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Biomedical subjects

Michael Green

Publications and source records attributed to Michael Green.

At least 37 records · Page 2Linked to original sources
PubMed2005

CpG-DNA protects against a lethal orthopoxvirus infection in a murine model.

CpG-DNA has been described as a potent activator of the innate immune system, with potential to protect against infection caused by a range of pathogens in a non-specific manner. Here two classes of CpG-DNA (CpG-A and CpG-B) have been investigated for their abilities to protect mice from infection with an orthopoxvirus (vaccinia virus). Dosing with either CpG-A or B by the intraperitonal or intranasal route protected mice against a subsequent intranasal challenge with vaccinia virus. To our knowledge, this is the first time CpG-mediated protection has been demonstrated at the lung surface. The level of protection was greater when CpG-DNA was administered intranasally demonstrating a clear relationship between the route of CpG dosing and infection route. Treatment with CpG-B reduced viral titer in the lung by 10,000-fold at day 3 post-infection. The CC chemokines RANTES and MIP-1beta were elevated in the broncho-alveolar lavage from animals treated intranasally with CpG-B compared to untreated and intraperitoneally dosed controls, and it is possible that these chemokines play a role in the clearance of intranasally delivered vaccinia virus.

Animals↗
PubMed2005

Teaching and improving quality of care in a primary care internal medicine residency clinic.

Purpose Learning and applying quality of care principles are essential to practice-based learning and improvement. The authors investigated the feasibility and effects of a self-directed curriculum in quality of care for residents. Method In 2001-02, 13 second-year residents at two community-based outpatient clinics in the Yale University primary care internal medicine residency program were asked to participate in a trial of a quality improvement curriculum (intervention group). Thirteen third-year residents in the same residency program served as the comparison group. The curriculum consisted of readings in quality of care, weekly self-reflection with a faculty member, completion of a commitment to change survey, and medical record audits. Study outcome measures were patient level quality of care measures for diabetes, satisfaction with the curriculum, and self-reported behavioral changes. Results In the follow-up, patients of the intervention group were significantly more likely to have received a monofilament foot examination and baseline electrocardiogram than were patients of the comparison group. When comparing the change between baseline and follow-up, patients for the second-year residents showed significantly more improvement in hemoglobin A1c and LDL cholesterol levels and Pneumovax administration than did patients of the comparison group. All residents in the intervention group were highly satisfied with the curriculum. Thirty-five of 54 residents' personal commitments to change were either partially or fully implemented six months after the curriculum. Conclusions A multifaceted curriculum in quality improvement led to modest improvements in the care of diabetic patients and meaningful changes in self-reported practice behaviors. Future research should include more focus on the microsystems of residency outpatient experiences.

Comorbidity↗
PubMed2005

In vitro activity of telithromycin against macrolide-susceptible and macrolide-resistant pharyngeal isolates of group A streptococci in the United States.

In vitro susceptibility testing of 2,797 group A streptococcus (GAS) isolates demonstrated that telithromycin was fully active against all macrolide-susceptible strains and among 80 of 115 macrolide-resistant GAS expressing the M phenotype. Telithromycin resistance was identified in 2 of 45 strains expressing the inducible macrolide-lincosamide-streptogramin B phenotype and four of nine isolates expressing the constitutive macrolide-lincosamide-streptogramin B resistance phenotype.

Anti-Bacterial Agents↗
PubMed2005

Safety and immunogenicity of the American Academy of Pediatrics--recommended sequential pneumococcal conjugate and polysaccharide vaccine schedule in pediatric solid organ transplant recipients.

OBJECTIVE: Solid organ transplant recipients are at increased risk for invasive pneumococcal disease. The American Academy of Pediatrics recommends immunization with sequential pneumococcal vaccines for this group; however, data are lacking. Accordingly, this study was designed to evaluate the safety and immunogenicity of the recommended regimen. METHODS: Pediatric solid organ transplant recipients (n = 25) between 2 and 18 years of age who had not previously received 7-valent conjugate pneumococcal vaccine (PCV7) were enrolled. These patients received 2 doses of the PCV7 and a single dose of the 23-valent polysaccharide pneumococcal vaccine (23V). Each vaccine dose was given 2 months apart. Healthy age-matched controls (n = 23) were enrolled for comparison. Controls received a single dose of PCV7 followed 2 months later by a single dose of 23V. Antibody concentrations to serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, and 23F were measured by enzyme-linked immunosorbent assay prevaccination, 2 months after each vaccine dose and 5 to 7 months after 23V. Local and systemic reactions to each vaccine dose were recorded. RESULTS: Systemic and injection-site reactions were comparable between the 2 groups. Significant rises in serotype-specific pneumococcal antibody geometric mean concentrations from prevaccination levels were observed in both groups; however, final antibody responses to serotypes 1, 4, 9V, 14, 18C, 19F, and 23F were significantly lower in solid organ transplant recipients compared with the control group. Antibody concentrations did not increase significantly among solid organ transplant patients after the second dose of PCV7. No additional increase in PCV7-associated serotype-specific antibody levels was observed after the 23V dose in both groups. Heart transplant recipients had lower antibody responses compared with liver transplant recipients. CONCLUSIONS: Although the pneumococcal vaccine regimen was safe and immunogenic among pediatric solid organ transplant recipients, the patients did not seem to benefit from the second dose of PCV7 or from the 23V dose given 2 months later. Additional studies are needed to determine the number of PCV7 doses and the interval between PCV7 and 23V to induce optimal responses.

Adolescent↗
PubMed2004

Structure and bonding in the isoelectronic series CnHnP5-n+: is phosphorus a carbon copy?

The relative stabilities of different isomers of the isoelectronic series C(n)H(n)P(5-n)(+) have been investigated using G3X theory. The results indicate that all species containing one or more phosphorus atom adopt a three-dimensional nido geometry, in marked contrast to the planar structure favoured by the all-carbon analogue. Within isomeric nido clusters, a strong correlation between total energy and the nucleus-independent chemical shift (NICS) indicates that three-dimensional aromaticity plays a significant role in determining the stability of the cluster. In the context of these nido clusters, the extent to which phosphorus is a carbon copy proves to be highly dependent on the global electronic environment. The first isolobal substitution of CH by P causes a complete switch from localised to delocalised bonding, accompanied by a transition from a two- to a three-dimensional structure, with the phosphorus atom showing a strong preference for the unique apical site. In contrast, further increasing the phosphorus content causes no further change in structure or bonding, suggesting that, at the basal sites, phosphorus is a rather better carbon copy. The low-energy pathways for interconversion of apical and basal atoms previously identified in C(2)H(2)P(3)(+) prove to be a general feature of all members of the series.

Journal Article↗
PubMed2004

Synthesis and evaluation of two 18F-labeled 6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for beta-amyloid in Alzheimer's disease.

This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K(i) = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for (18)F-2-fluoroethylation and (18)F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [(18)F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [(18)F]FPM-IMPY at 0.8 min. These values were similar to those of [(123)I/(125)I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [(18)F]FEM or [(18)F]FPM-IMPY. In contrast to the single-exponential washout of [(123)I/(125)I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [(18)F]FEM-IMPY and 2.1% ID/g for [(18)F]FPM-IMPY. Substantial skull uptake of [(18)F]fluoride was also clearly observed. With a view to slow the metabolism of [(18)F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D(4)-[(18)F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [(18)F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [(18)F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

Alzheimer Disease↗
PubMed2004

A novel combination of cisplatin, irinotecan, and capecitabine in patients with advanced cancer.

BACKGROUND: We conducted a dose escalation study combining cisplatin, irinotecan, and capecitabine (CIC), aiming to establish the maximum tolerated doses (MTD), side effect profile, and dose-limiting toxicity (DLT) of this novel regimen. PATIENTS AND METHODS: Intravenous cisplatin and irinotecan were to be administered on days 1 and 8, and oral capecitabine on days 1-14 of a 3-week cycle. The study was conducted in three parts. Part A: escalating doses of irinotecan (40 --> 80 mg/m2) and capecitabine (1000 --> 3300 mg/d) combined with a fixed dose of cisplatin (30 mg/m2). Part B: escalating doses of irinotecan (MTD-A --> MTD-A + 40 mg/m2) with fixed doses of cisplatin (20 mg/m2) and capecitabine (MTD-A level). Part C: escalating doses of capecitabine (1300 mg/d-->2600 mg/d) with fixed doses of cisplatin (20 mg/m2) and irinotecan (60 mg/m2). RESULTS: Of 51 eligible patients 27 (53%) were male, median age was 58 years and 88% had PS 0-1. Major primary disease sites were colorectal (24%), unknown (14%), stomach (14%), and pancreas (12%). MTD-A was cisplatin 30 mg/m2, irinotecan 60 mg/m2, capecitabine 1000 mg/d and MTD-B was cisplatin 20 mg/m2, irinotecan 90 mg/m2, capecitabine 1000 mg/d. An MTD was not formally established for part C. DLTs consisted of infection with neutropenia (1), diarrhea and fatigue (1), hypokalemia (1), diarrhea and febrile neutropenia (1) and C2 delay of > or = 2 weeks or 25% dose reduction in C1 due to neutropenia or thrombocytopenia (6). Seven patients had a partial response to treatment (four colorectal, one SCLC, one NSCLC, one unknown primary), twenty seven SD (53%), twelve PD (24%) and five NE (10%). CONCLUSION: CIC was associated with moderate toxicity and only modest antitumor activity. We conclude that this regimen has insufficient activity to justify further study in the phase II setting.

Adult↗
PubMed2004

Carcinoma of the anal canal: a local experience and review of the literature.

BACKGROUND: Through the 1970s patients presenting with anal canal carcinoma were managed with a surgical approach--abdomino-perineal resection. Since then, the pioneering work of Nigro et al. and a series of large clinical trials have clearly demonstrated that combined chemotherapy and radiotherapy result in greater local control, colostomy-free survival and increase in overall patient survival. The aim of the present study is to determine how widely the combined modality approach has been adopted in routine clinical practice and what outcomes are achieved in this setting. METHODS: All patients with anal cancer treated at three tertiary referral centres over an 11-year period (1991-2001) were identified. Data were collected by a retrospective record review. RESULTS: Our search identified a total of 50 patients: 22 men and 28 women, with a median age of 62 years. Four patients had metastatic disease diagnosed at presentation. Nine patients (18%) were at least 75 years of age and three were known to be HIV positive. Median potential follow up is 52 months. Of the 46 patients treated for cure, 38 received a combination of chemotherapy and radiation, with 79% achieving a complete response. Efficacy was maintained in treated elderly patients (> or =75 years). The 5-year survival of the 38 patients with local or locoregional disease who received combined chemoradiation modality was 63%. CONCLUSIONS: Overall this series demonstrates that combined chemotherapy and radiotherapy has been adopted as standard treatment with outcome data similar to those reported in the randomized clinical trials. Where possible elderly patients should receive combined modality therapy.

Aged↗
PubMed2004

Reemergence of macrolide resistance in pharyngeal isolates of group a streptococci in southwestern Pennsylvania.

We previously reported on the emergence of macrolide-resistant pharyngeal isolates of group A streptococci (GAS) in our community. The purpose of the present study was to track longitudinal trends in macrolide resistance in these isolates in southwestern Pennsylvania. Testing for susceptibility to erythromycin and clindamycin was performed for all pharyngeal GAS isolates recovered at the Children's Hospital of Pittsburgh and a local pediatric practice between September 2001 and May 2002. Macrolide resistance phenotypes and genotypes were determined by double-disk diffusion and PCR, respectively. Strain relatedness was determined by field inversion gel electrophoresis and emm gene sequence typing. A total of 708 isolates of GAS were recovered during the study period; 68 (9.6%) were macrolide resistant, while all isolates were sensitive to clindamycin. The monthly prevalence of macrolide resistance ranged from 0 to 41%. Only 21 of 573 (3.7%) strains recovered from September 2001 through March 2002 were macrolide resistant. A sudden increase in the rate of macrolide resistance (47 of 135 isolates [35%]) was seen in April and May 2002. Sixty-two isolates demonstrated the M phenotype (resistance to macrolide antibiotics), and six isolates demonstrated the MLS(B) phenotype (resistance to most macrolide, lincosamide, and streptogramin B antibiotics); these isolates were confirmed to be mef(A) and erm(A), respectively. Three unique mef(A) clones and four unique erm(A) clones were identified among the resistant isolates. The MIC at which 50% of isolates are inhibited (MIC(50)) for the mef(A) strains was 16 micro g/ml, while the MIC(50) for erm(A) strains was 8 micro g/ml. The finding of high levels of macrolide resistance among pharyngeal isolates of GAS for a second successive year in our community raises the concern that this problem may be more common in the United States than was previously appreciated. Longitudinal surveillance of isolates from multiple centers is needed to define the prevalence of antimicrobial agent-resistant GAS in the United States.

Anti-Bacterial Agents↗
PubMed2004

Surface immunoglobulin-deficient Epstein-Barr virus-infected B cells in the peripheral blood of pediatric solid-organ transplant recipients.

Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, normally causes an asymptomatic latent infection with very low levels of circulating virus in the peripheral blood of infected individuals. However, EBV does have pathogenic potential and has been linked to several diseases, including posttransplant lymphoproliferative disease (PTLD), which involves very high circulating viral loads. As a consequence of immunosuppression associated with transplantation, children in particular are at risk for PTLD. Even in the absence of symptoms of PTLD, very high viral loads are often observed in these patients. EBV-infected B cells in the circulations of 16 asymptomatic pediatric solid-organ transplant recipients from Children's Hospital of Pittsburgh were simultaneously characterized for their surface immunoglobulin (sIg) isotypes and EBV genome copy numbers. Patients were characterized as having high and low viral loads on the basis of their stable levels of circulating virus. Patients with high viral loads had both high- and low-copy-number cells. Cells with a high numbers of viral episomes (>20/cell) were predominantly Ig null, and cells with low numbers of episomes were predominantly sIgM positive. Patients with low viral loads carried the vast majority of their viral load in low-copy-number cells, which were predominantly IgM positive. The very rare high-copy-number cells detected in carriers with low viral loads were also predominantly Ig-null cells. This suggests that two distinct types of B-lineage cells contribute to the viral load in transplant recipients, with cells bearing high genome copy numbers having an aberrant Ig-null cellular phenotype.

B-Lymphocytes↗
PubMed2004

Group A streptococci among school-aged children: clinical characteristics and the carrier state.

OBJECTIVE: A 4-year longitudinal study of school-aged children was conducted to describe the clinical characteristics and epidemiologic features of infections with group A streptococci (GAS). METHODS: Between 1998 and 2002, surveillance throat cultures were performed twice per month (October to May) for a cohort of elementary school children in Pittsburgh, Pennsylvania. In addition, throat cultures were obtained during any respiratory illness. Erythromycin and clindamycin susceptibility testing was performed for all isolates. Molecular typing was performed with field-inversion gel electrophoresis. Representative isolates from each field-inversion gel electrophoresis group were emm typed. Strict definitions were used to characterize each GAS infection. Children were classified into 4 categories each year, ie, single episode, recurrent episodes, carriers of GAS, and no infections. RESULTS: A total of 48 to 100 children per year were studied for 4 years; 61 (49%) were male. The mean age was 9.6 years (range: 5-15 years). A total of 5658 throat cultures were performed; 878 (15.5%) were positive for GAS. Antimicrobial agents were used to treat 209 episodes of infection. Thirteen emm types were observed during the 4-year period. GAS were isolated most often from children who were carriers; isolates from single episodes were next most common. Children carried a single emm type for a mean of 10.8 weeks (range: 3-34 weeks). Carriers were likely to be classified again as carriers in subsequent years and frequently switched emm types. Sixty-two percent of the children had > or =1 year with no infections. CONCLUSIONS: GAS infections are common among school-aged children. The majority of positive throat cultures observed in this longitudinal study were obtained from children who were carriers of GAS. Carriers switched emm types but tended to become carriers repeatedly during the study. Practitioners should consider treating children known to be GAS carriers when they develop a new illness that is consistent with streptococcal pharyngitis, because they may acquire new emm types and be at risk for rheumatic heart disease.

Adolescent↗