Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies.

T-cell depletion of an HLA-haploidentical graft is often used to prevent GVHD, but the procedure may lead to increased graft failure, relapse and infections due to delayed immune recovery. We hypothesized that selective depletion of the CD45RA+ subset can effectively reduce GVHD through removal of naive T cells, while providing improved donor immune reconstitution through adoptive transfer of CD45RA- memory T cells. Herein, we present results from the first 17 patients with poor-prognosis hematologic malignancy, who received haploidentical donor transplantation with CD45RA-depleted progenitor cell grafts following a novel reduced intensity conditioning regimen without TBI or serotherapy. Extensive depletion of CD45RA+ T cells and B cells, with preservation of abundant memory T cells, was consistently achieved in all 17 products. Neutrophil engraftment (median day +10) and full donor chimerism (median day +11) was rapidly achieved post transplantation. Early T-cell reconstitution directly correlated with the CD45RA-depleted graft content. T-cell function recovered rapidly with broad TCR Vß spectra. There was no infection-related mortality in this heavily pretreated population, and no patient developed acute GVHD despite infusion of a median of >100 million per kilogram haploidentical T cells.

Risk-adapted donor lymphocyte infusion based on chimerism and donor source in pediatric leukemia.

Donor lymphocyte infusion (DLI) is commonly used to treat leukemia relapse following stem cell transplantation. In florid relapse, however, the efficacy of DLI is limited with substantial risk of severe graft-versus-host disease (GvHD). Here, we develop a novel risk-adapted strategy characterized by pre-emptive DLI initiated at the time of mixed chimerism, a small starting dose based on donor source, dose-escalation guided by real-time chimerism monitoring and withholding of DLI immediately in patients achieving full donor chimerism. A total of 178 DLIs were given to 38 patients with mixed chimerism; thereafter, 33 patients (86.8%) had donor chimerism successfully increased, including 30 (78.9%) who had chimerism fully converted back to 100% donor. Cumulative incidence of relapse was significantly lower (P=0.00004) and overall survival higher (P=0.0003) in patients with chimerism fully corrected as compared with those of patients whose chimerism remained mixed. Only 13.2% of the patients developed acute grade III-IV GvHD with no associated mortality. In conclusion, the risk-adapted DLI strategy is useful in minimizing the risk of childhood leukemia relapse, GvHD and death.

A wound caused by a small alkaline cell (button battery) under a plaster cast: report of a case.

This is a case report of only the second known instance of an alkaline cell (button battery) causing a wound under a plaster cast.

Rapamycin: something old, something new, sometimes borrowed and now renewed.

The molecular target of rapamycin (mTOR) is central to a complex intracellular signaling pathway and is involved in diverse processes including cell growth and proliferation, angiogenesis, autophagy, and metabolism. Although sirolimus (rapamycin), the oldest inhibitor of mTOR, was discovered more than 30 years ago, renewed interest in this pathway is evident by the numerous rapalogs recently developed. These newer agents borrow from the structure of sirolimus and, although there are some pharmacokinetic differences, they appear to differ little in terms of pharmacodynamic effects and overall tolerability. Given the multitude of potential applications for this class of agents and the decrease in cost that can be expected upon the expiration of sirolimus patents, renewed focus on this agent is warranted.

Genome scan implicates adhesion biological pathways in secondary leukemia.

The genetic risk factors for etoposide-induced leukemia with MLL translocations remain largely unknown. To identify genetic risk factors for and novel characteristics of secondary leukemia, we profiled 116,204 single nucleotide polymorphisms (SNPs) in germline and paired leukemic cell DNA from 13 secondary leukemia/myelodysplasia cases and germline DNA from 13 matched and 156 unmatched controls, all with acute lymphoblastic leukemia treated with etoposide. We analyzed global gene expression from a partially overlapping cohort. No single locus was altered in most cases. We discovered 81 regions of loss of heterozygosity (LOH) in leukemic blasts and 309 SNPs whose allele frequencies differed in cases vs controls. Candidate genes were prioritized on the basis of genes whose SNPs or expression differentiated cases from controls or showed LOH or copy number change in germline vs paired blast DNA from the 13 cases. Three biological pathways were altered: adhesion, Wnt signaling and regulation of actin. Validation experiments using a genome scan for etoposide-induced leukemogenic MLL chimeric fusions in 15 HapMap cell lines also implicated genes involved in adhesion, a process linked to de novo leukemogenesis. Independent clinical epidemiologic and in vitro genome-wide approaches converged to identify novel pathways that may contribute to therapy-induced leukemia.

Primate pleuroesophageal tissue barrier frequency response and esophageal pressure waveform bandwidth in health and acute lung injury.

BACKGROUND: Dynamic intraesophageal pressure (Pes) is used to estimate intrapleural pressure (Ppl) to calculate lung compliance and resistance. This study investigated the nonhuman primate Ppl-Pes tissue barrier frequency response and the dynamic response requirements of Pes manometers. METHODS: In healthy monkeys and monkeys with acute lung injury undergoing ventilation, simultaneous Ppl and Pes were measured directly to determine the Ppl-Pes tissue barrier amplitude frequency response, using the swept-sine wave technique. The bandwidths of physiologic Pes waveforms acquired during conventional mechanical ventilation were calculated using digital low-pass signal filtering. RESULTS: The Ppl-Pes tissue barrier is amplitude-uniform within the bandwidth of conventional Pes waveforms in healthy and acute lung injury lungs, and does not significantly attenuate Ppl-Pes signal transmission between 1 and 40 Hz. At Pes frequencies higher than conventional clinical regions of interest the Ppl-Pes barrier resonates significantly, is pressure amplitude dependent at low-pressure offsets, and is significantly altered by acute lung injury. Allowing for 5% or less Pes waveform error, the maximum Pes bandwidths during conventional ventilation were 1.9 Hz and 3.4 Hz for physiologic and extreme-case waveforms in healthy lungs and 4.6 Hz and 8.5 Hz during acute lung injury. CONCLUSIONS: In monkeys, the Ppl-Pes tissue barrier has a frequency response suitable for Ppl estimation during low-frequency mechanical ventilation, and Pes manometers should have a minimum uniform frequency response up to 8.5 Hz. However, the Ppl-Pes tissue barrier adversely affects the accurate estimation of dynamic Ppl at high frequencies, with varied airway pressure amplitudes and offsets, such as the Ppl encountered during high-frequency oscillatory ventilation.

Building a balanced scorecard for a burn center.

The Balanced Scorecard provides a model that can be adapted to the management of any burn center, burn service or burn program. This model enables an organization to translate its mission and vision into specific strategic objectives across the four perspective: (1) the financial perspective; (2) the customer service perspective; (3) the internal business perspective; and (4) the growth and learning perspective. Once the appropriate objectives are identified, the Balanced Scorecard guides the organization to develop reasonable performance measures and establishes targets, initiatives and alternatives to meet programmatic goals and pursue longer-term visionary improvements. We used the burn center at the University of Colorado Health Sciences Center to test whether the Balanced Scorecard methodology was appropriate for the core business plan of a healthcare strategic business unit (i.e. a burn center).

Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia.

NAD(P)H:quinone oxidoreductase (NQO1) converts benzene-derived quinones to less toxic hydroquinones and has been implicated in benzene-associated hematotoxicity. A point mutation in codon 187 (Pro to Ser) results in complete loss of enzyme activity in homozygous subjects, whereas those with 2 wild-type alleles have normal activity. The frequency of homozygosity for the mutant allele among Caucasians and African Americans is 4% to 5% but is higher in Hispanics and Asians. Using an unambiguous polymerase chain reaction (PCR) method, we assayed nonmalignant lymphoblastoid cell lines derived from 104 patients with myeloid leukemias; 56 had therapy-related acute myeloid leukemia (t-AML), 30 had a primary myelodysplastic syndrome (MDS), 9 had AML de novo, and 9 had chronic myelogenous leukemia (CML). All patients had their leukemia cells karyotyped. Eleven percent of the t-AML patients were homozygous and 41% were heterozygous for the NQO1 polymorphism; these proportions were significantly higher than those expected in a population of the same ethnic mix (P =.036). Of the 45 leukemia patients who had clonal abnormalities of chromosomes 5 and/or 7, 7 (16%) were homozygous for the inactivating polymorphism, 17 (38%) were heterozygous, and 21 (47%) had 2 wild-type alleles for NQO1. Thus, NQO1 mutations were significantly increased compared with the expected proportions: 5%, 34%, and 61%, respectively (P =.002). An abnormal chromosome no. 5 or 7 was observed in 7 of 8 (88%) homozygotes, 17 of 45 (38%) heterozygotes, and 21 of 51 (41%) patients with 2 wild-type alleles. Among 33 patients with balanced translocations [14 involving bands 11q23 or 21q22, 10 with inv(16) or t(15;17), and 9 with t(9;22)], there were no homozygotes, 15 (45%) heterozygotes, and 18 (55%) with 2 wild-type alleles. Whereas fewer than 3 homozygotes were expected among the 56 t-AML patients, 6 were observed; 19 heterozygotes were expected, but 23 were observed. The gene frequency for the inactivating polymorphism (0. 31) was increased approximately 1.4-fold among the 56 t-AML patients. This increase was observed within each of the following overlapping cohorts of t-AML patients: the 43 who had received an alkylating agent, the 27 who had received a topoisomerase II inhibitor, and the 37 who had received any radiotherapy. Thus, the frequency of an inactivating polymorphism in NQO1 appears to be increased in this cohort of myeloid leukemias, especially among those with t-AML or an abnormality of chromosomes 5 and/or 7. Homozygotes and heterozygotes (who are at risk for treatment-induced mutation or loss of the remaining wild-type allele in their hematopoietic stem cells) may be particularly vulnerable to leukemogenic changes induced by carcinogens.

Sustained antihypertensive actions of a dual angiotensin-converting enzyme neutral endopeptidase inhibitor, sampatrilat, in black hypertensive subjects.

Our objective was to evaluate the safety and antihypertensive efficacy of sampatrilat, a novel dual inhibitor of both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in subjects poorly responsive to ACE inhibitor monotherapy. The ability of sampatrilat (50 to 100 mg daily) (n = 28) to lower blood pressure was compared with that of the ACE inhibitor lisinopril (10 to 20 mg daily) (n = 30) using a double-blind, randomized, parallel group study design over a 56-day treatment period in black hypertensives. Changes in systolic (SBP) and diastolic (DBP) blood pressure were determined using repeated ambulatory blood pressure (ABP) monitoring. Both sampatrilat and lisinopril decreased plasma ACE concentrations after 28 and 56 days. The decrease in plasma ACE concentrations (U/L) was greater after lisinopril (-9.33 +/- 0.52) as compared with sampatrilat (-6.31 +/- 0.70) (P = .0001) therapy. Lisinopril, but not sampatrilat, increased plasma renin activity. Lisinopril produced a transient decrease in mean 24-h ABP (mm Hg) at 28 days (SBP = -9.0 +/- 2.3, DBP = -5.7 +/- 1.3; P < .01), which returned to pretreatment values by 56 days of therapy. Alternatively, sampatrilat produced a sustained decrease in mean ABP over the 56-day treatment period (day 28: SBP = -7.3 +/- 1.8, DBP = -5.2 +/- 1.2; P < .01: day 56: SBP = -7.8 +/- 1.5; DBP = -5.2 +/- 0.95; P < 0.01) with a greater treatment effect on DBP than that of lisinopril at day 56 (P = .05). Treatment-emergent adverse events were noted to be similar between both treatment groups. We conclude that the antihypertensive actions of ACE/NEP inhibitor monotherapy in black subjects offers a novel therapeutic approach to patients otherwise resistant to the sustained antihypertensive actions of ACE inhibitor monotherapy.

Magma flow instability and cyclic activity at soufriere hills volcano, montserrat, british west indies

Dome growth at the Soufriere Hills volcano (1996 to 1998) was frequently accompanied by repetitive cycles of earthquakes, ground deformation, degassing, and explosive eruptions. The cycles reflected unsteady conduit flow of volatile-charged magma resulting from gas exsolution, rheological stiffening, and pressurization. The cycles, over hours to days, initiated when degassed stiff magma retarded flow in the upper conduit. Conduit pressure built with gas exsolution, causing shallow seismicity and edifice inflation. Magma and gas were then expelled and the edifice deflated. The repeat time-scale is controlled by magma ascent rates, degassing, and microlite crystallization kinetics. Cyclic behavior allows short-term forecasting of timing, and of eruption style related to explosivity potential.

Myocardial stiffness is attributed to alterations in cross-linked collagen rather than total collagen or phenotypes in spontaneously hypertensive rats.

BACKGROUND: The relative contributions of increases in myocardial collagen, collagen cross-linking, and the ratio of type I to type III collagen to the stiff myocardium in hypertension were determined. METHODS AND RESULTS: We compared the action of hydralazine (0.07 mmol x kg(-1) x d(-1)) with that of captopril (0.22 mmol x kg(-1) x d(-1)) on the left ventricular end-diastolic (LVED) myocardial stiffness constant, k (g x cm(-2)) and LV myocardial interstitial characteristics in spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) control rats. LVED k (SHR, 27.9+/-1; WKY, 19.5+/-1.2; P<.01), myocardial hydroxyproline concentrations (HPRO; microg/mg dry wt) (SHR, 4.19+/-0.16; WKY, 3.17+/-0.09; P<.001), and collagen type I/III ratios (SHR, 7.1+/-0.7; WKY, 2.1+/-0.2; P<.001) were increased, whereas the percentage of myocardial collagen extracted after cyanogen bromide digestion (an index of cross-linked collagen) was decreased (SHR, 17+/-3; WKY, 41+/-4; P<.001) in SHRs compared with WKY controls. Captopril therapy reduced LVED k, myocardial HPRO, collagen type I/III, and augmented collagen solubility (43+/-4) in SHRs to values similar to those measured in WKY controls. Hydralazine therapy, despite a favorable effect on LVED k in SHRs (20.+/-1.6, P<.01 compared with untreated SHRs), failed to influence either myocardial HPRO (4.18+/-0.18) or collagen type I/III (8+/-1) but did improve collagen solubility (31+/-2). CONCLUSIONS: An association between alterations in LVED k and collagen solubility but not between changes in LVED k and total collagen or phenotype ratios after antihypertensive therapy in SHRs suggests that myocardial stiffness in hypertension is the consequence of an enhanced myocardial collagen cross-linking rather than of an increase in total collagen or type I phenotype concentrations.

Correctly selecting a liquid-filled nasogastric infant feeding catheter to measure intraesophageal pressure.

Polyvinyl chloride (PVC) nasogastric feeding catheters are used clinically to measure intraesophageal pressure as an estimate of pleural pressure for calculating lung compliance in infants. The accuracy of pressure measurement of 4 French gauge (FG) catheter sizes and three brands of liquid-filled catheter manometer systems (CMS) was evaluated by determining their resonance-frequency amplitude and phase properties. All CMS were underdamped and resonated. No CMS exhibited a uniform mean frequency response above 11 Hz. The maximum respiratory rate (Frr) within which CMS could potentially measure dynamic intraesophageal pressure within a 5% error limit was determined (Frr): the highest mean Frr recorded reliably in large-diameter catheters was 82 breaths/min. Significant CMS differences in accuracy existed between catheter FG sizes and between catheters of similar diameters but differing brands. Correlation (r2) between catheter inner diameter and CMS Frr was 0.66 across brands. In conclusion, intraesophageal PVC liquid-filled feeding catheters are suitable for estimating pleural pressures in subjects mechanically ventilated without sharp inspiratory waveforms or high respiratory rates. Quantitative frequency response characterization of different nasogastric catheter brands and different diameters is mandatory prior to their utilization.

Frequency responses of infant air-balloon versus liquid-filled catheters for intra-esophageal pressure measurement.

Amplitude and phase frequency response characteristics of infant air-balloon catheters (IABC) of differing French gauge (FG) sizes and brands were quantified to determine their suitability for measuring dynamic intra-esophageal pressure (Pes) accurately. Frequency response performances of matching IABC and water-filled catheters (WFC) were also compared using the swept sine wave technique. The maximum respiratory rate within which IABCs could potentially measure Pes within a 5% error limit was calculated (FRR). Frequency responses of IABCs greater than FG size 5 exhibited underdamped resonant properties, while smaller FG size IABCs exhibited near-critical damping or overdamping. IABCs maintained uniform amplitude frequency responses up to 25 Hz, demonstrating the ability to measure Pes potentially up to 148 breaths/min within a 5% error limit. The frequency response performance of FG size 6 IABCs was similar to that of FG size 10 IABCs. Compared with matching WFCs, the frequency response performance of IABCs was significantly superior, the frequency response variability within IABC samples was lower, and IABC correlation between FG size and FRR was advantageously lower than for WFCs. FRR values for differing IABC brands and FG sizes are presented. We conclude that IABCs manufactured to infant-appropriate balloon specifications exhibit significantly superior frequency response characteristics compared with matching WFCs. Measurement accuracy is not improved using IABCs greater than FG size 6. Inexpensive intra-esophageal IABCs are technical suitable for the accurate measurement of dynamic Pes during high-frequency respiratory mechanics encountered during infant artificial ventilation.

Lipoprotein (a) and cholesterol in body builders using anabolic androgenic steroids.

We examined the influence of self-administered anabolic androgenic steroids (AAS) on the lipogram of male body builders. Serum lipoprotein (a) (Lp(a)), total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were measured in 10 experimental and 8 control male competitive body builders. The proportion of subjects with serum Lp(a) levels above 30 mg.dl-1 was significantly lower in the AAS group than the non-AAS group. HDL-C levels were significantly lower and LDL-C levels significantly higher in the AAS group than the non-AAS group. These data suggest that AAS in male body builders have a beneficial effect on serum Lp(a) levels but reduce the HDL-C:LDL-C ratio.