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Innate immune evasion of Escherichia coli clinical strains from orthopedic implant infections. - European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology
Escherichia coli is one of the first causes of Gram-negative orthopedic implant infections (OII). Those infections, usually hematogenous, mostly originate from the urinary tract. We investigated the strategies developed by E. coli in this context to evade host innate immune responses, i.e. complement and polymorphonuclear neutrophils (PMN). Twenty strains from OII were compared with 20 strains from bacteremia in patients with non-infected orthopedic implant. In both groups, 6/20 (30Â %) strains lysed PMNs, due to the production of the pore-forming toxin Î±-hemolysin (HlyA). For the others, resistance to phagocytic killing by PMN was not significantly different between both groups. In contrast, resistance to complement-mediated serum killing was significantly higher in OII strains than in the others (65Â % vs 10Â %; P <0.001). In E. coli, different mechanisms have been involved in complement resistance. Here, serum resistance was not linked to a group 2 capsule, or a loss of outer membrane permeability, or the recruitment of the complement inhibitor C4bp, but was significantly associated with the synthesis of long-chain LPS, regardless of the O-antigen. Thus, serum resistance could promote seeding of peri-implant tissues by helping E. coli to either persist in blood and reach the site of infection or overcome localized complement activation.
MIC score, a new tool to compare bacterial susceptibility to antibiotics application to the comparison of susceptibility to different penems of clinical strains of Pseudomonas aeruginosa. - The Journal of antibiotics
This study aimed to compare the susceptibility to carbapenems (imipenem, meropenem and doripenem) of clinical strains of Pseudomonas aeruginosa. It also studied whether susceptibility to imipenem or meropenem could predict, reliably, susceptibility to doripenem. Pseudomonal strains were collected from respiratory specimens, half of them from cystic fibrosis patients. MICs were determined according to European Committee on Antimicrobial Susceptibility Testing recommendations. Carbapenems were compared according to the susceptible, intermediate or resistant categories. A new approach also allowed comparing these carbapenems in a 'MIC score' taking into account the differences in breakpoints between drugs. One hundred thirty-nine strains were studied. They were found to be statistically more susceptible to meropenem than to the two other drugs. However, this difference was small: less than one dilution between the agents. This study also highlighted a significant correlation between susceptibility to penems taken in pairs. However, susceptibility to imipenem or meropenem did not reliably predict susceptibility to doripenem. Despite potential differences in resistance mechanisms, the Pseudomonas aeruginosa strains showed close susceptibility to three carbapenems. This was true for both cystic fibrosis patients and others. However, there were variations between strains. That justifies MICs to be determined for each of the three penems. This might be useful in case of elevated MICs and/or for potentially difficult-to-treat infections such as pneumonia in patients with cystic fibrosis patients.The Journal of Antibiotics advance online publication, 30 March 2016; doi:10.1038/ja.2016.38.
Adaptive processes of Staphylococcus aureus isolates during the progression from acute to chronic bone and joint infections in patients. - Cellular microbiology
Staphylococcus aureus bone and joint infection (BJI) is associated with significant rates of chronicity and relapse. In this study, we investigated how S. aureus is able to adapt to the human environment by comparing isolates from single patients with persisting or relapsing BJIs that were recovered during the initial and recurrent BJI episodes. In vitro and in vivo assays and whole-genome sequencing analyses revealed that the recurrent isolates induced a reduced inflammatory response, formed more biofilm, persisted longer in the intracellular compartments of host bone cells, were less cytotoxic and induced less mortality in a mouse infection model compared to the initial isolates despite the lack of significant changes at the genomic level. These findings suggest that S. aureus BJI chronicization is associated with an in vivo bacterial phenotypical adaptation that leads to decreased virulence and host immune escape, which is linked to increased intraosteoblastic persistence and biofilm formation. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
New in vitro and in vivo models to evaluate antibiotic efficacy in Staphylococcus aureus prosthetic vascular graft infection. - The Journal of antimicrobial chemotherapy
Prosthetic vascular graft infection (PVGI) is an emerging disease, mostly caused by staphylococci, with limited data regarding efficacy of current antistaphylococcal agents. We aimed to assess the efficacy of different antibiotic regimens.Six different strains of MSSA and MRSA were used. We compared results of minimal biofilm inhibitory and eradicating concentrations (MBICs and MBECs) obtained with a Calgary Biofilm Pin Lid Device (CBPD) with those yielded by an original Dacron(Â®)-related minimal inhibitory and eradicating concentration measure model. We then used a murine model of Staphylococcus aureus vascular prosthetic material infection to evaluate efficacy of different antibiotic regimens: vancomycin and daptomycin combined or not with rifampicin for MRSA and the same groups with cloxacillin and cloxacillin combined with rifampicin for MSSA.We demonstrated that classical measures of MBICs and MBECs obtained with a CPBD could overestimate the decrease in antibiotic susceptibility in material-related infections and that the nature of the support used might influence the measure of biofilm susceptibility, since results yielded by our Dacron(Â®)-related minimal eradicating assay were lower than those found with a plastic device. In our in vivo model, we showed that daptomycin was significantly more bactericidal than comparators for some strains of MRSA or MSSA but not for all. For the majority of strains, it was as efficient as comparators. The addition of rifampicin to daptomycin did not enhance daptomycin efficacy.Despite the heterogeneity of results according to bacterial strains, these innovative models represent an option to better evaluate the in vitro efficacy of antibiotics on Dacron(Â®)-related biofilm S. aureus infections, and to screen different antibiotic regimens in a mouse model of PVGIs.Â© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: email@example.com.
Host manipulation by cancer cells: Expectations, facts, and therapeutic implications. - BioEssays : news and reviews in molecular, cellular and developmental biology
Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research.Â© 2016 WILEY Periodicals, Inc.
Pathogenic potential of Escherichia coli clinical strains from orthopedic implant infections towards human osteoblastic cells. - Pathogens and disease
Escherichia coli is one of the first causes of Gram-negative orthopedic implant infections (OII), but little is known about the pathogenicity of this species in such infections that are increasing due to the ageing of the population. We report how this pathogen interacts with human osteoblastic MG-63 cells in vitro, by comparing 20 OII E. coli strains to two Staphylococcus aureus and two Pseudomonas aeruginosa strains. LDH release assay revealed that 6/20 (30%) OII E. coli induced MG-63 cell lysis whereas none of the four control strains was cytotoxic after 4â€‰h of coculture. This high cytotoxicity was associated with hemolytic properties and linked to hlyA gene expression. We further showed by gentamicin protection assay and confocal microscopy that the non-cytotoxic E. coli were not able to invade MG-63 cells unlike S. aureus strains (internalization rate <0.01% for the non-cytotoxic E. coli versus 8.88 Â± 2.31% and 4.60 Â± 0.42% for both S. aureus). The non-cytotoxic E. coli also demonstrated low adherence rates (<7%), the most adherent E. coli eliciting higher IL-6 and TNF-Î± mRNA expression in the osteoblastic cells. Either highly cytotoxic or slightly invasive OII E. coli do not show the same infection strategies as S. aureus towards osteoblasts.Â© FEMS 2015. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis. - Mucosal immunology
Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel diseases (IBDs), are characterized by high levels of IL-22 production. Rodent studies revealed that this cytokine is protective during colitis but whether this is true in IBDs is unclear. We show here that levels of the soluble inhibitor of IL-22, interleukin 22-binding protein (IL-22BP), are significantly enhanced during IBDs owing to increased numbers of IL-22BP-producing eosinophils, that we unexpectedly identify as the most abundant source of IL-22BP protein in human gut. In addition, using IL-22BP-deficient rats, we confirm that endogenous IL-22BP is effective at blocking protective actions of IL-22 during acute colitis. In conclusion, our study provides new important insights regarding the biology of IL-22 and IL-22BP in the gut and indicates that protective actions of IL-22 are likely to be suboptimal in IBDs thus making IL-22BP a new relevant therapeutic target.
A Malaysia 97 monovalent foot-and-mouth disease vaccine (>6PD50/dose) protects pigs against challenge with a variant FMDV A SEA-97 lineage virus, 4 and 7 days post vaccination. - Vaccine
Pigs play a significant role during outbreaks of foot-and-mouth disease (FMD) due to their ability to amplify the virus. It is therefore essential to determine what role vaccination could play to prevent clinical disease and lower virus excretion into the environment. In this study we investigated the efficacy of the double oil emulsion A Malaysia 97 vaccine (>6PD50/dose) against heterologous challenge with an isolate belonging to the A SEA-97 lineage at 4 and 7 days post vaccination (dpv). In addition, we determined whether physical separation of pigs in the same room could prevent virus transmission. Statistically there was no difference in the level of protection offered by 4 and 7 dpv. However, no clinical disease or viral RNA was detected in the blood of pigs challenged 4 dpv, although three of the pigs had antibodies to the non-structural proteins (NSPs), indicating viral replication. Viral RNA was also detected in nasal and saliva swabs, but on very few occasions. Two of the pigs vaccinated seven days prior to challenge had vesicles distal from the injection site, but on the inoculated foot, and two pigs had viral RNA detected in the blood. One pig sero-converted to the NSPs. In contrast, all unvaccinated and inoculated pigs had evidence of infection. No infection occurred in any of the susceptible pigs in the same room, but separated from the infected pigs, indicating that strict biosecurity measures were sufficient under these experimental conditions to prevent virus transmission. However, viral RNA was detected in the nasal swabs of one group of pigs, but apparently not at sufficient levels to cause clinical disease. Vaccination led to a significant decrease in viral RNA in vaccinated pigs compared to unvaccinated and infected pigs, even with this heterologous challenge, and could therefore be considered as a control option during outbreaks.Copyright Â© 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Evolutionary perspective of cancer: myth, metaphors, and reality. - Evolutionary applications
The evolutionary perspective of cancer (which origins and dynamics result from evolutionary processes) has gained significant international recognition over the past decade and generated a wave of enthusiasm among researchers. In this context, several authors proposed that insights into evolutionary and adaptation dynamics of cancers can be gained by studying the evolutionary strategies of organisms. Although this reasoning is fundamentally correct, in our opinion, it contains a potential risk of excessive adaptationism, potentially leading to the suggestion of complex adaptations that are unlikely to evolve among cancerous cells. For example, the ability of recognizing related conspecifics and adjusting accordingly behaviors as in certain free-living species appears unlikely in cancer. Indeed, despite their rapid evolutionary rate, malignant cells are under selective pressures for their altered lifestyle for only few decades. In addition, even though cancer cells can theoretically display highly sophisticated adaptive responses, it would be crucial to determine the frequency of their occurrence in patients with cancer, before therapeutic applications can be considered. Scientists who try to explain oncogenesis will need in the future to critically evaluate the metaphorical comparison of selective processes affecting cancerous cells with those affecting organisms. This approach seems essential for the applications of evolutionary biology to understand the origin of cancers, with prophylactic and therapeutic applications.
Cancer: an emergent property of disturbed resource-rich environments? Ecology meets personalized medicine. - Evolutionary applications
For an increasing number of biologists, cancer is viewed as a dynamic system governed by evolutionary and ecological principles. Throughout most of human history, cancer was an uncommon cause of death and it is generally accepted that common components of modern culture, including increased physiological stresses and caloric intake, favor cancer development. However, the precise mechanisms for this linkage are not well understood. Here, we examine the roles of ecological and physiological disturbances and resource availability on the emergence of cancer in multicellular organisms. We argue that proliferation of 'profiteering phenotypes' is often an emergent property of disturbed, resource-rich environments at all scales of biological organization. We review the evidence for this phenomenon, explore it within the context of malignancy, and discuss how this ecological framework may offer a theoretical background for novel strategies of cancer prevention. This work provides a compelling argument that the traditional separation between medicine and evolutionary ecology remains a fundamental limitation that needs to be overcome if complex processes, such as oncogenesis, are to be completely understood.
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2 1/2 Dearfield Dr Ste 102 Greenwich, CT 06831
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