-Rs) have a crucial role in working memory (WM). In this study, we investigated the role of NMDA-Rs in the brain activation and connectivity that subserve WM. Because of its importance in WM, the lateral prefrontal cortex, particularly the dorsolateral prefrontal cortex and its connections, were the focus of analyses. Healthy participants (n=22) participated in a single functional magnetic resonance imaging session. They received saline and then the NMDA-R antagonist ketamine while performing a spatial WM task. Time-course analysis was used to compare lateral prefrontal activation during saline and ketamine administration. Seed-based functional connectivity analysis was used to compare dorsolateral prefrontal connectivity during the two conditions and global-based connectivity was used to test for laterality in these effects. Ketamine reduced accuracy on the spatial WM task and brain activation during the encoding and early maintenance (EEM) period of task trials. Decrements in task-related activation during EEM were related to performance deficits. Ketamine reduced connectivity in the DPFC network bilaterally, and region-specific reductions in connectivity were related to performance. These results support the hypothesis that NMDA-Rs are critical for WM. The knowledge gained may be helpful in understanding disorders that might involve glutamatergic deficits such as schizophrenia and developing better treatments.
PMCID: PMC3828532  PMID: 23856634
Biological Psychiatry; Cognition; connectivity; Glutamate; ketamine; Learning & Memory; networks; NMDA-R; working memory; NMDA; working memory; connectivity; schizophrenia; prefrontal cortex; ketamine
15.  A Content Analysis of Popular Smartphone Apps for Smoking Cessation 
American journal of preventive medicine  2013;45(6):10.1016/j.amepre.2013.07.008.
Smartphone applications (apps) are increasingly available for smoking cessation.
This study examined the content of popular apps for smoking cessation for both iPhone and Android operating systems in February 2012.
A total of 252 smoking-cessation apps were identified for the iPhone and 148 for the Android. Across both operating systems, the most popular apps were identified (n=47 for the iPhone and n=51 for the Android) and analyzed for their (1) approach to smoking cessation and (2) adherence to an index based on the U.S. Public Health Service’s Clinical Practice Guidelines for Treating Tobacco Use and Dependence. Where available, apps were coded for frequency of downloads. The analysis took place in 2012.
Overall, popular apps have low levels of adherence, with an average score of 12.9 of a possible 42 on the Adherence Index. No apps recommended calling a quitline, and only a handful of apps recommended using approved medications (4.1%). Android apps in the sample were downloaded worldwide between 310,800 and 1,248,000 times per month. For both the iPhone and Android, user ratings were positively associated with scores on the Adherence Index. For the iPhone, display order was also positively associated with scores on the Adherence Index.
Apps could be improved by better integration with the Clinical Practice Guidelines and other evidence-based practices.
PMCID: PMC3836190  PMID: 24237915
Clinical and translational science  2013;6(6):10.1111/cts.12116.
In dilated cardiomyopathy (DCM), the clinical and prognostic implications of rare variants in sarcomeric genes remain poorly understood. To address this question, we analyzed the outcome of rare sarcomeric gene variants in patients enrolled in our Familial Cardiomyopathy Registry.
DCM families harboring rare sarcomeric variants in MYH6, MYH7, MYBPC3, TNNT2 and TTN were identified. Genotype-phenotype association analysis was performed, and long-term survival-free from death or heart transplant was compared between carriers and non-carriers.
We found 24 rare variants (3 in MYH6, 3 in MYH7, 3 in MYBPC3, 2 in TNNT2 and 13 in TTN) affecting 52 subjects in 25 families. The phenotypes of variant carriers were severe (3 sudden deaths, 6 heart failure deaths, 8 heart transplants, 2 ventricular fibrillations). There was no difference in the overall long-term survival between carriers and the 33 non-carriers (p=0.322). However after 50 years of age, the combined endpoint of death or transplant was decreased in carriers as compared to non-carriers (p=0.026).
Patients with DCM carrying rare variants in sarcomeric genes manifest a poorer prognosis as compared to non-carriers after the age of 50 years. These data further support the role genetic testing in DCM for risk stratification.
PMCID: PMC3865161  PMID: 24119082
Cardiomyopathy; genes; prognosis; molecular genetics; genetics; phenotyping
17.  Comparative genomic analysis of Helicobacter pylori from Malaysia identifies three distinct lineages suggestive of differential evolution 
Nucleic Acids Research  2014;43(1):324-335.
The discordant prevalence of Helicobacter pylori and its related diseases, for a long time, fostered certain enigmatic situations observed in the countries of the southern world. Variation in H. pylori infection rates and disease outcomes among different populations in multi-ethnic Malaysia provides a unique opportunity to understand dynamics of host–pathogen interaction and genome evolution. In this study, we extensively analyzed and compared genomes of 27 Malaysian H. pylori isolates and identified three major phylogeographic lineages: hspEastAsia, hpEurope and hpSouthIndia. The analysis of the virulence genes within the core genome, however, revealed a comparable pathogenic potential of the strains. In addition, we identified four genes limited to strains of East-Asian lineage. Our analyses identified a few strain-specific genes encoding restriction modification systems and outlined 311 core genes possibly under differential evolutionary constraints, among the strains representing different ethnic groups. The cagA and vacA genes also showed variations in accordance with the host genetic background of the strains. Moreover, restriction modification genes were found to be significantly enriched in East-Asian strains. An understanding of these variations in the genome content would provide significant insights into various adaptive and host modulation strategies harnessed by H. pylori to effectively persist in a host-specific manner.
PMCID: PMC4288169  PMID: 25452339
18.  Synchronous Presentation of Chronic Myeloid Leukemia with Carcinoma Penis: A Rare Presentation 
We report here a case of 52-year-old male presenting with penile ulcer. On evaluation, he was diagnosed to have Carcinoma penis with concurrent CML in chronic phase. Clinical examination showed pallor, bilateral inguinal lymphadenopathy, bilateral pitting pedal oedema and hepatosplenomegaly. He was diagnosed to have chronic myeloid leukemia based on peripheral smear examination showing raised counts with shift to left and fluorescence in situ hydridisation (FISH) showing t (9:22). The ilio-inguinal block dissection specimen showed inguinal metastasis of squamous cell carcinoma (SCC). This case is being presented here in view of the rarity in combination of CML with another malignancy.
PMCID: PMC4225951  PMID: 25386499
Chronic myeloid leukemia- chronic phase (CML-CP); Fluorescence in situ hybridization (FISH); Squamous cell carcinoma (SCC)
19.  Gene Profiling of Postnatal Mfrprd6 Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs 
PLoS ONE  2014;9(10):e110299.
Mutations in the membrane frizzled-related protein (MFRP/Mfrp) gene, specifically expressed in the retinal pigment epithelium (RPE) and ciliary body, cause nanophthalmia or posterior microphthalmia with retinitis pigmentosa in humans, and photoreceptor degeneration in mice. To better understand MFRP function, microarray analysis was performed on eyes of homozygous Mfrprd6 and C57BL/6J mice at postnatal days (P) 0 and P14, prior to photoreceptor loss. Data analysis revealed no changes at P0 but significant differences in RPE and retina-specific transcripts at P14, suggesting a postnatal influence of the Mfrprd6 allele. A subset of these transcripts was validated by quantitative real-time PCR (qRT-PCR). In Mfrprd6 eyes, a significant 1.5- to 2.0-fold decrease was observed among transcripts of genes linked to retinal degeneration, including those involved in visual cycle (Rpe65, Lrat, Rgr), phototransduction (Pde6a, Guca1b, Rgs9), and photoreceptor disc morphogenesis (Rpgrip1 and Fscn2). Levels of RPE65 were significantly decreased by 2.0-fold. Transcripts of Prss56, a gene associated with angle-closure glaucoma, posterior microphthalmia and myopia, were increased in Mfrprd6 eyes by 17-fold. Validation by qRT-PCR indicated a 3.5-, 14- and 70-fold accumulation of Prss56 transcripts relative to controls at P7, P14 and P21, respectively. This trend was not observed in other RPE or photoreceptor mutant mouse models with similar disease progression, suggesting that Prss56 upregulation is a specific attribute of the disruption of Mfrp. Prss56 and Glul in situ hybridization directly identified Müller glia in the inner nuclear layer as the cell type expressing Prss56. In summary, the Mfrprd6 allele causes significant postnatal changes in transcript and protein levels in the retina and RPE. The link between Mfrp deficiency and Prss56 up-regulation, together with the genetic association of human MFRP or PRSS56 variants and ocular size, raises the possibility that these genes are part of a regulatory network influencing postnatal posterior eye development.
PMCID: PMC4214712  PMID: 25357075
20.  Randomized Trial of Plastic Bags to Prevent Term Neonatal Hypothermia in a Resource-Poor Setting 
Pediatrics  2013;132(3):e656-e661.
Term infants in resource-poor settings frequently develop hypothermia during the first hours after birth. Plastic bags or wraps are a low-cost intervention for the prevention of hypothermia in preterm and low birth weight infants that may also be effective in term infants. Our objective was to test the hypothesis that placement of term neonates in plastic bags at birth reduces hypothermia at 1 hour after birth in a resource-poor hospital.
This parallel-group randomized controlled trial was conducted at University Teaching Hospital, the tertiary referral center in Zambia. Inborn neonates with both a gestational age ≥37 weeks and a birth weight ≥2500 g were randomized 1:1 to either a standard thermoregulation protocol or to a standard thermoregulation protocol with placement of the torso and lower extremities inside a plastic bag within 10 minutes after birth. The primary outcome was hypothermia (<36.5°C axillary temperature) at 1 hour after birth.
Neonates randomized to plastic bag (n = 135) or to standard thermoregulation care (n = 136) had similar baseline characteristics (birth weight, gestational age, gender, and baseline temperature). Neonates in the plastic bag group had a lower rate of hypothermia (60% vs 73%, risk ratio 0.76, confidence interval 0.60–0.96, P = .026) and a higher axillary temperature (36.4 ± 0.5°C vs 36.2 ± 0.7°C, P < .001) at 1 hour after birth compared with infants receiving standard care.
Placement in a plastic bag at birth reduced the incidence of hypothermia at 1 hour after birth in term neonates born in a resource-poor setting, but most neonates remained hypothermic.
PMCID: PMC3876758  PMID: 23979082
infant, term; infant, newborn; infant, hypothermia/prevention and control; plastic bag; bedding and linens; body temperature, regulation; polyethylenes; delivery, obstetrics
21.  Patient-Centered Care or Patient Data-Centered Care: A Tale of 2 Admissions 
PMCID: PMC3771162  PMID: 24404296
22.  Outcome of surgical management of developmental dysplasia of hip in children between 18 and 24 months 
Indian Journal of Orthopaedics  2014;48(5):458-462.
Developmental dysplasia of hip (DDH) is a common condition presenting to a pediatric orthopedic surgeon. There is a consensus on the surgical treatment of children with ages ranged from 18 to 24 months where majority agree on open reduction and hip spica. Open reduction was done with an additional pelvic procedure wherever required to get better results and prevent residual acetabular dysplasia (RAD) and early osteoarthritis.
Materials and Methods:
35 children with unilateral DDH were operated between 2002 and 2007 at our institute. Open reduction was performed in all using the standard anterior approach and peroperative test for hip stability was done. Nine children got an additional pelvic procedure in the form of Dega acetabuloplasty. All were followed up for a minimal period of 2 years (range 2-7 years).
No hip got redislocated. At the end of 18 months, there were seven cases of RAD with acetabular index (AI) of 35° and above. These were all from the group where open reduction alone was done.
We feel that a preoperative AI of >40° and a per-operative safe-zone <20° increases the need for supplementary pelvic osteotomy in age group of 18 to 24 months because in such cases, the remodeling capacity of the acetabulum is unable to overcome the dysplasia and to form a relatively normal acetabulum.
PMCID: PMC4175858  PMID: 25298551
Dega osteotomy; developmental dysplasia of hip; pelvic procedure; children; Osteotomy; congenital; pediatrics; hip dysplasia
23.  Rec-8 dimorphism affects longevity, stress resistance and X-chromosome nondisjunction in C. elegans, and replicative lifespan in S. cerevisiae 
Frontiers in Genetics  2014;5:211.
A quantitative trait locus (QTL) in the nematode C. elegans, “lsq4,” was recently implicated by mapping longevity genes. QTLs for lifespan and three stress-resistance traits coincided within a span of <300 kbp, later narrowed to <200 kbp. A single gene in this interval is now shown to modulate all lsq4-associated traits. Full-genome analysis of transcript levels indicates that lsq4 contains a dimorphic gene governing the expression of many sperm-specific genes, suggesting an effect on spermatogenesis. Quantitative analysis of allele-specific transcripts encoded within the lsq4 interval revealed significant, 2- to 15-fold expression differences for 10 of 33 genes. Fourteen “dual-candidate” genes, implicated by both position and expression, were tested for RNA-interference effects on QTL-linked traits. In a strain carrying the shorter-lived allele, knockdown of rec-8 (encoding a meiotic cohesin) reduced its transcripts 4-fold, to a level similar to the longer-lived strain, while extending lifespan 25–26%, whether begun before fertilization or at maturity. The short-lived lsq4 allele also conferred sensitivity to oxidative and thermal stresses, and lower male frequency (reflecting X-chromosome non-disjunction), traits reversed uniquely by rec-8 knockdown. A strain bearing the longer-lived lsq4 allele, differing from the short-lived strain at <0.3% of its genome, derived no lifespan or stress-survival benefit from rec-8 knockdown. We consider two possible explanations: high rec-8 expression may include increased “leaky” expression in mitotic cells, leading to deleterious destabilization of somatic genomes; or REC-8 may act entirely in germ-line meiotic cells to reduce aberrations such as non-disjunction, thereby blunting a stress-resistance response mediated by innate immunity. Replicative lifespan was extended 20% in haploid S. cerevisiae (BY4741) by deletion of REC8, orthologous to nematode rec-8, implying that REC8 disruption of mitotic-cell survival is widespread, exemplifying antagonistic pleiotropy (opposing effects on lifespan vs. reproduction), and/or balancing selection wherein genomic disruption increases genetic variation under harsh conditions.
PMCID: PMC4120681  PMID: 25136348
longevity; lifespan; stress resistance; C. elegans; S. cerevisiae; genetics of aging; rec-8 or REC8; meiotic cohesin
24.  Non-Cartesian MRI Reconstruction With Automatic Regularization Via Monte-Carlo SURE 
IEEE transactions on medical imaging  2013;32(8):1411-1422.
Magnetic resonance image (MRI) reconstruction from undersampled k-space data requires regularization to reduce noise and aliasing artifacts. Proper application of regularization however requires appropriate selection of associated regularization parameters. In this work, we develop a data-driven regularization parameter adjustment scheme that minimizes an estimate (based on the principle of Stein’s unbiased risk estimate—SURE) of a suitable weighted squared-error measure in k-space. To compute this SURE-type estimate, we propose a Monte-Carlo scheme that extends our previous approach to inverse problems (e.g., MRI reconstruction) involving complex-valued images. Our approach depends only on the output of a given reconstruction algorithm and does not require knowledge of its internal workings, so it is capable of tackling a wide variety of reconstruction algorithms and nonquadratic regularizers including total variation and those based on the ℓ1-norm. Experiments with simulated and real MR data indicate that the proposed approach is capable of providing near mean squared-error (MSE) optimal regularization parameters for single-coil undersampled non-Cartesian MRI reconstruction.
PMCID: PMC3735835  PMID: 23591478
Image reconstruction; non-Cartesian MRI; regularization parameter; Stein’s unbiased risk estimate (SURE); Monte-Carlo methods
25.  Verrucous carcinoma of the esophagus: A case report and literature review 
Verrucous carcinoma of the esophagus is a variant of a squamous cell cancer. Our case is a 78-year-old male patient comes in with the dysphagia and weight loss, and on endoscopy (EGD) he is found to have an irregular intraluminal mass at the distal esophagus. With the deep EGD assisted biopsy, diagnosis of the verrucous carcinoma is made. Due to multiple co morbidities and possible infiltration to the pericardium, patient is taken for the esophageal stent placement and is being referred for the chemo-radiation treatment. The diagnosis can be very difficult to make with the superficial biopsies due to very non specific histological changes and requires very high clinical suspicion and deep mucosal biopsies are required for accurate diagnosis of the tumor. Chronic and local disease process is the main risk factor for the development of the verrucous carcinoma of the esophagus. Surgery is the treatment of the choice for the early stage tumor and advanced cases are treated with the palliation and possibly chemo- radiation. The prognosis is usually guarded and needs long term follow up.
PMCID: PMC4097156  PMID: 25032204
Verrucous carcinoma; Hyperkeratosis; Esophageal stent placement; Esophageal carcinoma; Endoscopic Ultrasound

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