Carbapenem-resistant Klebsiella pneumoniae infections in kidney transplant recipients: a case-control study.

INTRODUCTION: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections have emerged as a significant challenge in solid organ transplantation. CRKP infections in other patient populations have been associated with higher mortality, when compared to infections caused by carbapenem-sensitive K. pneumoniae (CSKP). AIMS: The aim of this study was to evaluate possible risk factors, clinical characteristics, and outcomes of CRKP infections compared with CSKP infections in kidney transplant recipients (KTR). METHODS: We retrospectively investigated 13 CRKP infections and 39 CSKP infections in KTR (2006-2010). RESULTS: CRKP was not significantly associated with age, gender, or comorbidities. CRKP infections were significantly associated with recent exposure to broad-spectrum antibiotics and were more likely to have been managed on an inpatient basis and to have required source control. CRKP was significantly associated with earlier mortality. Six of 13 (46%) patients with CRKP infection, and none of the patients with CSKP infection, died within 6.5 months of infection onset. Although cases and controls did not differ significantly with respect to diabetes, all patients (100%, n = 9) who died during the study had diabetes, while 58% of the 43 survivors had diabetes (P = 0.02). CONCLUSION: In conclusion, CRKP compared with CSKP is associated with greater risk of mortality. Investigations on ways to better prevent CRKP are urgently needed.

N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties.

N-cadherin and HER2/neu were found to be co-expressed in invasive breast carcinomas. To test the contribution of N-cadherin and HER2 in mammary tumor metastasis, we targeted N-cadherin expression in the mammary epithelium of the MMTV-Neu mouse. In the context of ErbB2/Neu, N-cadherin stimulated carcinoma cell invasion, proliferation and metastasis. N-cadherin caused fibroblast growth factor receptor (FGFR) upmodulation, resulting in epithelial-to-mesenchymal transition (EMT) and stem/progenitor like properties, involving Snail and Slug upregulation, mammosphere formation and aldehyde dehydrogenase activity. N-cadherin potentiation of the FGFR stimulated extracellular signal regulated kinase (ERK) and protein kinase B (AKT) phosphorylation resulting in differential effects on metastasis. Although ERK inhibition suppressed cyclin D1 expression, cell proliferation and stem/progenitor cell properties, it did not affect invasion or EMT. Conversely, AKT inhibition suppressed invasion through Akt 2 attenuation, and EMT through Snail inhibition, but had no effect on cyclin D1 expression, cell proliferation or mammosphere formation. These findings suggest N-cadherin/FGFR has a pivotal role in promoting metastasis through differential regulation of ERK and AKT, and underscore the potential for targeting the FGFR in advanced ErbB2-amplified breast tumors.

Measurements of medication adherence in diabetic patients with poorly controlled HbA(1c).

AIMS: To assess pharmacy claims and self-report data as measures of medication adherence and to describe baseline characteristics of subjects in the Improving Diabetes Outcomes Study. METHODS: Multi-ethnic, lower-income, insured adults (n = 526) in New York City with Type 2 diabetes were enrolled in a randomized, controlled, behavioural intervention study delivered by telephone. Baseline data were examined, including glycated haemoglobin (HbA(1c)), objective measures of diabetes medication adherence [claims data medication possession ratio (MPR)], and two self-report measures [Morisky Medication-taking Scale and the medication-taking item of the Summary of Diabetes Self-Care Activities (SDSCA)]. Associations of highest tertile HbA(1c) (>or= 9.3%) with lowest tertile MPR (< 42%) were assessed with logistic regression models adjusting for potential confounders. Subset analyses were performed based on assessment of potential interaction. RESULTS: Participants (mean +/- sd age 56 +/- 7 years) had median (interquartile range) HbA(1c) 8.6% (8.0-10.0). Correlations of baseline MPR with Morisky score and SDSCA medication-taking item were strongly significant (both rho = 0.21, P < 0.001). Lowest MPR was significantly (P = 0.008) associated with highest HbA(1c) in the group as a whole and among the subset taking two or more oral glucose-lowering agents (OGLA) (P = 0.002), but not among the subset taking only one (P = 0.83). Self-report adherence measures were not significantly associated with HbA(1c) in either the whole group or either subset. CONCLUSIONS: These results support the validity of MPR as an adherence measure for OGLA among insured diabetes patients with poorly controlled HbA(1c), especially those taking two or more OGLA.

Efficacy of inferior vena cava filters in anticoagulated patients.

BACKGROUND AND OBJECTIVES: The benefit of an inferior vena cava (IVC) filter in addition to standard anticoagulation regimens is unknown. METHODS: We examined data for patients who received IVC filters with anticoagulation (AC-Filter) after an episode of venous thromboembolism (VTE) and compared them with data for those who received anticoagulation only (AC-Only). Outcome measures were new pulmonary embolism (PE), recurrent deep vein thrombosis (DVT), and mortality at 90 days and at 5 years. Demographic data included age, gender, and ethnicity/race, prior thromboembolic history, cancer, serum albumin, and time in therapeutic range. In addition, subsets matched for age, gender and race/ethnicity were examined in detail. RESULTS: AC-Filter patients (n = 251), when compared to AC-Only patients (n = 1377), did not differ significantly with regard to gender or cancer status, but white males in general had better outcomes. AC-Filter patients were more likely to have had a previous history of PE or VTE (P < 0.001). In comparison to AC-Only patients, AC-Filter patients had lower mean serum albumin levels (3.1 +/- 0.8 vs. 3.6 +/-0.8 mg dL(-1), P < 0.001) and were older (65 +/- 16.1 years vs. 60 +/- 17.5 years, P < 0.001). After stratification according to previous history of PE or VTE prior to the index VTE event, no differences in the outcome measures of new PE, recurrent DVT or mortality were identified between groups, but patients with a prior history of PE from either group were more likely to have a new PE (hazard ratio 1.9, P < 0.001). CONCLUSIONS: These data suggest that IVC filters may not provide any substantial additional benefit for patients who can tolerate anticoagulant therapy.

High and low serum potassium associated with cardiovascular events in diuretic-treated patients.

OBJECTIVE: To determine the relationship of moderately high and low concentrations of serum potassium with cardiovascular disease events among treated hypertensive patients. DESIGN: An observational cohort study with prospectively collected data. SETTING: A worksite treatment program for mild hypertension. PATIENTS: All program participants with baseline and at least one annual follow-up measure of serum potassium; 7,653 individuals with 6.7 years mean follow-up met these criteria. MAIN OUTCOME MEASURES: Outcome events were admissions to hospital because of cardiovascular disease, and deaths. The research question regarding serum potassium categories was formulated after data collection. The serum potassium concentration (mean +/- 2SD) of the study population was used to define low (3.0-3.5 mmol/l), high (5.1-5.9 mmol/l) and middle (3.6-5.0 mmol/l) categories. RESULTS: Individuals with low (n = 146) and high (n = 226) serum potassium had significantly greater risk for cardiovascular disease events than those in the middle category (n = 7,281). Multivariate adjusted hazard ratios from Cox models were 2.6 [95% confidence intervals (CI) 1.5-4.4] for the low potassium group and 1.7 (95% CI 1.0-2.7) for the high potassium group, with the middle group as reference. Among 1,679 individuals who regularly took diuretics, hazard ratios were 4.3 (95% CI 2.4-7.9) for the low potassium group and 6.7 (95% CI 2.8-15.9) for the high group. Neither low nor high potassium was significantly associated with outcome events for those not regularly using diuretics. CONCLUSIONS: These data confirm an association of mild hypokalemia with increased cardiovascular events among diuretic-treated hypertensive patients. In addition, we have found a similar increased cardiovascular risk associated with modest hyperkalemia among these patients. Whether modification of these serum potassium concentrations would alter that risk remains to be determined.

History of treatment for depression: risk factor for myocardial infarction in hypertensive patients.

OBJECTIVE: Psychological factors have been suspected of contributing to the development of cardiovascular disease. This study examined the relationship between a self-reported history of treatment for depression and subsequent myocardial infarction among treated hypertensive patients. METHODS: Participants (5564) in a union-sponsored, hypertension control program in New York City, who entered the program during 1981-1994 without a history of cardiovascular disease and who were asked whether they had been treated for depression, were followed in a prospective cohort study. The primary outcome of interest was hospitalization or death due to myocardial infarction. RESULTS: At entry, 3.5% of men and 6.4% of women reported a history of treatment for depression. During 4.9 years (average) of follow-up, 112 fatal and nonfatal myocardial infarctions were recorded. The sex-adjusted relative risk of myocardial infarction was 2.24 (confidence interval = 1.13-4.45). Controlling for known cardiovascular risk factors with multivariate proportional hazards models, history of treatment for depression was significantly associated with subsequent myocardial infarction (hazard ratio = 2.10, confidence interval = 1.04-4.23). CONCLUSIONS: A self-reported history of treatment for depression is independently associated with subsequent myocardial infarction in treated hypertensive patients without prior cardiovascular disease. Whether additional or different treatment for depression will be cardioprotective is unknown and merits further study.

Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents.

PURPOSE: Several studies have found that depression and the use of antidepressant medications are associated with an increased risk of cardiovascular disease. We assessed the association between the use of antidepressant drugs and myocardial infarction, and whether that association differs between the tricyclic and selective serotonin reuptake inhibitor (SSRI) classes of medication. PARTICIPANTS AND METHODS: We compared the experience of a cohort of 2,247 working, union health plan members who received at least one prescription for an antidepressant in an accrual period of 1991-1992 with that of 52,750 members who did not. Patients were followed for up to 4.5 years (minimum 6 months). Three antidepressant medication classes were defined: tricyclics, SSRIs, and others. The primary outcome was hospitalization or death due to myocardial infarction. RESULTS: Adjusted for age and sex, antidepressant users had a relative risk of myocardial infarction of 2.2 (95% confidence interval [CI] 1.3 to 3.7) compared with nonusers of antidepressants. There were 16 myocardial infarctions among 1,650 users of tricyclic antidepressants, 2 among 655 SSRI users, and none among 279 users of other antidepressants. Adjusting for age, gender, baseline heart disease, diabetes, hypertension, hyperlipidemia, anxiety, and cancer, the relative risk of myocardial infarction was 2.2 (95% CI 1.2 to 3.8) in users of tricyclic agents and 0.8 (95% CI 0.2 to 3.5) in users of SSRIs, as compared with subjects who did not use antidepressants. CONCLUSION: The association between use of tricyclic antidepressants, but not SSRIs, with an increased risk of myocardial infarction in our patients suggests that an earlier report that there is no difference in risk between the antidepressant classes, based on short-term studies, may not apply to long-term adverse cardiovascular outcomes.

Myocardial infarction in treated hypertensive patients: the paradox of lower incidence but higher mortality in young blacks compared with whites.

BACKGROUND: Despite the impressive decline in coronary heart disease death rates, a mortality differential between blacks and whites persists. Our study objective was to determine whether excess mortality among well-controlled hypertensive black men compared with whites is due to differences in disease incidence or in case fatality. METHODS AND RESULTS: Of 3382 male subjects (1266 blacks and 2116 whites) enrolled between 1973 and 1996 and followed up through 1997 in a work-site hypertension control program, 2343 were followed up until 60 years of age, and 1884 were followed up until >60 years of age (either continuing after 60 years [n=845] or beginning treatment at >/=60 years [n=1039]), with a mean follow-up of 5.2 and 5.5 years, respectively. During follow-up, 186 myocardial infarction (MI) events (including 31 revascularizations) occurred, with 63 in patients <60 years and 123 in patients >/=60 years of age. Age-adjusted MI incidence was nearly twice as high for whites as blacks in younger (6.3 versus 3.4/1000 person-years) and older (14.1 versus 7.5 person-years) subjects. In contrast, the age-adjusted case fatality rate was 3-fold higher for younger blacks than for whites (37.8% versus 12.2%). In older patients, case fatality did not differ significantly between blacks and whites (37.6% versus 50. 3%). In separate Cox regression analyses, among younger blacks but not younger whites, history of diabetes and smoking were significantly associated with both incidence and fatality. CONCLUSIONS: In these treated male hypertensive patients with good blood pressure control (139.6/85.7 mm Hg), young blacks, despite a lower MI incidence, had higher MI mortality than did their white counterparts. Their higher case fatality rate was associated with fewer coronary artery revascularizations and a higher prevalence of diabetes and smoking.

Antiangiogenic effects of camptothecin analogues 9-amino-20(S)-camptothecin, topotecan, and CPT-11 studied in the mouse cornea model.

Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated clinically as progressive or stable disease. We have investigated the antiangiogenic properties of three camptothecin analogues, 9-amino-20(S)-camptothecin, topotecan, and camptosar (CPT-11), currently under investigation in clinical settings. Angiogenesis was induced by basic fibroblast growth factor in the cornea of inbred Swiss-Webster mice, with the aim of exploring the suppression of neovascularization by the analogues injected into the mice daily over a period of 6 days. The dose range chosen is known to inhibit, in the mouse model, the growth of various human tumor xenografts or murine tumors. The statistical analysis evaluated the association between the area of neoangiogenesis and the dose of the drugs tested and correlated the effects with observed drug toxicity. It was established that, as the drug doses increased, the area of neovascularization decreased, appearing to approximate a negative exponential curve. 9-Amino-20(S)-camptothecin at 6.89 and 8.26 micromol/kg (2.5 and 3.0 mg/kg) and topotecan at 8.31 micromol/kg (3.5 mg/kg), both drugs being delivered over a 6-day period, had statistically significant reduction (47.2-72.5%) of neoangiogenesis and acceptable toxicity. At higher doses of the two analogues, toxic body-weight losses and deaths were observed. CPT-11 showed statistically significant reduction of neoangiogenesis at a dose of 359 micromol/kg (210 mg/kg) delivered over a 6-day course. Unlike camptothecin analogues, the nontoxic dose of vincristine did not induce a statistically significant inhibition of angiogenesis, and there was no dose-dependent escalation of antiangiogenic effects. The results indicate that camptothecins are most likely cytotoxic against two tumor compartments: in addition to tumor cells of epithelial origin, the drugs act against endothelial cells and prevent the growth of the tumor microvessels. We have hypothesized that treatment failure in some patients is due to incomplete or inadequate inhibition of the microvessel growth by camptothecins. Presumably, an intensive inhibition of the remaining tumor microvasculature in such patients could be achieved by combining a camptothecin with another antiangiogenic anticancer agent or with a highly selective angiogenic inhibitor exerting minimal dose-limiting toxicity. Such treatment by a camptothecin plus a less toxic inhibitor of angiogenesis can improve antitumor efficacy. To validate this concept, preclinical studies followed by clinical trials are planned.

Inclusion of the S2 dorsal rootlets in functional posterior rhizotomy for spasticity in children with cerebral palsy.

Many neurosurgeons have made a practice of sectioning the S2 dorsal roots during selective posterior rhizotomy for the treatment of spasticity in children with cerebral palsy, but the efficacy of this treatment has not previously been proven. S2 afferents are involved in reflex arcs of the plantar flexors (PFs), so that S2 lesioning should in theory reduce PF spasticity. To test this assumption, we determined the frequency of postoperative residual spasticity in the PFs when S2 lesioning was or was not performed. We assessed 85 children for whom 6-month follow-up was available. Functional rhizotomy from L2-S1 was performed on 13 of them (26 legs with PF spasticity) and from L2-S2 on 72 (141 legs with PF spasticity). Rootlets were lesioned if there was an abnormal response to intraoperative electrical stimulation. In 20 patients, lesioning of the S2 rootlets was assisted by the "pudendal neurogram," a technique previously shown to prevent bladder dysfunction during sectioning of the sacral roots. When S2 roots were excluded from the lesioning process, residual PF spasticity was detected in 35% of the legs that had it preoperatively, leaving 5 (38%) of 13 children with functionally impairing spasticity. When S2 roots were included, 6% of legs that had PF spasticity retained it postoperatively (P < 0.001), leaving 8 (11%) of 72 patients with functionally limiting spasticity (P < 0.05). Thus, the addition of the S2 roots to the procedure resulted in an 81% reduction in the number of legs with residual PF spasticity and a 71% reduction in the number of patients with residual PF spasticity.(ABSTRACT TRUNCATED AT 250 WORDS)