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Beyond type 2 diabetes, obesity and hypertension: an axis including sleep apnea, left ventricular hypertrophy, endothelial dysfunction, and aortic stiffness among Mexican Americans in Starr County, Texas. - Cardiovascular diabetology
There is an increasing appreciation for a series of less traditional risk factors that should not be ignored when considering type 2 diabetes, obesity, hypertension, and cardiovascular disease. These include aortic stiffness, cardiac structure, impaired endothelial function and obstructive sleep apnea. They are associated to varying degrees with each disease categorization and with each other. It is not clear whether they represent additional complications, concomitants or antecedents of disease. Starr County, Texas, with its predominantly Mexican American population has been shown previously to bear a disproportionate burden of the major disease categories, but little is known about the distribution of these less traditional factors.Type 2 diabetes, obesity and hypertension frequencies were determined through a systematic survey of Starr County conducted from 2002 to 2006. Individuals from this examination and an enriched set with type 2 diabetes were re-examined from 2010 to 2014 including assessment of cardiac structure, sleep apnea, endothelial function and aortic stiffness. Individual and combined frequencies of these inter-related (i.e., axis) conditions were estimated and associations evaluated.Household screening of 5230 individuals aged 20Â years and above followed by direct physical assessment of 1610 identified 23.7Â % of men and 26.7Â % of women with type 2 diabetes, 46.2 and 49.5Â % of men and women, respectively with obesity and 32.1 and 32.4Â % with hypertension. Evaluation of pulse wave velocity, left ventricular mass, endothelial function and sleep apnea identified 22.3, 12.7, 48.6 and 45.2Â % of men as having "at risk" values for each condition, respectively. Corresponding numbers in women were 16.0, 17.9, 23.6 and 28.8Â %. Cumulatively, 88Â % of the population has one or more of these while 50Â % have three or more.The full axis of conditions is high among Mexican Americans in Starr County, Texas. Individual and joint patterns suggest a genesis well before overt disease. Whether they are all mediated by common underlying factors or whether there exist multiple mechanisms remains to be seen.
Whole Genome DNA Sequence Analysis of Salmonella subspecies enterica serotype Tennessee obtained from related peanut butter foodborne outbreaks. - PloS one
Establishing an association between possible food sources and clinical isolates requires discriminating the suspected pathogen from an environmental background, and distinguishing it from other closely-related foodborne pathogens. We used whole genome sequencing (WGS) to Salmonella subspecies enterica serotype Tennessee (S. Tennessee) to describe genomic diversity across the serovar as well as among and within outbreak clades of strains associated with contaminated peanut butter. We analyzed 71 isolates of S. Tennessee from disparate food, environmental, and clinical sources and 2 other closely-related Salmonella serovars as outgroups (S. Kentucky and S. Cubana), which were also shot-gun sequenced. A whole genome single nucleotide polymorphism (SNP) analysis was performed using a maximum likelihood approach to infer phylogenetic relationships. Several monophyletic lineages of S. Tennessee with limited SNP variability were identified that recapitulated several food contamination events. S. Tennessee clades were separated from outgroup salmonellae by more than sixteen thousand SNPs. Intra-serovar diversity of S. Tennessee was small compared to the chosen outgroups (1,153 SNPs), suggesting recent divergence of some S. Tennessee clades. Analysis of all 1,153 SNPs structuring an S. Tennessee peanut butter outbreak cluster revealed that isolates from several food, plant, and clinical isolates were very closely related, as they had only a few SNP differences between them. SNP-based cluster analyses linked specific food sources to several clinical S. Tennessee strains isolated in separate contamination events. Environmental and clinical isolates had very similar whole genome sequences; no markers were found that could be used to discriminate between these sources. Finally, we identified SNPs within variable S. Tennessee genes that may be useful markers for the development of rapid surveillance and typing methods, potentially aiding in traceback efforts during future outbreaks. Using WGS can delimit contamination sources for foodborne illnesses across multiple outbreaks and reveal otherwise undetected DNA sequence differences essential to the tracing of bacterial pathogens as they emerge.
Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. - Nature medicine
A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.
A Comprehensive, CRISPR-based Functional Analysis of Essential Genes in Bacteria. - Cell
Essential gene functions underpin the core reactions required for cell viability, but their contributions andÂ relationships are poorly studied inÂ vivo. Using CRISPR interference, we created knockdowns of every essential gene in Bacillus subtilis and probed their phenotypes. Our high-confidence essential gene network, established using chemical genomics, showed extensive interconnections among distantly related processes and identified modes of action for uncharacterized antibiotics. Importantly, mild knockdown of essential gene functions significantly reduced stationary-phase survival without affecting maximal growth rate, suggesting that essential protein levels are set to maximize outgrowth from stationary phase. Finally, high-throughput microscopy indicated that cell morphology is relatively insensitive to mild knockdown but profoundly affected by depletion of gene function, revealing intimate connections between cell growth and shape. Our results provide a framework for systematic investigation of essential gene functions inÂ vivo broadly applicable to diverse microorganisms and amenable to comparative analysis.Published by Elsevier Inc.
Quantification of Focal Outflow Enhancement Using Differential Canalograms. - Investigative ophthalmology & visual science
To quantify regional changes of conventional outflow caused by ab interno trabeculectomy (AIT).Gonioscopic, plasma-mediated AIT was established in enucleated pig eyes. We developed a program to automatically quantify outflow changes (R, package eye-canalogram, github.com) using a fluorescent tracer reperfusion technique. Trabecular meshwork (TM) ablation was demonstrated with fluorescent spheres in six eyes before formal outflow quantification with two-dye reperfusion canalograms in six additional eyes. Eyes were perfused with a central, intracameral needle at 15 mm Hg. Canalograms and histology were correlated for each eye.The pig eye provided a model with high similarity to AIT in human patients. Histology indicated ablation of TM and unroofing of most Schlemm's canal segments. Spheres highlighted additional circumferential and radial outflow beyond the immediate area of ablation. Differential canalograms showed that AIT caused an increase of outflow of 17 Â± 5-fold inferonasally, 14 Â± 3-fold superonasally, and also an increase in the opposite quadrants with a 2 Â± 1-fold increase superotemporally, and 3 Â± 3 inferotemporally. Perilimbal specific flow image analysis showed an accelerated nasal filling with an additional perilimbal flow direction into adjacent quadrants.A quantitative, differential canalography technique was developed that allows us to quantify supraphysiological outflow enhancement by AIT.
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