In Vitro Activity of Plazomicin against 5,015 Gram-Negative and Gram-Positive Clinical Isolates Obtained from Patients in Canadian Hospitals as Part of the CANWARD Study, 2011-2012

Plazomicin is a next-generation aminoglycoside that is not affected by most clinically relevant aminoglycoside-modifying enzymes. The in vitro activities of plazomicin and comparator antimicrobials were evaluated against a collection of 5,015 bacterial isolates obtained from patients in Canadian hospitals between January 2011 and October 2012. Susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method, with MICs interpreted according to CLSI breakpoints, when available. Plazomicin demonstrated potent in vitro activity against members of the family Enterobacteriaceae, with all species except Proteus mirabilis having an MIC₉₀ of ≤1 μg/ml. Plazomicin was active against aminoglycoside-nonsusceptible Escherichia coli, with MIC₅₀ and MIC₉₀ values identical to those for aminoglycoside-susceptible isolates. Furthermore, plazomicin demonstrated equivalent activities versus extended-spectrum β-lactamase (ESBL)-producing and non-ESBL-producing E. coli and Klebsiella pneumoniae, with 90% of the isolates inhibited by an MIC of ≤1 μg/ml. The MIC₅₀ and MIC₉₀ values for plazomicin against Pseudomonas aeruginosa were 4 μg/ml and 16 μg/ml, respectively, compared with 4 μg/ml and 8 μg/ml, respectively, for amikacin. Plazomicin had an MIC₅₀ of 8 μg/ml and an MIC₉₀ of 32 μg/ml versus 64 multidrug-resistant P. aeruginosa isolates. Plazomicin was active against methicillin-susceptible and methicillin-resistant Staphylococcus aureus, with both having MIC₅₀ and MIC₉₀ values of 0.5 μg/ml and 1 μg/ml, respectively. In summary, plazomicin demonstrated potent in vitro activity against a diverse collection of Gram-negative bacilli and Gram-positive cocci obtained over a large geographic area. These data support further evaluation of plazomicin in the clinical setting.     

Studies on passive transfer of anti-dextran and anti-egg albumin reactivity in the rat.

We were unable, passively, to transfer reactivity against dextran to the skin or peritoneal mast cells of non-dextran-reactive rats, by using serum or material eluted at pH 3 from mast cells of spontaneously dextran-reactive rats. When the dextran-reactive donor rats had also been immunized against egg albumin (EA) with pertussis vaccine (inducing IgE anti-EA antibody), passive sensitivity against EA (but not against dextran) could easily be transferred. The results indicated that the anti-dextran reactivity is not due to IgE antibody. Systemic reactions against dextran and EA differed in pattern, supporting the concept that the two substances acted through different mechanisms.     

Variations in Surgical Treatment and Outcomes of Patients With Pancreatic Cancer: A Population-Based Study

Background There is ongoing debate on how variations in surgical technique affect outcomes in pancreatic cancer. This population-based study examines current surgical practice and outcomes for cancer of the pancreatic head. Methods All patients 18 to 85 years old diagnosed with nonmetastatic adenocarcinoma of the pancreatic head from 1998 through 2003 were identified from the Surveillance, Epidemiology and End Results (SEER) Program registry. Multivariable regression was used to elucidate factors associated with the type of pancreaticoduodenectomy performed, extent of lymph node (LN) assessment, early mortality, and late survival. Results Overall, 2111 patients were included in the study, with 83.7% treated with a standard Whipple pancreaticoduodenectomy (PD). However, there was marked regional variation in the use of pylorus-preserving pancreaticoduodenectomy (PPPD; range, .03%–32.0%; P < .0001) and total pancreatectomy (TP; range, .04%–19.5%; P < .0001). TP was associated with significantly higher early mortality (odds ratio, 2.6; 95% confidence interval, 1.6 to 4.1; P < .0001), but late survival did not differ significantly between TP, PPPD, and PD (P = .69). Significant variation was also seen in the number of LN assessed (range across SEER regions, 7.3–13.5; P < .0001). Decreased LN assessment reduced the odds of diagnosing a patient as node positive and was associated with worse late survival. Conclusions In this population-based study, we found marked clinically important variability in the surgical treatment of adenocarcinoma of the pancreatic head, with respect to the use of TP, PPPD, or PD, and the extent of LN assessment. Further research is warranted to elucidate the underlying reasons, and to clarify the role of adequate lymphadenectomy.     

MMP-12 has a role in abdominal aortic aneurysms in mice

BACKGROUND: Matrix metalloproteinase (MMP)-12 levels are increased in the abdominal aortic aneurysm (AAA), implicating this protease in AAA pathogenesis. The purpose of this study was to assess the role of MMP-12 in aneurysm formation. METHODS: A murine aneurysm model was generated by periaortic application of 0.25 mol/L calcium chloride (CaCl 2 ) for 15 minutes. Aortic diameters were measured and compared before and 10 weeks after aneurysm induction. Aortic diameter changes for wild type (WT) and MMP-12 knockout (MMP-12 -/- ) mice were determined. MMP-12 production in mouse aorta was analyzed by casein zymography. MMP-2 and MMP-9 expressions were examined by gelatin zymography. Immunohistochemical study was used to measure macrophage infiltration into the aorta. RESULTS: There is an increase of 63 +/- 5% (mean +/- SEM) in aortic diameters of WT mice after CaCl 2 inductions, while MMP-12 -/- mice increased only 26 +/- 14%. Connective tissue staining of aortic sections from WT mice showed disruption and fragmentation of medial elastic fibers, while MMP-12 -/- mice showed only focal elastic lamellae breakdown. MMP-12 levels in WT mice were significantly increased after CaCl 2 treatment, whereas no MMP-12 was detected in MMP-12 -/- mice. There was no difference in the MMP-2 and MMP-9 productions between WT and MMP-12 -/- mice. Immunohistochemical analysis demonstrated that infiltrating macrophages in the aorta of MMP-12 -/- mice were significantly less than WT controls. CONCLUSIONS: MMP-12 deficiency attenuates aneurysm growth, possibly by decreasing macrophage recruitment.     

Dynamic Challenges Inhibiting Optimal Adoption of Kidney Paired Donation: Findings of a Consensus Conference

While kidney paired donation (KPD) enables the utilization of living donor kidneys from healthy and willing donors incompatible with their intended recipients, the strategy poses complex challenges that have limited its adoption in United States and Canada. A consensus conference was convened March 29–30, 2012 to address the dynamic challenges and complexities of KPD that inhibit optimal implementation. Stakeholders considered donor evaluation and care, histocompatibility testing, allocation algorithms, financing, geographic challenges and implementation strategies with the goal to safely maximize KPD at every transplant center. Best practices, knowledge gaps and research goals were identified and summarized in this document.     

Does Physical Activity in Adolescence Have Site‐Specific and Sex‐Specific Benefits on Young Adult Bone Size,Content, and Estimated Strength?

The long‐term benefits of habitual physical activity during adolescence on adult bone structure and strength are poorly understood. We investigated whether physically active adolescents had greater bone size, density, content, and estimated bone strength in young adulthood when compared to their peers who were inactive during adolescence. Peripheral quantitative computed tomography (pQCT) was used to measure the tibia and radius of 122 (73 females) participants (age mean ± SD, 29.3 ± 2.3 years) of the Saskatchewan Pediatric Bone Mineral Accrual Study (PBMAS). Total bone area (ToA), cortical density (CoD), cortical area (CoA), cortical content (CoC), and estimated bone strength in torsion (SSI_p) and muscle area (MuA) were measured at the diaphyses (66% tibia and 65% radius). Total density (ToD), trabecular density (TrD), trabecular content (TrC), and estimated bone strength in compression (BSI_c) were measured at the distal ends (4%). Participants were grouped by their adolescent physical activity (PA) levels (inactive, average, and active) based on mean PA Z‐scores obtained from serial questionnaire assessments completed during adolescence. We compared adult bone outcomes across adolescent PA groups in each sex using analysis of covariance followed by post hoc pairwise comparisons with Bonferroni adjustments. When adjusted for adult height, MuA, and PA, adult males who were more physically active than their peers in adolescence had 13% greater adjusted torsional bone strength (SSI_p, p < 0.05) and 10% greater adjusted ToA (p < 0.05) at the tibia diaphysis. Females who were more active in adolescence had 10% larger adjusted CoA (p < 0.05), 12% greater adjusted CoC (p < 0.05) at the tibia diaphysis, and 3% greater adjusted TrC (p < 0.05) at the distal tibia when compared to their inactive peers. Benefits to tibia bone size, content, and strength in those who were more active during adolescence seemed to persist into young adulthood, with greater ToA and SSI_p in males, and greater CoA, CoC, and TrC in females. © 2014 American Society for Bone and Mineral Research.     

The efficacy of removable devices to offload and heal neuropathic plantar forefoot ulcers in people with diabetes: a single‐blinded multicentre randomised controlled trial

Non‐removable offloading is the ‘gold standard’ treatment for neuropathic diabetic plantar forefoot ulcers. However, removable offloading is the common ‘standard of care’. We compared three removable offloading devices for ulcer healing efficacy. In this multicentre, randomised controlled trial, 60 persons with neuropathic diabetic plantar forefoot ulcers were randomly assigned to wear a custom‐made knee‐high cast [BTCC (bivalved TCC)], custom‐made ankle‐high cast shoe or a prefabricated ankle‐high forefoot‐offloading shoe (FOS). Primary outcome was healing at 12 weeks. Dynamic plantar pressures, daily stride count and treatment adherence were assessed on a randomly selected subset (n = 35). According to intention‐to‐treat analysis, 58% of patients healed with BTCC [OR 0·77 (95% CI 0·41–1·45) versus FOS], 60% with cast shoe [OR 0·81 (95% CI 0·44–1·49) versus FOS] and 70% with FOS (P = 0·70). Mean ± SD peak pressure in kPa at the ulcer site was 81 ± 55 for BTCC, 176 ± 80 for cast shoe and 107 ± 52 for FOS (P = 0·005); stride count was 4150 ± 1626, 3514 ± 1380 and 4447 ± 3190, respectively (P = 0·71); percentage of 2‐week intervals that patients wore the device <50% of time was 17·3%, 5·2% and 4·9%, respectively. Non‐significant differences in healing efficacy between the three devices suggest that, when non‐removable offloading is contraindicated or not available, each can be used for plantar forefoot ulcer offloading. Efficacy is lower than previously found for non‐removable offloading maybe because suboptimal adherence and high stride count expose the patient to high repetitive stresses. These factors should be carefully considered in decision making regarding ulcer treatment.     

A Novel Method of Determining Portal Systemic Shunting using Biodegradable TC Labelled Albumin Microspheres

Portal systemic shunting (PSS) and portal pressure were measured in control rats and in animals with portal hypertension induced by partial portal vein ligation (PPVL). The portal pressure in rats with partial portal vein ligation (13.4 +/- 0.5 mm.Hg.) was significantly higher (p < 0.005) than in the control group (9.6 +/- 0.6 mm.Hg.). Portal systemic shunting measured by consecutive injections of radiolabelled methylene diphosphonate (MDP), a non-diffusable marker and albumin microspheres directly into the splenic pulp was significantly increased (P < 0.005) in the portal hypertensive animals (30.8 +/- 2.5%) compared to sham operated rats (2.6 +/- 1.5%). Similarly, in portal hypertensive rats portal systemic shunting measured by intrasplenic injections of radiolabelled cobalt microspheres (37.1 +/- 3.9%) was significantly greater (p < 0.005) than in control animals. There was a good correlation and agreement (r = 00.97) between the two methods of measuring portal systemic shunting. However because the (99)Tc(m)-albumin microspheres are biodegradable the method allows portal systemic shunting to be measured in man. Furthermore since the computer adjusts the baseline to zero after each determination of portal systemic shunting the methodology allows repeated measurements to be made.     

Renal arteries in patients at risk of renal arterial stenosis: multicenter evaluation of the echo-enhancer SH U 508A at color and spectral Doppler US. Levovist Renal Artery Stenosis Study Group

PURPOSE: To assess SH U 508A in the diagnosis of suspected renal arterial stenosis by means of ultrasonography (US) and to confirm the safety of SH U 508A in a clinical setting. MATERIALS AND METHODS: A randomized crossover study was performed in 198 patients from 14 European centers who were referred for renal arterial angiography because they were suspected of having renal arterial stenosis. All patients underwent nonenhanced and SH U 508A-enhanced Doppler US of the renal arteries. Doppler criteria included measurement of renal arterial peak systolic velocity (threshold, 1.4-2.0 m/sec) in all centers and renoaortic ratio (threshold, 3.0-3.5) in nine. RESULTS: The number of examinations with successful results increased following enhanced Doppler US examination--160 (83.8%) compared with 122 (63.9%) with nonenhanced Doppler US (P = .001), including patients with obesity or renal dysfunction. Renal arterial stenosis (> or =50%) was detected at angiography in 72 patients. Results at enhanced Doppler US were in agreement with results at angiography more often than with results at nonenhanced Doppler US in the diagnosis or exclusion of renal arterial stenosis (P = .001). For patients examined with nonenhanced and enhanced Doppler US, sensitivity (80.0% and 83.7%, respectively) and specificity (80.8% and 83.6%, respectively) remained unchanged. There were no clinically important adverse events following use of SH U 508A. CONCLUSION: In patients suspected of having renal arterial stenosis, SH U 508A increased the number of diagnostic renal arterial Doppler studies.     

Functional connectivity‐based parcellation of amygdala using self‐organized mapping: A data driven approach

The overall goal of this work is to demonstrate how resting state functional magnetic resonance imaging (fMRI) signals may be used to objectively parcellate functionally heterogeneous subregions of the human amygdala into structures characterized by similar patterns of functional connectivity. We hypothesize that similarity of functional connectivity of subregions with other parts of the brain can be a potential basis to segment and cluster voxels using data driven approaches. In this work, self‐organizing map (SOM) was implemented to cluster the connectivity maps associated with each voxel of the human amygdala, thereby defining distinct subregions. The functional separation was optimized by evaluating the overall differences in functional connectivity between the subregions at group level. Analysis of 25 resting state fMRI data sets suggests that SOM can successfully identify functionally independent nuclei based on differences in their inter subregional functional connectivity, evaluated statistically at various confidence levels. Although amygdala contains several nuclei whose distinct roles are implicated in various functions, our objective approach discerns at least two functionally distinct volumes comparable to previous parcellation results obtained using probabilistic tractography and cytoarchitectonic analysis. Association of these nuclei with various known functions and a quantitative evaluation of their differences in overall functional connectivity with lateral orbital frontal cortex and temporal pole confirms the functional diversity of amygdala. The data driven approach adopted here may be used as a powerful indicator of structure–function relationships in the amygdala and other functionally heterogeneous structures as well. Hum Brain Mapp 35:1247–1260, 2014. © 2013 Wiley Periodicals, Inc.