Clonal diversity of Ig and T-cell receptor gene rearrangements in childhood B-precursor acute lymphoblastic leukaemia

The majority of paediatric B precursor acute lymphoblastic leukaemias in children are derived from a single transformed haematopoietic cell with complete or partial VDJ recombination within the immunoglobulin heavy chain gene. A high frequency of patients also show rearrangements within TCRdelta and TCRgamma loci and in up to 40% of children there is an excess of immune system gene rearrangements compared with the number of identified alleles of immune system genes, suggesting the presence of multiple leukaemic subclones -clonal diversity. It has been observed by us and other investigators that in individual patients the pattern of immune system gene rearrangements often changes between presentation and relapse. In order to explore the possibility that clonal diversity plays a biological role during disease progression we optimised methods for subclone detection and analysed the prognostic significance of clonal diversity among 75 children with B precursor-ALL. Our results suggest that clonal diversity plays a role in disease progression as patients with oligoclonal disease showed a significantly shorter disease free survival than patients with monoclonal disease. This trend was of particular importance in the 'standard risk' group of ALL where aggressive disease could not be recognised by other means. In addition, generation of independent subclones from an early, non-rearranged tumour progenitor appears to be a common feature among leukaemias with aggressive clinical behaviour. We speculate on the type of genetic factors which may participate both in the generation of subclones and also in wider genomic instability and which are likely to be required for the aggressive clinical phenotype in children with ALL.     

Phencyclidine-induced impairment in attention and response control depends on the background genotype of mice: reversal by the mGLU<Subscript>2/3</Subscript> receptor agonist LY379268

Rationale Converging evidence implicates glutamate neurotransmission in attention and inhibitory response control.Objective To investigate how the background genotype contributes to glutamates effects on attention and response control, we examined how phencyclidine (PCP) affected the performance of a five-choice serial reaction time (5-CSRT) task in two inbred mouse strains, C57BL/6N and DBA/2N. We also tested a potent mGlu_2/3 receptor agonist, LY379268, against PCPs effects.Methods Mice were trained on a 5-CSRT task, which measures visual attention and response control until they reached asymptotic performance. Both strains of mice were then injected intraperitoneally with 0.5, 1.5 or 3.0 mg/kg PCP. Doses of 1.0 and 3.0 mg/kg of LY379268 were injected subcutaneously to vehicle or PCP-treated mice.Results At asymptotic performance DBA/2N mice were less accurate and made more anticipatory responses than C57BL/6N. PCP impaired accuracy (% correct) and increased perseverative responses of DBA/2N mice at 1.5 mg/kg. However, at doses up to 3.0 mg/kg it had no effect on these measures in C57BL/6N. In DBA/2N mice 1.5 mg/kg PCP increased anticipatory responses far more than 3.0 mg/kg in C57BL/6N mice. No dose of LY379268 prevented the PCP-induced accuracy deficit of DBA/2N mice. The PCP-induced anticipatory and perseverative responding of DBA/2N mice was reduced by 3.0 mg/kg LY379268, while 1.0 and 3.0 mg/kg reduced anticipatory responding in C57BL/6N.Conclusions The background genotype may determine the effects of PCP on attentional performance and the results confirm the importance of glutamate transmission in some aspects of this performance.     

Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents

Context  Traditionally, stent thrombosis has been regarded as a complication of percutaneous coronary interventions during the first 30 postprocedural days. However, delayed endothelialization associated with the implantation of drug-eluting stents may extend the risk of thrombosis beyond 30 days. Data are limited regarding the risks and the impact of this phenomenon outside clinical trials. Objective  To evaluate the incidence, predictors, and clinical outcome of stent thrombosis after implantation of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice. Design, Setting, and Patients  Prospective observational cohort study conducted at 1 academic hospital and 2 community hospitals in Germany and Italy. A total of 2229 consecutive patients underwent successful implantation of sirolimus-eluting (1062 patients, 1996 lesions, 2272 stents) or paclitaxel-eluting (1167 patients, 1801 lesions, 2223 stents) stents between April 2002 and January 2004. Interventions  Implantation of a drug-eluting stent (sirolimus or paclitaxel). All patients were pretreated with ticlopidine or clopidogrel and aspirin. Aspirin was continued indefinitely and clopidogrel or ticlopidine for at least 3 months after sirolimus-eluting and for at least 6 months after paclitaxel-eluting stent implantation. Main Outcome Measures  Subacute thrombosis (from procedure end through 30 days), late thrombosis (>30 days), and cumulative stent thrombosis. Results  At 9-month follow-up, 29 patients (1.3%) had stent thrombosis (9 [0.8%] with sirolimus and 20 [1.7%] with paclitaxel; P = .09). Fourteen patients had subacute thrombosis (0.6%) and 15 patients had late thrombosis (0.7%). Among these 29 patients, 13 died (case fatality rate, 45%). Independent predictors of stent thrombosis were premature antiplatelet therapy discontinuation (hazard ratio [HR],  89.78; 95% CI, 29.90-269.60; P<.001), renal failure (HR,  6.49; 95% CI, 2.60-16.15; P<.001), bifurcation lesions (HR,  6.42; 95% CI, 2.93-14.07; P<.001), diabetes (HR,  3.71; 95% CI, 1.74-7.89; P = .001), and a lower ejection fraction (HR,  1.09; 95% CI, 1.05-1.36; P<.001 for each 10% decrease). Conclusions  The cumulative incidence of stent thrombosis 9 months after successful drug-eluting stent implantation in consecutive "real-world" patients was substantially higher than the rate reported in clinical trials. Premature antiplatelet therapy discontinuation, renal failure, bifurcation lesions, diabetes, and low ejection fraction were identified as predictors of thrombotic events.      

Assessment of hemodialysis adequacy by ionic dialysance: comparison to standard method of urea removal

BACKGROUND: The hemodialysis adequacy is one of the most important issues influencing the survival of patients on maintenance hemodialysis (HD). Assessment of measuring the delivered dialysis dose using clearance x time/volume (Kt/V) index requires multiple blood sampling. New methods for assessment of dialysis dose based on ionic dialysance (ID) have been suggested. Online conductivity monitoring (using sodium flux as a surrogate for urea) allows the repeated noninvasive measurement of Kt/V on each HD treatment. In this study we have compared this method with the standard method of estimating Kt/V. METHODS: We studied 24 established HD patients over a 4 week time period. Patients were dialyzed using Fresenius 4008S dialysis monitors, equipped with modules to measure ID. Data were manually collected and analyzed using the appropriate statistical software. Urea removal (UR) was measured once a week by a two-pool calculation, estimating an eKt/V. RESULTS: The Kt/V measured by ID highly correlated with the one derived from the measurement of the UR (r=0.8959, p< 0.0001). The ID underestimated UR by the mean of 6%. The ID varied greatly within individual patients with a median of 1.29 +/- 0.22. If the eKt/V > or = 1.2 is considered adequate, 33% of the patients would have been inadequately dialyzed. The mean HD duration to achieve an adequate dialysis was 4 hours and 47 minutes with high interpatient variability. CONCLUSION: The ID seems to be an easily obtained measure of the delivered dialysis dose, correlating well with standard UR method. Substantial individual variations imply that repeated measures (ideally for all treatments) are necessary to obtain a real answer to the mean treatment dose being delivered to the patients.     

A simplified nutrition screen for hospitalized patients using readily available laboratory and patient information

OBJECTIVE: We assessed admission screening information that best identifies patients who are at risk for malnutrition-related complications (MRCs). METHODS: We evaluated 13 patient characteristics associated with MRC for adults screened over a 3-mo period (n = 448) to determine which factors correlated best with the risk level assigned. The existing screen stratified patients into four levels defined as no risk, mild risk, moderate, and high risk for MRC. The analyzed variables were weight for height, wound, surgery/cancer therapy, fever, vomiting/diarrhea, poor oral intake, no oral intake, unplanned weight loss, malnutrition-related admission diagnosis, serum albumin, white blood cell count, hemoglobin, and total lymphocyte count. We modeled the relation between assigned MRC and the predictors by using state-of-the-art methods. RESULTS: The characteristics that correlated best with MRC risk level assignment were occurrence of a wound, poor oral intake, malnutrition-related admission diagnosis, serum albumin value, hemoglobin value, and total lymphocyte count. A model using four variables (malnutrition-related admission diagnosis, serum albumin value, hemoglobin value, and total lymphocyte count) was almost as good as that using six predictors. CONCLUSIONS: The ability of admission information to accurately reflect MRC risk is crucial to early initiation of restorative medical nutritional therapy. There is currently no uniform or proved standard for identifying MRC risk within 24 h of acute care admission. The ideal nutritional screen correlates well with the occurrence of MRC and also uses data routinely obtained at admission. The models described can be uniformly used by hospitals to screen patients for MRC risk.     

Multi-field surface electrode for selective electrical stimulation

We designed a 24-field array and an on-line control box that selects which and how many of 24 fields will conduct electrical charge during functional electrical stimulation. The array was made using a conductive microfiber textile, silver two-component adhesive, and the conductive ink imprint on the polycarbonate. The control box comprised 24 switches that corresponded one-to-one to the fields on the array. Each field could be made conductive or nonconductive by simple pressing of the corresponding push-button type switch on the control box. We present here representative results of the selectivity of the new electrode measured in three tetraplegic patients during functional electrical stimulation of the forearm. The task was to generate finger flexion and extension with minimal interference of the wrist movement during lateral and palmar grasps. Therapists determined the appropriate pattern that lead to effective grasping, lasting on average 5 min per stimulation channel in the first session. This optimal conductive pattern (size and shape) provided effective finger flexion and extension with minimal wrist flexion/extension and ulnar/radial deviations (<10 degrees). The optimal size and shape of the electrode in all cases had a branched pattern. The selection of the optimal stimulation site was achieved without moving the electrode. The size and shape were reproducible in the same subject from session to session, yet were different from subject to subject. The optimal electrode size and shape changed when subjects pronated and supinated their forearm. The control box includes a program that can dynamically change the number and sites of the conductive fields; hence, it is feasible to use this during functional movements. Subjects learned how to determine the optimal electrode pattern; hence, these electrodes could be effective for home usage.     

The use of a bedside assay for plasma B-type natriuretic peptide as a biomarker in the management of patent ductus arteriosus in premature neonates

OBJECTIVE: To test the utility of the bedside plasma concentration of B-type natriuretic peptide (BNP) assay as a screen for patent ductus arteriosus (PDA) in premature neonates. STUDY DESIGN: Newborn infants admitted to the neonatal intensive care unit (NICU) had paired echocardiography and BNP measurements at enrollment and every 4 to 5 days. RESULTS: Twenty neonates (gestational age approximately 28.6 weeks and birth weight approximately 1161 g) had 81 paired echocardiography and BNP determinations. BNP ranged from 5 to 3900 pg/mL. Fifty-six of 81 echocardiograms showed PDA. Significant correlations were found between BNP and ductal size and degree of shunting. Correlation was greater in infants >2 days of age. BNP >300 pg/mL predicted significant PDA, whereas BNP <105 pg/mL predicted absence of significant PDA. CONCLUSION: Bedside measurement of BNP correlates with magnitude of PDA in premature newborns, particularly beyond day 2, and may be useful in guiding diagnostic and management strategies.     

The experimental toxicology of metallic mercury on the murine peripheral motor system: a novel method of assessing axon calibre spectra using the phrenic nerve

The toxicology of metallic mercury on motor neurons and their processes requires further work to resolve controversial implications in the aetiology of human motor neuron disease (MND). The assessment of experimental neurotoxicity in the peripheral motor system is, however, technically problematic and difficult to interpret. The mean number of axons in a nerve can vary considerably due to a high degree of biological variation. Atrophy of large axons can appear as loss when, in fact, their numbers appear in smaller diameter axonal categories. We addressed these quantitative problems using the murine phrenic nerve (MPN), a mono-fascicular, predominantly motor nerve as a model system. One micrometer transverse sections of gluteraldehyde/osmium tetroxide fixed MPNs were stained for myelin using a silver technique. Axon areas were measured from digital images of the nerve in cross-section (ImagePro Plus software) and transformed to circular diameter equivalents, then displayed as frequency distributions. We found a high biological variation in the mean axon number between paired nerves within experimental groups. Therefore, axon diameter data within individuals group was pooled. Theoretical simulation of axonal degeneration, atrophy and hypertrophy of larger myelinated axons (also affected in MND) were modelled by manipulating the original data set. With this model, by comparing normal distributions, it is possible to distinguish axonal atrophy, degenerative loss, and hypertrophy as distinct pathological processes in the large calibre axon subgroup that are selectively vulnerable to metallic toxins such as mercury.     

Serious diabetes-specific emotional problems and depression in a Croatian-Dutch-English Survey from the European Depression in Diabetes [EDID] Research Consortium

It has been hypothesized that coverage of diabetes-specific issues (e.g. coping with complications, incapacity, pain) during psychotherapy may optimize the likelihood of treatment success for depression in patients with diabetes. However, it is still unclear how often depression is confounded by diabetes-specific emotional problems. We aim to determine the levels of diabetes-specific emotional problems in diabetic individuals with high versus low levels of depression in a sample of 539 outpatients with diabetes (202 Dutch, 185 Croatian and 152 English). Subjects completed the Center for Epidemiological Studies Depression and the Problem Areas in Diabetes scales. Percentages of patients with high depression scores were: 39 and 34% (Croatian men and women), 19 and 21% (Dutch men and women), 19 and 39% (English men and women). Moreover, 79% (Croatian), 47% (Dutch) and 41% (English) of the patients with a severe depression score reported to have four or more serious diabetes-specific emotional problems. For patients with low depression scores, these percentages were: 29% (Croatian), 11% (Dutch) and 1% (English). Serious diabetes-specific emotional problems are particularly prevalent in depressed diabetes patients. Randomized controlled trials are warranted to test whether coverage of diabetes-specific issues during psychotherapy can further improve the treatment of depression in diabetes.