Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Analgesic requirements and pain experience after caesarean section under neuraxial anesthesia in women with preeclampsia.

OBJECTIVE: We determined pain experience and analgesic usage in women with preeclampsia (PE) after caesarean section (CS). METHOD: We conducted a one-year retrospective case (PE), control (healthy pregnancy HP) study in women undergoing CS. RESULTS: Sixty-two women were included. Cases received more intrathecal bupivacaine (mean difference 0.4 mg) and in the first six hours postoperatively received (mean ± SD, % or median (interquartile range, IQR)), less oxycodone (11.5 ± 3.9 mg versus 14.3 ± 5.1 mg, p < 0.031), less often received parecoxib (43% versus 100%, p < 0.001), and reported less maximum pain scores (0 (0,5) versus 4 (3,6), p < 0.005). CONCLUSION: Women with PE received less analgesia and experienced less pain compared to controls.

A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study.

In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10(-5)). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10(-4)) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10(-6)). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL.

Multifocal central nervous system demyelination and Lhermitte's phenomenon secondary to combination chemotherapy for chronic lymphocytic leukaemia.

The CRF regime (cyclophosphamide, rituximab and fludarabine) is used for the treatment of chronic lymphocytic leukaemia. We report a case of diffuse CNS demyelination following treatment with CRF, presenting with Lhermitte's phenomenon, and imaging and neurophysiological evidence of demyelination. Fludarabine is the most likely causative agent, although CNS demyelination has not been previously described in low dose therapy.

Chronic lymphocytic leukaemia: current first-line therapy.

There is a major evolution in progress in the first-line therapy of chronic lymphocytic leukaemia. Several recent, large, clinical trials have documented superior outcomes with fludarabine-based therapy compared with treatment with alkylating agents. Monoclonal antibodies, especially rituximab, are establishing an important role for targeted treatment. It is expected that chemoimmunotherapy will become the preferred treatment for many patients in the near future. Specific challenges remain to be answered, however, especially the optimal treatment for the elderly, patients with autoimmune haemolysis and those with P53 deletions and mutations.

Fludarabine induces differential expression of proteins in human leukemia and lymphoma cells.

The purine analog fludarabine (FdAMP) is widely used for chemotherapy of B-lymphoid malignancies, and multiple mechanisms of action leading to apoptosis have been proposed. We examined changes at the protein level induced in the Raji cell line (Burkitt's lymphoma) by fludarabine nucleoside (FdA). Raji cells are sensitive to FdA. Raji cells treated with FdA (3 micro M, 24 hours), accumulate multiple phosphorylated forms of p53 in the nucleus that in turn degrade to phosphorylated forms of p40. Using CD antibody microarrays to determine surface expression profiles for Raji cells treated with FdA, we found up-regulation of the following CD antigens: CD20, CD54, CD80, CD86, and CD95. FdA thus induces changes in the genetic program of the cells that might be exploited to obtain synergy with therapeutic antibodies.

Water sorption isotherms and enthalpies of water sorption by lysozyme using the quartz crystal microbalance/heat conduction calorimeter.

The water sorption isotherm and the water vapor activity dependence of the enthalpy of water sorption Delta(sorp)Hdegrees of lysozyme have been measured at 25 degrees C. A thin film of lysozyme of mass 250 microg was exposed to H2O/N2 mixtures in a quartz crystal microbalance/heat conduction calorimeter (QCM/HCC). The QCM/HCC is a new gravimetric/calorimetric method that measures simultaneously and with high precision the mass change and the corresponding heat flow in a thin film exposed to a gas. Delta(sorp)Hdegrees for lysozyme agrees with previous determinations, although hysteresis effects are evident in the data. No van't Hoff analysis is necessary because sorption enthalpies are measured calorimetrically. The water vapor activity dependence of Delta(sorp)Hdegrees agrees with that measured previously by Bone. As the water content of the lysozyme film drops below 10 mass%, Delta(sorp)Hdegrees becomes more exothermic, indicating that water is being bound to the charged or highly polar groups of the solvent-accessible surface of lysozyme. The dynamics of water uptake and release from lysozyme thin films are much slower than in polymer films of comparable thickness. Because the QCM/HCC operates with sub-milligram samples, any protein is now amenable to study by this technique.

Compilation and evaluation of a Paso del Norte emission inventory.

Emission inventories of ozone precursors are routinely used as input to comprehensive photochemical air quality models. Photochemical model performance and the development of effective control strategies rely on the accuracy and representativeness of an underlying emission inventory. This paper describes the tasks undertaken to compile and evaluate an ozone precursor emission inventory for the El Paso/Ciudad Juárez/Southern Doña Ana region. Point, area and mobile source emission data were obtained from local government agencies and were spatially and temporally allocated to a gridded domain using region-specific demographic and land-cover information. The inventory was then processed using the US Environmental Protection Agency (EPA) recommended Emissions Preprocessor System 2.0 (UAM-EPS 2.0) which generates emissions files compatible with the Urban Airshed Model (UAM). A top down evaluation of the emission inventory was performed to examine how well the inventory represented ambient pollutant compositions. The top-down evaluation methodology employed in this study compares emission inventory ratios of non-methane hydrocarbon (NMHC)/nitrogen oxide (NOx) and carbon monoxide (CO)/NOx ratios to corresponding ambient ratios. Detailed NMHC species comparisons were made in order to investigate the relative composition of individual hydrocarbon species in the emission inventory and in the ambient data. The emission inventory compiled during this effort has since been used to model ozone in the Paso del Norte airshed (Emery et al., CAMx modeling of ozone and carbon monoxide in the Paso del Norte airshed. In: Proc of Ninety-Third Annual Meeting of Air & Waste Management Association, 18-22 June 2000, Air & Waste Management Association, Pittsburgh, PA, 2000).

Immunophenotyping of leukemias using a cluster of differentiation antibody microarray.

Different leukemias express on their plasma membranes particular subsets of the 247 defined cluster of differentiation (CD) antigens, which may resemble those of precursor cells along the lineages of differentiation to mature myeloid and lymphoid leukocytes. The extent of use of CD antigen expression (immunophenotyping) for identification of leukemias has been constrained by the technique used, flow cytometry, which commonly specifies only three CD antigens in any one assay. Currently, leukemias and lymphomas are diagnosed using a combination of morphology, immunophenotype, cytochemistry, and karyotype. We have developed a rapid, simple procedure, which enables concurrent determination of 50 or more CD antigens on leukocytes or leukemia cells in a single analysis using a microarray of antibodies. A suspension of cells is applied to the array, and cells only bind to antibody dots for which they express the corresponding CD antigen. For patients with significantly raised leukocyte counts, the resulting dot pattern then represents the immunophenotype of those cells. For patients at earlier stages of disease, the diagnosis depends on recognition of dot patterns distinct from the background of normal leukocytes. Distinctive and reproducible dot patterns have been obtained for normal peripheral blood leukocytes, chronic lymphocytic leukemia (CLL), hairy cell leukemia, mantle cell lymphoma, acute myeloid leukemia, and T-cell acute lymphoblastic leukemia. The consensus pattern for CD antigen expression found on CLL cells taken from 20 patients in descending order of cells bound was CD44, HLA-DR, CD37, CD19, CD20, CD5, CD52, CD45RA, CD22, CD24, CD45, CD23, CD21, CD71, CD11c, and CD9. The antigens that provided the best discrimination between CLL and normal peripheral blood leukocytes were CD19, CD20, CD21, CD22, CD23, CD24, CD25, and CD37. Results obtained for the expression of 48 CD antigens from the microarray compared well with flow cytometry. The microarray enables extensive immunophenotyping, and the intact cells captured on antibody dots can be further characterized using soluble, fluorescently labeled antibodies.

Classroom strategies used by teachers of students with attention deficit hyperactivity disorder.

Pediatric therapists working in schools commonly function as consultants to assist teachers to develop strategies to help promote the classroom performance of students with attention deficit hyperactivity disorders (ADHD). This study surveyed general education teachers in northern New England to determine the classroom strategies teachers commonly use and perceive as being effective for improving the performance of children with ADHD. The strategies receiving the highest frequency and effectiveness ratings were enforcing routine and structure, frequent contact, preferential seating, use of motor breaks, and teaching self-monitoring of behaviors. The strategies receiving the lowest effectiveness ratings were peer tutoring, timeout, and giving assistance during transitions. Cross tabulations with chi-square analysis of the effectiveness ratings by grade level indicated the ratings for 3 of the 15 strategies, use of a designated quiet space, use of motor breaks, and sensory modulation techniques, were dependent on grade level. Qualitative analysis of teacher responses to open-ended questions provided recommendations for improving the education of children with ADHD, including: increasing special education support in the classroom, smaller class sizes, frequent parent-teacher collaboration, and more hands-on learning experiences. Implications of the results of the study for therapists working with students with ADHD and their teachers are discussed.

Decreased density of neurons in the medial preoptic nucleus and increased testicular weights for rats exposed perinatally to an 0.5 Hz Rotating Magnetic Field.

Pregnant Wistar rats were exposed to either 0.5 Hz Rotating Magnetic Fields (50 microT to 300 microT or 1.5 mT to 3.0 mT) or to sham field or control environments for 3 days before to 3 days after the day of birth. The adult male offspring that had been exposed perinatally to the RMF displayed significantly heavier testicle weights but fewer neurons within the medial preoptic nucleus (MPO) and caudal ventromedial hypothalamus relative to sham field controls (effect size about 30%). There was no statistically significant difference between the two ranges of RMF intensities for these measures. RMF-exposed rats relative to sham-field exposed rats did not differ with respect to spleen weights, body weights, or mounting (reproductive) activity. The heavier testicle weights replicated previous studies and suggest that permanent, selective alterations in neuronal density can also occur subsequent to perinatal exposure to relatively weak, extremely low frequency magnetic fields.

Mitral cell presynaptic Ca(2+) influx and synaptic transmission in frog amygdala.

Dextran-conjugated Ca(2+) indicators were injected into the accessory olfactory bulb of frogs in vivo to selectively fill presynaptic terminals of mitral cells at their termination in the ipsilateral amygdala. After one to three days of uptake and transport, the forebrain hemisphere anterior to the tectum was removed and maintained in vitro for simultaneous electrophysiological and optical measurements. Ca(2+) influx into these terminals was compared to synaptic transmission between mitral cells and amygdala neurons under conditions of reduced Ca(2+) influx resulting from reduced extracellular [Ca(2+)], blockade of N- and P/Q-type channels, and application of the cholinergic agonist carbachol. Reducing extracellular [Ca(2+)] had a non-linear effect on release; release was proportional to Ca(2+) influx raised to the power of approximately 3.6, as observed at numerous other synapses. The N-type Ca(2+) channel blocker, omega-conotoxin-GVIA (1 microM), blocked 77% of Ca(2+) influx and 88% of the postsynaptic field potential. The P/Q-type Ca(2+) channel blocker, omega-agatoxin-IVA (200 nM), blocked 19% of Ca(2+) influx and 25% of the postsynaptic field, while the two toxins combined to block 92% of Ca(2+) influx and 97% of the postsynaptic field. The relationship between toxin blockade of Ca(2+) influx and synaptic transmission was therefore only slightly non-linear; release was proportional to Ca(2+) influx raised to the power approximately 1.4. Carbachol (100 microM) acting via muscarinic receptors had no effect on the afferent volley, but rapidly and reversibly reduced Ca(2+) influx through both N- and P/Q-type channels by 51% and postsynaptic responses by 78%, i.e. release was proportional to Ca(2+) raised to the power approximately 2.5. The weak dependence of release on changes in Ca(2+) when channel toxins block channels suggests little overlap between Ca(2+) microdomains from channels supporting release or substantial segregation of channel subtypes between terminals. The proportionately greater reduction of transmission by muscarinic receptors compared to Ca(2+) channel toxins suggests that they directly affect the release machinery in addition to reducing Ca(2+) influx.

Traumatic intramuscular orbital haemorrhage.

Retrobulbar haemorrhage is an uncommon but well-documented complication of retrobulbar anaesthetic blocks in ocular surgery. Peribulbar anaesthesia has been advocated to be equally effective but safer. The incidence of retrobulbar haemorrhage with peribulbar blocks is very low. We report a case in which a peribulbar anaesthetic for cataract surgery resulted in sight-threatening retrobulbar haemorrhage within the medial rectus muscle and required an anterior orbitotomy and direct decompression of the muscle. The surgery was successful. This case illustrates a potentially serious complication of peribulbar anaesthesia, with the successful outcome achieved by rapid definitive diagnosis and intervention.

Apparent low frequency of undernutrition in Dublin hospital in-patients: should we review the anthropometric thresholds for clinical practice?

Protein-energy undernutrition, or the possibility of its development, has been documented to occur frequently in patients on admission to hospital. Deterioration in nutritional status is known to occur in hospital. In a prospective study of 594 sequential hospital admissions, we aimed to assess the prevalence of undernutrition among patients on admission to two acute teaching hospitals in Dublin, Republic of Ireland using the widely-accepted anthropometric criteria applied in a large study from Dundee, Scotland, UK (McWhirter & Pennington, 1994) and to determine changes in nutritional status in hospital. The mean prevalence of undernutrition (11 %) was considerably lower than was reported from Dundee (40 %). Unintentional weight loss before admission and functional impairment on admission occurred to a similar extent in both centres. Weight loss in hospital occurred in the same proportion of patients, but less frequently among those undernourished on admission to hospital, in Dublin compared with Dundee. The patients found to be undernourished on admission in this study had a mortality rate in hospital (6.5 %) over three times that of the adequately nourished group (2 %). The magnitude of the difference in prevalence of undernutrition between the two centres cannot be explained by ethnicity, case-mix or age distribution. With the secular increase in BMI in the population, the thresholds for classifying patients as undernourished or at risk of nutritional deterioration may need to be reviewed. For clinical use, recent weight loss and functional status may be more appropriate variables to use in the evaluation of nutritional status on admission to hospital.

Heterotopic calcification and tears of the ulnar collateral ligament: radiographic and MR imaging findings.

OBJECTIVE: The purpose of this paper is to describe the radiographic and MR imaging appearance of heterotopic calcification in the ulnar collateral ligament. MATERIALS AND METHODS: Retrospective radiographic review of 710 patients examined for elbow pain yielded 42 individuals (age range, 16-38 years) with heterotopic calcification in the ulnar collateral ligament. Radiographic and MR imaging findings were compared with surgical findings. RESULTS: Fifty-one heterotopic calcifications were identified in 42 patients; nine patients had two sites of heterotopic calcification. Average initial calcification size in the craniocaudal dimension was 4 mm (range, 1-12 mm) and in the transverse dimension was 1 mm (range, 1-4 mm). Five of 42 patients had enlargement of the calcification on follow-up radiography. The largest heterotopic calcification that was not visualized on MR imaging measured 5 x 4 mm in craniocaudal and transverse dimensions. Of 34 patients with heterotopic calcification who underwent surgery, 26 patients (76%) had either partial or complete tears of the ulnar collateral ligament. CONCLUSION: Heterotopic calcification in the ulnar collateral ligament may be associated with partial or complete tears. The MR imaging detection of heterotopic calcification is less sensitive than that of radiography of the elbow.

The identification and assessment of undernutrition in patients admitted to the age related health care unit of an acute Dublin general hospital.

OBJECTIVES: To profile those over 65 yr admitted to an acute geriatric medical service. To identify and assess their undernutrition risk and quantify the nutritional intervention they received. METHODS: Forty-nine consecutive admissions were recruited, 23 various parameters were assessed. A diagnosis of undernutrition was made according to a specifically designed flow chart. RESULTS: Eighty-four per cent of recruits were at risk of undernutrition on admission and 80 per cent were moderately to severely at risk. There was deterioration from baseline nutritional status in 29 per cent of previously well nourished patients with hospitalization. In the undernourished group, an improvement and/or stasis from baseline was achieved in 75 per cent, with intervention. CONCLUSIONS: The risk of undernutrition on admission to hospital and during treatment is an indicator of the need for nutrition services and nutritional screening for all acute medical services for older people.

Transurethral resection or incision of the prostate and other therapies: a survey of treatments for benign prostatic obstruction in the UK.

OBJECTIVE: To establish the current usage of transurethral incision of the prostate (TUIP) and other forms of treatment for benign prostatic obstruction (BPO). METHODS: The Prostate Trial Office (PROTO) sent a survey questionnaire to all 376 consultant urologists in the UK which asked for estimates of their clinical practice in treating BPO. The survey had three principle aims: to assess the role that the determination of prostate size has in clinical practice, to determine the nature and frequency of use of a range of therapies including TUIP, and to examine the feasibility of conducting a randomized controlled trial comparing transurethral resection of the prostate (TURP) and TUIP. RESULTS: Of the 376 urologists, 349 replied (response rate 93%); most respondents used prostate size as a determinant when deciding on therapy for BPO (60%). Of their patients with BPO who were treated, 38% received surgical treatment, 33% drug therapies and 29% conservative management. Of the types of surgical treatment, the most commonly used procedure was TURP, in 79% of patients, with only 15% undergoing TUIP. When compared with TURP, TUIP tended to be used for patients with a mean prostate volume of