Angioplasty of Long Venous Stenoses in Hemodialysis Access: At Last an Indication for Cutting Balloon?

PURPOSE: To compare the postintervention primary patency rates of cutting balloon angioplasty (CBA) with those of conventional percutaneous transluminal angioplasty (PTA) in the treatment of hemodialysis-related stenoses at least 2 cm long. MATERIALS AND METHODS: This retrospective and controlled study included 29 patients with a hemodialysis-related stenosis at least 2 cm long. From August 2002 to August 2003, nine patients (PTA group, six upper-arm and three forearm fistulas) were treated with a conventional balloon (5-8 mm, 4 cm long). From September 2003 to December 2005, 20 patients (CBA group, 12 upper-arm and seven forearm fistulas; one polytetrafluoroethylene hemodialysis graft) were treated with a cutting balloon (5-7 mm, 1 cm long). The median follow-up was 22.1 months for the CBA group and 15.6 months for the PTA group. The Kaplan-Meier method was used to calculate the primary cumulative patency rates, and the log-rank test was used for comparison. Multivariate Cox models were generated by combining three variables: patient age, stenosis length, and treatment type (CBA or PTA). RESULTS: In the CBA group, the postintervention primary patency was 85% +/- 16 at 6 months, 70% +/- 20 at 1 year, and 32% +/- 26 at 18 months. In the PTA group, the postintervention primary patency was 56% +/- 32 at 6 months and 21% (range, 0%-53%) at 1 year. When comparing PTA versus CBA with the log-rank test, there was a statistically significant difference (P = .009). With the multivariate Cox models, treatment was again a statistically significant (P = .007) determinant of primary patency; patient age and stenosis length were not. CONCLUSION: The use of a cutting balloon as the first-line treatment for stenoses at least 2 cm long significantly improves the postintervention primary patency rate.     

N-terminal pro-brain natriuretic peptide identifies patients at high risk for adverse cardiac outcome after vascular surgery

BACKGROUND: Preoperative N-terminal pro-BNP (NT-proBNP) is independently associated with adverse cardiac outcome but does not anticipate the dynamic consequences of anesthesia and surgery. The authors hypothesized that a single postoperative NT-proBNP level provides additional prognostic information for in-hospital and late cardiac events. METHODS: Two hundred eighteen patients scheduled to undergo vascular surgery were enrolled and followed up for 24-30 months. Logistic regression and Cox proportional hazards model were performed to evaluate predictors of in-hospital and long-term cardiac outcome. The optimal discriminatory level of preoperative and postoperative NT-proBNP was determined by receiver operating characteristic analysis. RESULTS: During a median follow-up of 826 days, 44 patients (20%) experienced 51 cardiac events. Perioperatively, median NT-proBNP increased from 215 to 557 pg/ml (interquartile range, 83/457 to 221/1178 pg/ml; P<0.001). The optimum discriminate threshold for preoperative and postoperative NT-proBNP was 280 pg/ml (95% confidence interval, 123-400) and 860 pg/ml (95% confidence interval, 556-1,054), respectively. Adjusted for age, previous myocardial infarction, preoperative fibrinogen, creatinine, high-sensitivity C-reactive protein, type, duration, and surgical complications, only postoperative NT-proBNP remained significantly associated with in-hospital (adjusted hazard ratio, 19.8; 95% confidence interval, 3.4-115) and long-term cardiac outcome (adjusted hazard ratio, 4.88; 95% confidence interval, 2.43-9.81). CONCLUSION: A single postoperative NT-proBNP determination provides important additional prognostic information to preoperative levels and may support therapeutic decisions to prevent subsequent structural myocardial damage.     

Hypertonic resuscitation modulates the inflammatory response in patients with traumatic hemorrhagic shock

OBJECTIVE: To determine the effect of resuscitation with hypertonic saline/dextran (HSD) on the innate immune response after injury. SUMMARY OF BACKGROUND DATA: Hypovolemic shock causes a whole body ischemia/reperfusion injury, leading to dysregulation of the inflammatory response and multiple organ dysfunction syndrome. Hypertonicity has been shown to modulate the innate immune response in vitro and in animal models of hemorrhagic shock, but the effect on the inflammatory response in humans is largely unknown. METHODS: Serial blood samples were drawn (12, 24, 72 hours and 7 days after injury) from patients enrolled in a prospective, randomized, double-blind trial of traumatic hypovolemic shock, HSD (250 mL) versus lactated Ringer's solution (LR) as the initial resuscitation fluid. Neutrophil (PMN) CD11b/CD18 expression was assessed via whole blood FACS analysis with and without stimulation (fMLP 5 micromol/L or PMA 5 micromol/L). PMN respiratory burst was assessed using the nitro-blue tetrazolium assay. Monocytes stimulated with 100 ng LPS for 18 hours were assessed for cytokine production (TNF-alpha, IL-1Beta, IL-6, IL-10, IL-12). RESULTS: Sixty-two patients (36 HSD, 26 LR) and 20 healthy volunteers were enrolled. CD11b expression, 12 hours after injury, was increased 1.5-fold in patients resuscitated with LR compared with controls. Those resuscitated with HSD had a significant reduction in CD11b expression 12 hours after injury, compared with LR. There was no difference in respiratory burst early after injury. Monocytes from injured patients expressed lower levels of all cytokines in comparison to normal controls. Patients give HSD showed a trend toward higher levels of IL-1beta and IL10 production in response to LPS, 12 hours after injury. CONCLUSION: HSD resuscitation results in transient inhibition of PMN CD11b expression and partial restoration of the normal monocyte phenotype early after injury.     

The practice of venous thromboembolism prophylaxis in the major trauma patient

BACKGROUND: The incidence of venous thromboembolism (VTE) without prophylaxis is as high as 80% after major trauma. Initiation of prophylaxis is often delayed because of concerns of injury-associated bleeding. As the effect of delays in the initiation of prophylaxis on VTE rates is unknown, we set out to evaluate the relationship between late initiation of prophylaxis and VTE. METHODS: Data were derived from a multicenter prospective cohort study evaluating clinical outcomes in adults with hemorrhagic shock after injury. Analyses were limited to patients with an Intensive Care Unit length of stay >or=7 days. The rate of VTE was estimated as a function of the time to initiation of pharmacologic prophylaxis. A multivariate stepwise logistic regression model was used to evaluate factors associated with late initiation. RESULTS: There were 315 subjects who met inclusion criteria; 34 patients (11%) experienced a VTE within the first 28 days. Prophylaxis was initiated within 48 hours of injury in 25% of patients, and another one-quarter had no prophylaxis for at least 7 days after injury. Early prophylaxis was associated with a 5% risk of VTE, whereas delay beyond 4 days was associated with three times that risk (risk ratio, 3.0, 95% CI [1.4-6.5]). Factors associated with late (>4 days) initiation of prophylaxis included severe head injury, absence of comorbidities, and massive transfusion, whereas the presence of a severe lower extremity fracture was associated with early prophylaxis. CONCLUSIONS: Clinicians are reticent to begin timely VTE prophylaxis in critically injured patients. Patients are without VTE prophylaxis for half of all days within the first week of admission and this delay in the initiation of prophylaxis is associated with a threefold greater risk of VTE. The relative risks and benefits of early VTE prophylaxis need to be defined to better direct practice in this high-risk population.     

Regional differences in the severity of Lewy body pathology across the olfactory cortex

We studied α-synuclein pathology in the rhinencephalon of ten cases of Parkinson's disease (PD) and twelve neurologically normal controls, of which seven had incidental Lewy bodies in the substantia nigra at autopsy and five had no pathological evidence of neurological disease. In all PD and incidental Lewy bodies cases, α-synuclein pathology was found in all five subregions of the primary olfactory cortex that were sampled, and amongst them the pathology was significantly more severe in the temporal division of the piriform cortex than in the frontal division of the piriform cortex, olfactory tubercle or anterior portions of the entorhinal cortex. The orbitofrontal cortex, which is an area of projection from the primary olfactory cortex, was affected in some cases but overall the α-synuclein pathology was less severe in this area than in the primary olfactory cortex. Because different areas of the rhinencephalon are likely to play different roles in olfaction and our data indicate a differential involvement by α-synuclein deposition of structures implicated in smell, future prospective studies investigating the pathophysiological basis of hyposmia in PD should consider to examine the areas of primary olfactory cortex separately.     

High Interlaboratory Reproducibility of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry-Based Species Identification of Nonfermenting Bacteria

Matrix-assisted laser desorption ionization-time of flight mass spectrometry has emerged as a rapid, cost-effective alternative for bacterial species identification. Identifying 60 blind-coded nonfermenting bacteria samples, this international study (using eight laboratories) achieved 98.75% interlaboratory reproducibility. Only 6 of the 480 samples were misidentified due to interchanges (4 samples) or contamination (1 sample) or not identified because of insufficient signal intensity (1 sample).Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a fast and cost-effective alternative for bacterial species identification in microbiology. On the basis of mass analysis of the protein composition of a bacterial cell, which is assumed to be characteristic for each bacterial species, it is possible to determine the species within few minutes, starting from whole cells, cell lysates, or crude bacterial extracts (2, 3, 5, 6). The proof of principle of MALDI-TOF MS for bacterial species identification was shown a decade ago (2, 5, 6); however, due to low reproducibility, it has not been widely adopted in clinical microbiology. We have recently shown that use of a larger mass range for detection (2,000 to 20,000 Da), dedicated analysis software for spectral pattern matching, and a high-quality reference database of spectra generated from quality-controlled culture collection strains resulted in accurate species identifications, with high intralaboratory reproducibility (7). For interlaboratory reproducibility, there are only very limited data available (8, 10). We therefore evaluated the interlaboratory reproducibility for MALDI-TOF MS-based species identification in a multicenter study, applying the above-described MALDI-TOF MS improvements.(This study was presented in part at the 19th European Congress of Clinical Microbiology and Infectious Diseases [ECCMID] in Helsinki, Finland, 16 to 19 May 2009.)Sixty blind-coded samples were shipped worldwide by mail to eight laboratories with access to Bruker MALDI-TOF MS platforms and personnel trained in MALDI-TOF MS-based species identification (Centre de Ressources Biologiques de l′Institut Pasteur [CRBIP], Department of Microbiology, Institut Pasteur, Paris, France; Department of Microbiology and Molecular Cell Biology, Center for Biomedical Proteomics, Eastern Virginia Medical School, Norfolk, VA; Labor Limbach, Heidelberg, Germany; Research Institute of Physical-Chemical Medicine, Moscow, Russia; Bruker Daltonik, GmbH, Bremen, Germany; Institut de Bactériologie, Strasbourg, France; Microbiology Unit, Bambino Gesù Children''s Hospital, Health Care and Research Institute, Rome, Italy; and Molecular Infectious Diseases Laboratory, Vanderbilt University Hospital, Nashville, TN). Samples 001 to 030 of the 60 samples included pure cultures of different nonfermenting bacteria, either culture collection strains from the German Collection of Microorganisms and Cell Cultures (DSMZ, Braunschweig, Germany) and Laboratorium voor Microbiologie, Universiteit Gent (LMG, Gent, Belgium), or strains isolated at the Institute of Hygiene, Münster, Germany, during routine diagnostic efforts. They contained single strains of Alcaligenes faecalis subsp. faecalis (DSMZ 30030), Brevundimonas andropogonis (DSMZ 9511), Brevundimonas aurantiaca (DSMZ 4731), Burkholderia caribensis (DSMZ 13236), Brevundimonas diminuta (DSMZ 7234), Brevundimonas intermedia (DSMZ 4732), Brevundimonas vesicularis (DSMZ 7226), Comamonas nitrativorans (DSMZ 13191), Comamonas testosteroni (DSMZ 50244), Flavobacterium johnsoniae (DSMZ 2064), Inquilinus limosus (DSMZ 16000), Sphingobacterium mizutaii (DSMZ 11724), Pseudomonas beteli (LMGZ 978), Pseudomonas boreopolis (LMGZ 979), Pseudomonas extremorientalis (DSMZ 15824), 13 Pseudomonas aeruginosa strains (DSMZ 50071 and 12 clinical isolates), and 2 Stenotrophomonas maltophilia strains (clinical isolates). The 16 culture collection strains listed above were among the 248 strains used for constructing a nonfermenter reference database (7). All species designations were unambiguously confirmed using partial 16S rRNA gene sequencing as described elsewhere (7). Samples 031 to 060 contained preprocessed cell extracts from the first 30 strains as described recently (7). Accompanying the samples, each participating laboratory received a “sample cultivation and preparation guide” and a “result reporting guide” to facilitate and standardize data generation and interpretation. Briefly, the laboratories were asked to streak out samples 001 to 030 onto blood agar plates (irrespective of the vender) and to incubate them for 48 h at 30°C in an ambient atmosphere. Using a single colony, extraction for MALDI-TOF MS analysis was initiated. For preprocessed samples 031 to 060, the guide included instructions for matrix preparation and MALDI-TOF MS analysis (7). For spectral calibration, the Bruker bacterial test standard (Escherichia coli lysate) was used during the measuring step. All laboratories used the MALDI Biotyper 2.0 software package (Bruker Daltonik, GmbH, Bremen, Germany) and the MALDI Biotyper database, containing spectra of more than 2,800 microorganisms (including the 248 nonfermenter species) as reference data. The software generates a list of probable species identifications ranked by the log(score) value, which reflects the peak matches as well as intensities and results in values between 0 and 3 (0 to 100% pattern match). After comparison of an unknown spectrum with all reference spectra of the database, the log(score)s are ranked. Values of ≥2.0 were required for secure identification at the species level and values between <2 and ≥1.7 for secure identification at the genus level. Results based on log(score) values of <1.7 were rated as not identifiable. These thresholds were empirically determined based on the whole MALDI Biotyper database contents.Each of the eight participating laboratories received 60 blind-coded samples for MALDI-TOF MS-based species identification. The aggregated results for each laboratory and the machines used are shown in Table ​Table1.1. Of the total 480 samples, 474 (98.75%) were correctly identified at the species level by using the highest log(score) value for the identified species after MALDI-TOF MS spectral comparisons. Five of the remaining six samples were misidentified, and one sample did not result in any valid species designation, due to low signal intensity. Overall, six of the eight laboratories identified all 60 samples correctly (Table ​(Table1).1). Four hundred sixty-seven of the 480 samples (97.29%) with log(score) values of ≥2 (mean, 2.353; standard deviation, 0.146) were identified, indicating a probable secure species identification level (Table ​(Table1).1). Twelve of the remaining 13 samples showed log(score) values between 1.7 and 2, which correlated with at least a secure identification at the genus level; only sample 044, which was not identified, due to low signal intensity, had a log(score) value of 0. The 12 samples were distributed among four laboratories; no pattern of an especially problematic sample was discerned. The five misidentified samples showed log(score) values of ≥2. Figure ​Figure11 displays the mean log(score) value for each sample and its standard deviation. Of the 60 samples investigated, only sample 044 showed a significantly higher standard deviation and lower mean value due to the failure in laboratory B. There was no significant difference between the mean log(score) values of cultured samples versus those of preprocessed samples as determined by t test statistics (P = 0.20).Open in a separate windowFIG. 1.Mean log(score) values and standard deviations for all 60 blind-coded samples identified using MALDI-TOF MS, calculated from the results for all eight participating laboratories.

TABLE 1.

Aggregated log(score) values and final species identification results for each of the eight participating laboratories (not specified) for 60 blind-coded samples (n = 480 in total) containing nonfermenting bacteria either as pure culture or as preprocessed cell extract

Training physicians in shared decision-making-Who can be reached and what is achieved?

Objective

To report on experiences with a general shared decision-making (SDM) physician training program offered to physicians throughout Germany.

Methods

This study enrolled 150 physicians in an 8-h SDM training program. Physicians were assessed with standardized instruments before and after training. Main variables of interest were physician professional attributes, personality characteristics, attitudes, measures of training success (quality rating, knowledge, competency ratings), and variables associated with training success.

Results

The SDM training obtained positive quality ratings, led to an amelioration in an objective SDM knowledge test (p < .001), and highly improved physicians’ confidence in their SDM competencies (p < 0.001). It attracted experienced, middle-aged (45 years), male and female (46%) physicians, mostly office-based (2/3) general practitioners and internists (2/3). Most physicians (94%) reported positive attitudes towards SDM. They were securely attached (63%) with predominant social career choice motives (46%). Physicians with personality characteristics clashing with the SDM concept benefited mostly from the training.

Conclusion

A voluntary SDM training program is attractive to practicing physicians and effective in increasing SDM-related confidence and knowledge.

Practice implications

Even physicians who are highly motivated to use SDM can improve their skills and benefit from SDM training. The dissemination of SDM training programs should be encouraged.     

Unilateral Blood Flow Decrease Induces Bilateral and Symmetric Responses in the Immature Brain

The effects of hemodynamic changes in the developing brain have yet to be fully understood. The aim of this study was to explore the relationship between perturbations of the cerebral blood flow in the developing brain via unilateral hypoperfusion in P7 rats. As expected, nuclear caspase-3 (casp3) cleavage and DNA fragmentation were detected at 48 hours after stroke in the injured cortex. Surprisingly, casp3 was also cleaved in the contralateral cortex, although without cell death markers. Delayed (48 hours) casp3 cleavage without DNA fragmentation was also identified after unilateral common carotid artery occlusion, both in the hypoperfused cortex and the unaffected cortex, producing mirror images. Upstream calpain activation, caspase-2 cleavage, and mitochondrial cytochrome c release initiated casp3 cleavage, but did not produce preconditioning. The neuronal marker NeuN co-localized with cleaved casp3 in cortical layers II–III and VI and with gaba-amino butyric acid in layer III. Indeed, collateral supply was provided from the opposite side during carotid artery occlusion but not after reperfusion, and the number of cleaved casp3-positive cells significantly negatively correlated with the common carotid artery immediate reperfusion percentage. In summary, unilateral hypoperfusion, while insufficient to induce cell death, may active bilateral and symmetric casp3 in the P7 rat brain. Additionally, the opposite healthy hemisphere is altered due to the injury and thus should not be used as an internal control.Perinatal hypoxia-ischemia followed by reperfusion is an important cause of neonatal brain injury. In approximately 8 out of 100,000 children affected, it results in cerebral palsy, learning disabilities, visual field deficits, and epilepsy.¹ However, recent data suggest a higher incidence of focal ischemia in neonates compared with the incidence of global cerebral ischemia arising from systemic asphyxia,^2,3 whereas mechanisms of arterial ischemic injury without the confounding effect of hypoxia are not fully understood.To investigate cell death pathways and neuroprotection, the most commonly used model of hypoxia-ischemia (HI)⁴ and others stroke models^5,6 have been designed in the developing brain (age range from P3 up to P12) in both rats and mice. In all of these models, injury is only seen in the ipsilateral hemisphere and in a great number of studies the contralateral hemisphere was used as an internal control. However, two recent studies have pointed out that multiple molecular/cellular mediators were also activated in the contralateral hemisphere. In the first work, HI in P12 rats produced increased cytokine expression, hypoxic-inducing factor (HIF-1) α, and phospho (p)-Akt to the same extent in both hemispheres, although injury was unilateral. Conversely, hypoxia alone was sufficient to regulate these mediators, but not sufficient to induce long-term damage.⁷ In the second study, we demonstrated that after stroke (electrocoagulation of the left middle cerebral artery (MCA) in association with transient homolateral common carotid artery occlusion) in P7 rats,⁶ cell injury was visible in the ipsilateral (IL) parietal cortex, but cell death also affected the contralateral white matter during the first 24 hours of recovery followed by delayed repair mechanisms in both the IL and contralateral (CL) hemispheres.⁸ Because the molecular mechanisms of cell death/survival in remote regions and particularly in the CL hemisphere are still poorly understood, the aim of this study was to explore the relationship between the molecular pathways and perturbations of the cerebral blood flow (CBF) in the developing brain.Arterial occlusion causes hemodynamic perturbations and a redistribution of blood flow. The circulatory system can compensate for this by various processes, for example, using collateral circulation and/or autoregulatory mechanisms.⁹ However, the reserve capacity of the circulatory system is limited, and when these processes offer insufficient compensation, inevitably tissue will enter a state of hypoperfusion. This study highlights that unilateral hypoperfusion, not sufficient to induce cell death, may active cellular mechanisms bilaterally and symmetrically producing images in mirror in P7 rat brain.     

Validation of MCADD newborn screening

Medium‐chain acyl‐CoA dehydrogenase deficiency (MCADD) represents a potentially fatal fatty acid β‐oxidation disorder. Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has been implemented worldwide, but is associated with unresolved questions regarding population heterogeneity, burden on healthy carriers, cut‐off policies, false‐positive and negative rates. In a retrospective case‐control study, 333 NBS samples showing borderline acylcarnitine patterns but not reaching recall criteria were genotyped for the two most common mutations (c.985A>G/c.199C>T) and compared with genotypes and acylcarnitines of 333 controls, 68 false‐positives, and 34 patients. c.985A>G was more frequently identified in the study group and false‐positives compared to controls (1:4.3/1:2.3 vs. 1:42), whereas c.199C>T was found more frequently only within the false‐positives (1:23). Biochemical criteria were devised to differentiate homozygous (c.985A>G), compound heterozygous (c.985A>G/c.199C>T), and heterozygous individuals. Four false‐negatives were identified because our initial algorithm required an elevation of octanoylcarnitine (C₈) and three secondary markers in the initial and follow‐up sample. The new approach allowed a reduction of false‐positives (by defining high cut‐offs: 1.4 μmol/l for C₈; 7 for C₈/C₁₂) and false‐negatives (by sequencing the ACADM gene of few suspicious samples). Our validation strategy is able to differentiate healthy carriers from patients doubling the positive predictive value (42→88%) and to target NBS to MCADD‐subsets with potentially higher risk of adverse outcome. It remains controversial, if NBS programs should aim at identifying all subsets of all diseases included. Because the natural course of milder variants cannot be assessed by observational studies, our strategy could serve as a general model for evaluation of MS/MS‐based NBS.