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M G Loudin,
J Wang,
H-C Eastwood Leung,
S Gurusiddappa,
J Meyer,
G Condos,
D Morrison,
A Tsimelzon, M Devidas,
N A Heerema,
A J Carroll,
S E Plon,
S P Hunger,
G Basso,
A Pession,
D Bhojwani,
W L Carroll,
K R Rabin
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ABSTRACT: Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P=0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2011; 25(10):1555-63. · 8.30 Impact Factor
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M Blink,
T D Buitenkamp,
M M van den Heuvel-Eibrink,
A A Danen-van Oorschot,
V de Haas,
D Reinhardt,
J-H Klusmann,
M Zimmermann, M Devidas,
A J Carroll,
G Basso,
A Pession,
H Hasle,
R Pieters,
K R Rabin,
S Izraeli,
C M Zwaan
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2011; 25(8):1365-8. · 8.30 Impact Factor
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ABSTRACT: From 1984 to 2001, the Pediatric Oncology Group (POG) conducted 12 acute lymphoblastic leukemia (ALL) studies. Ten-year event-free survival (EFS) for patients >12 months of age with B-precursor ALL on acute leukemia in children 14, 15 and 16 series were 66.7+/-1.2%, 68.1+/-1.4% and 73.2+/-2.1%, respectively. Intermediate dose methotrexate (ID MTX; 1 g/m(2)) improved outcomes for standard risk patients (10-year EFS 77.5+/-2.7% vs 66.3+/-3.1% for oral MTX). Neither MTX intensification (2.5 g/m(2)) nor addition of cytosine arabinoside/daunomycin/teniposide improved outcomes for higher risk patients. Intermediate dose mercaptopurine (1 g/m(2)) failed to improve outcomes for either group. Ten-year EFS for patients with T-cell ALL, POG 8704 and 9404 were 49.1+/-3.1% and 72.2+/-4.7%, respectively. Intensive asparaginase (10-year EFS 61.8 vs 42.7%) and high-dose MTX (5 g/m(2)) (10-year EFS 78.0 vs 65.8%) improved outcomes. There was a non-significant improvement in EFS for infants (10-year EFS 17.7+/-7.2-31.9+/-8.3%). Prognostic indicators for B-precursor ALL were age and WBC at diagnosis, gender, central nervous system disease, DNA index and cytogenetic abnormalities. Only gender was prognostic in T-cell ALL. In infants, WBC and MLL translocation were linked to inferior outcome.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2009; 24(2):355-70. · 8.30 Impact Factor
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ABSTRACT: The Children's Cancer Group enrolled 13 298 young people age <21 years on 1 of 16 protocols between 1983 and 2002. Outcomes were examined in three time periods, 1983-1988, 1989-1995, 1996-2002. Over the three intervals, 10-year event-free survival (EFS) for Rome/National Cancer Institute standard risk (SR) and higher risk (HR) B-precursor patients was 68 and 58%, 77 and 63%, and 78 and 67%, respectively, whereas for SR and HR T-cell patients, EFS was 65 and 56%, 78 and 68%, and 70 and 72%, respectively. Five-year EFS for infants was 36, 38, and 43%, respectively. Seminal randomized studies led to a number of important findings. Stronger post-induction intensification improved outcome for both SR and HR patients. With improved systemic therapy, additional intrathecal (IT) methotrexate effectively replaced cranial radiation. For SR patients receiving three-drug induction, iso-toxic substitution of dexamethasone for prednisone improved EFS. Pegylated asparaginase safely and effectively replaced native asparaginase. Thus, rational therapy modifications yielded better outcomes for both SR and HR patients. These trials provide the platforms for current Children's Oncology Group trials.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2009; 24(2):285-97. · 8.30 Impact Factor
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A Larson Gedman,
Q Chen,
S Kugel Desmoulin,
Y Ge,
K LaFiura,
C L Haska,
C Cherian, M Devidas,
S B Linda,
J W Taub,
L H Matherly
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ABSTRACT: We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). In T-ALL lymphoblasts, we identified high-frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and PTEN (n=26). NOTCH1 mutations resulted in 1.3- to 3.3-fold increased transactivation of an HES1 reporter construct over wild-type NOTCH1; mutant FBW7 resulted in further augmentation of reporter gene activity. NOTCH1 and FBW7 mutations were accompanied by increased median transcripts for NOTCH1 target genes (HES1, DELTEX1 and cMYC). However, none of these mutations were associated with treatment outcome. Elevated HES1, DELTEX1 and cMYC transcripts were associated with significant increases in transcript levels of several chemotherapy relevant genes, including MDR1, ABCC5, reduced folate carrier, asparagine synthetase, thiopurine methyltransferase, BCL2 and dihydrofolate reductase. PTEN transcripts positively correlated with HES1 and cMYC transcript levels. Our results suggest that (1) multiple factors should be considered with attempting to identify molecular-based prognostic factors for pediatric T-ALL, and (2) depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs for T-ALL, or combinations of agents capable of targeting NOTCH1, AKT and/or mTOR with standard chemotherapy agents may be warranted.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2009; 23(8):1417-25. · 8.30 Impact Factor
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ABSTRACT: Despite great progress in curing childhood acute lymphoblastic leukemia (ALL), survival after relapse remains poor. We analyzed survival after relapse among 9585 pediatric patients enrolled on Children's Oncology Group clinical trials between 1988 and 2002. A total of 1961 patients (20.5%) experienced relapse at any site. The primary end point was survival. Patients were subcategorized by the site of relapse and timing of relapse from initial diagnosis. Time to relapse remains the strongest predictor of survival. Patients experiencing early relapse less than 18 months from initial diagnosis had a particularly poor outcome with a 5-year survival estimate of 21.0+/-1.8%. Standard risk patients who relapsed had improved survival compared with their higher risk counterparts; differences in survival for the two risk groups was most pronounced for patients relapsing after 18 months. Adjusting for both time and relapse site, multivariate analysis showed that age (10+ years) and the presence of central nervous system disease at diagnosis, male gender, and T-cell disease were significant predictors of inferior post-relapse survival. It can be noted that there was no difference in survival rates for relapsed patients in earlier vs later era trials. New therapeutic strategies are urgently needed for children with relapsed ALL and efforts should focus on discovering the biological pathways that mediate drug resistance.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2008; 22(12):2142-50. · 8.30 Impact Factor
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M Eapen,
M-J Zhang, M Devidas,
E Raetz,
J C Barredo,
A K Ritchey,
K Godder,
S Grupp,
V A Lewis,
K Malloy,
W L Carroll,
S M Davies,
B M Camitta
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ABSTRACT: In children with acute lymphoblastic leukemia (ALL) with isolated central nervous system (CNS) relapse and a human leucocyte antigen (HLA)-matched sibling, the optimal treatment after attaining second remission is unknown. We compared outcomes in 149 patients enrolled on chemotherapy trials and 60 HLA-matched sibling transplants, treated in 1990-2000. All patients achieved a second complete remission. Groups were similar, except the chemotherapy recipients were younger at diagnosis, less likely to have T-cell ALL and had longer duration (> or = 18 months) first remission. To adjust for time-to-transplant bias, left-truncated Cox's regression models were constructed. Relapse rates were similar after chemotherapy and transplantation. In both treatment groups, relapse rates were higher in older children (11-17 years; RR 2.81, P=0.002) and shorter first remission (< 18 months; RR 3.89, P<0.001). Treatment-related mortality rates were higher after transplantation (RR 4.28, P=0.001). The 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar after chemotherapy with irradiation and transplantation (66 and 58%, respectively). In the absence of an advantage for one treatment option over another, the data support use of either intensive chemotherapy with irradiation or HLA-matched sibling transplantation with total body irradiation containing conditioning regimen for children with ALL in second remission after an isolated CNS relapse.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2008; 22(2):281-6. · 8.30 Impact Factor
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Journal of Clinical Oncology - J CLIN ONCOL. 01/2008; 26(24):3971-3978.
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P A Mehta,
S M Davies,
A Kumar, M Devidas,
S Lee,
T Zamzow,
J Elliott,
J Villanueva,
J Pullen,
Y Zewge,
A Filipovich
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ABSTRACT: Perforin plays a key role in the cytotoxicity of natural killer and cytotoxic T cells. Genetic mutations in the perforin gene (PRF1) give rise to approximately 30% cases of familial hemophagocytic lymphohistiocytosis. A frequent polymorphism, A91V (C to T transition at position 272), may impair processing of perforin protein to the active form, and has been suggested to increase susceptibility to childhood acute lymphoblastic leukemia (ALL). To investigate the role of A91V in ALL, we genotyped 2272 children with de novo ALL registered on the Pediatric Oncology Group ALL Classification study P9900 and 655 normal controls. Allele frequencies in the controls showed a very low frequency of the variant allele in blacks, 0.7% compared to 4% in white controls. In light of this, analysis was restricted to a comparison of white cases and controls only. Overall genotype frequencies were similar in white ALL cases and normal white controls (P=0.58), indicating that in contrast to the previous report, A91V polymorphism is not associated with increased risk of childhood ALL. PRF1 A91V frequency was significantly increased in children with BCR-ABL positive ALL (24 vs 8.5%; P=0.0048); however, this observation includes a relatively small number of cases and needs further exploration.
Leukemia 10/2006; 20(9):1539-41. · 9.56 Impact Factor
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ABSTRACT: The purpose of this study was to analyze valve station changes noted during venous valve reconstruction and the associated outcome. One hundred and forty-nine valve reconstructions were available for analysis at the time of surgical exploration; the venous valve was graded according to valve station changes (VS grades) from zero through six. Ascending venography was analyzed by a similar grading system and the two methods were compared. The results of this analysis showed that valve station wall changes are frequently present in patients with deep venous reflux and pose technical challenges during valve reconstruction; the outcome, however, appears unaffected. Grade 0 to 1 valve station changes are predominantly due to "primary" reflux, with an occasional instance of postthrombotic etiology. Grade 2 or 3 valve station changes are roughly evenly divided between phlebosclerosis of primary reflux and postthrombotic etiologies. The mechanism of onset of reflux with preservation of valve cusps in the latter group of postthrombotic cases is probably different from currently accepted theories of evolution of postthrombotic changes. Postthrombotic valve damage is variable, and the valve station anatomy may be sufficiently preserved in some patients to allow direct valve repair.
Annals of Vascular Surgery 06/2000; 14(3):193-9. · 1.03 Impact Factor
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ABSTRACT: The plaque control record (O'Leary index) appears to be a commonly used oral hygiene index for assessing oral health skills. This index provides sufficient information for patient education; however, the time involved in data collection reduces its value. Most other indices limit the number of teeth and surfaces and function well for researchers, but are limited for patient education. A new oral hygiene index was developed based on the concepts of the Periodontal Screening and Recording (PSR). The highest score obtained in each buccal and lingual sextant is recorded. In addition, proximal and gingival plaque are noted separately. This study assesses the index for inter- and intrarater reliability and validity. Two calibrated hygienists examined 47 patients 3 times. The University of Mississippi Oral Hygiene Index (UM-OHI) was recorded for times 1 and 3, the O'Leary for time 2. There was a strong positive correlation between scores obtained for both hygienists for each method and repetition. The intrarater reliability was high for the 2 methods and also over time for the UM-OHI. Pearson's correlation coefficients ranged from 0.79 to 0.92. Paired t-tests used to compare scores for the 2 hygienists over time showed significant differences. Despite observer bias, these data seem to indicate that the UM-OHI has sufficient reliability and validity to be used as a health education teaching tool.
Journal of Periodontology 11/1998; 69(10):1176-80. · 2.60 Impact Factor
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ABSTRACT: The results of saphenectomy in patients with morphologic and functional obstruction were compared with those in patients without obstruction. Excision of secondary saphenous varices associated with deep venous obstruction has long been considered contraindicated for fear of compromising its collateral contribution. Recent advances in accurate functional assessment of venous obstruction make it possible to test this concept.
Saphenectomy was carried out in 51 limbs without morphologic or functional obstruction and 64 limbs with varying grades of venous obstruction. Significant deep venous obstruction on ascending venography was present in the latter group. Functional assessment of obstruction was based on the arm/foot venous pressure differential technique, outflow fraction measurements, and outflow resistance calculations. Valve reconstruction was carried out in conjunction with saphenectomy in 81% of cases.
Saphenectomy was clinically well tolerated in both groups, and there was no difference in outcome as measured by objective tests for obstruction; improvement in reflux and calf venous pump function was largely similar. Among seven limbs with severe preoperative venous obstruction (grade III or IV), five (70%) had significantly improved obstructive grading, presumably as a result of elimination of reflux flow.
The traditional admonition against removal of secondary varices should be reexamined. Saphenectomy may be indicated in postthrombotic syndrome with mixed obstruction/reflux. The procedure is clinically well tolerated and without malsequelae. Improvement in reflux parameters without significant worsening of objective measures of obstruction is documented in this group.
Surgery 07/1998; 123(6):637-44. · 3.10 Impact Factor
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ABSTRACT: To highlight a special subset of cases of venous stasis in which the profunda femoris vein enlarges to a variable extent (axial transformation) to compensate for severe postthrombotic changes in the accompanying superficial femoral vein.
Among 500 consecutively treated patients with severe venous stasis, 57 patients had axial transformation of the profunda femoris vein. Venous obstruction and reflux were assessed by means of arm-foot pressure differential, ambulatory venous pressure measurement, air plethysmography, and duplex examination. Ascending and descending venograms also were obtained. A variety of valve reconstruction techniques were useful in correcting reflux in the enlarged profunda femoris vein and the companion postthrombotic superficial femoral vein.
In 55% of patients the profunda femoris vein was larger than normal and provided partial outflow from the leg through a profunda-popliteal connection, but the superficial femoral vein was still the dominant outflow tract (grades I and II). In 36% of patients the profunda femoris was the dominant outflow tract from the leg, and in another 9% it was the sole axial outflow tract (grades III and IV). The skin changes of advanced venous stasis were present among 92% of patients and frank ulceration among 88%. Antireflux operations on the profunda femoris vein and companion superficial femoral vein, including ligation and division in some instances, were well tolerated. Despite a postthrombotic cause, obstruction did not worsen after surgical treatment, and reflux improved according to most laboratory measurements. Complete ulcer healing was obtained with the surgical techniques described. The actuarial recurrence-free survival rates were 90% 1 year and 66% 5 years after treatment.
Axial transformation of the profunda femoris vein is present in a subset of instances in which severe postthrombotic changes are present in the companion superficial femoral vein. Profunda femoris reflux is invariably present in these instances because of compensatory dilatation and enlargement of this vessel. Simultaneous valve repair of the axially transformed profunda femoris vein and companion superficial femoral vein to abolish reflux yields excellent long-term results and healing of stasis ulceration.
Journal of Vascular Surgery 05/1998; 27(4):651-9. · 3.21 Impact Factor
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ABSTRACT: To compare directly measured pressures at the cuff/trachea interface that are associated with two different bronchial cuff designs and four different methods of bronchial cuff inflation suggested for use with one-lung ventilation.
In vitro study.
Experimental laboratory in a university-affiliated hospital.
The bronchial cuffs of two different endotracheal tubes were inflated using one of four different methods of determining the cuff volume and pressure necessary to "just seal" the bronchus and obtain lung separation; positive-pressure test, negative-pressure test, CO2 analysis, and a new test using an anesthesia ventilator. When each method predicted the "just-seal" state, the pressure at the cuff/bronchus interface as well as cuff inflation pressure and volume were recorded.
Although the new test was incompatible with the bronchial blocker, the other three tests all accurately predicted lung separation with the Univent, with no significant differences in pressures exerted on the trachea. However, when used with the double-lumen tube, the new test produced significantly lower measured parameters than the other inflation methods. CO2 analysis did not reliably predict bronchial seal with the double-lumen tube.
To achieve lung separation with the lowest pressure on the trachea, the new test is the most appropriate method for use with the double-lumen tube; however, the negative-pressure test appeared to be the easiest and fastest method for use with the bronchial blocker. Although the bronchial blocker was associated with lower pressures transmitted from the cuff to the trachea, the in vitro model cannot predict which bronchial cuff design would be superior in vivo.
Journal of Cardiothoracic and Vascular Anesthesia 09/1997; 11(5):599-603. · 1.64 Impact Factor
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ABSTRACT: To identify factors involved in the development of fetal cephalohematoma from vacuum extraction.
Patients at > or = 34 weeks' gestation were randomly assigned to delivery by vacuum (n = 322) using the continuous (n = 164) or intermittent (n = 158) technique. Neonatal outcome with cephalohematoma was analyzed subsequently and related to prospectively recorded data.
Approximately equal numbers of cephalohematoma were recorded in the two groups (continuous 20, intermittent 17; P = .686). Station at point of application (P = .008), increasing asynclitism (P < .001) and increasing application to delivery time (P = .002) correlated significantly with cephalohematoma. Only the last two factors achieved significance after stepwise multiple logistic regression analysis. Factors that did not achieve statistical significance were gestational age (P = .755), birth weight (P = .982), instrumental rotation (P = .896) and previous vaginal delivery (P = .051).
In this prospective, randomized, controlled trial of vacuum-assisted delivery, the only predelivery factor found to predispose to neonatal cephalohematoma formation was increasing asynclitism. Although cephalohematoma formation was more likely to develop as the duration of vacuum application increased during delivery, only 28% of neonates exhibited this finding when the time from vacuum application to delivery exceeded five minutes.
The Journal of reproductive medicine 09/1997; 42(9):565-9. · 0.87 Impact Factor
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ABSTRACT: The immune environment of human soft-tissue injury is unstudied. We studied fracture soft-tissue hematomas (FxSTH) in 56 patients with high-energy bony fractures. FxSTH serum and mononuclear cells (MNC) as well as fracture patient plasma and blood MNC were studied. Twenty healthy controls donated plasma and MNC. Soluble tumor necrosis factor (TNF)-alpha, interleukin (IL-1 beta, IL-2, 6, 8, 10, 12, and interferon-gamma were studied by enzyme linked immunosorbent assay. Cells were studied by flow cytometry after cell-membrane stains for CD-14, TNF-alpha (mTNF), and human leukocyte antigen-DR, or intracellular stains for TNF (icTNF) and IL-10. Thirty-six patients with Injury Severity Score < 15 were analyzed further to evaluate the effects of isolated fracture on systemic immunity. Cytokines were rarely detectable in control plasma. TNF-alpha, IL-1 beta, IL-2, and interferon-gamma were rarely found in FxSTH serum or fracture patient plasma. All FxSTH sera were rich in IL-6, peaking before 48 hours (12,538 +/- 4,153 vs. 3,494 +/- 909 pg/mL, p = 0.02, U test). In Injury Severity Score < 15, IL-6 was not detectable in most early fracture patient plasma, but rose after 48 hours (p = 0.028). FxSTH serum IL-8 peaked after 48 hours (440 +/- 289 vs. 4,542 +/- 1,219 pg/mL, p = 0.006) and circulating IL-8 appeared after 72 hours. IL-6 and IL-8 showed gradients from FxSTH serum to paired PtS (p < 0.05, Wilcoxon). IL-10 was abundant (884 +/- 229 pg/mL) in FxSTH serum < 24 hours old. FxSTH serum IL-12 peaked late (3,323 +/- 799 pg/mL, day 4-7) then fell (p < 0.001, analysis of variance). Only IL-12 was higher in fracture patient plasma (1,279 +/- 602 pg/mL) than FxSTH serum (591 +/- 327 pg/mL) during the first 48 hours (p = 0.032, U test). On flow cytometry, control monocytes expressed 201 +/- 31 mTNF sites/cell, but icTNF was absent. mTNF was up-regulated after injury more in FxSTH monocytes (3,202 +/- 870 sites/cell) than peripheral blood monocytes (584 +/- 186 sites/cell) (p < 0.05 vs. peripheral blood monocytes by Wilcoxon, p < 0.001 vs. control monocytes by U test). Intracellular IL-10 was abundant in all MNC, but varied widely after injury. Fracture and peripheral blood monocytes expressed far less human leukocyte antigen-DR than control monocytes. Fractures create an inflammatory local environment. Proximal mediators are cell-associated and relatively confined to the wound, but soluble IL-6, IL-8, and IL-10 are abundant and probably exported. Systemic MNC have complex responses to local injuries. These may reflect the combined impact of multiple soluble cytokines initially generated within the wound. FxSTH appear to be a potentially important source of immunomodulatory cytokines in trauma.
The Journal of trauma 05/1997; 42(5):895-903; discussion 903-4. · 2.48 Impact Factor
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ABSTRACT: Trauma has a high rate of recurrence, suggesting that some people are more injury-prone than others. This study was performed to evaluate some of the psychological and social factors that might influence the likelihood of traumatic injury.
A case-control study was conducted to evaluate the relationship between selected psychosocial factors and traumatic injury. At a Level I trauma center, victims of intentional trauma (excluding attempted suicide), victims of nonintentional trauma, and patients undergoing elective surgery were interviewed by a person blinded to the purposes of the study. They were given an intelligence test and underwent a structured interview, yielding psychiatric diagnostic categories established in the third edition of the Diagnostic and Statistical Manual of Mental Disorders, Revised (DSM-III-R).
Trauma patients were younger than elective surgery patients (p < 0.01) and were more likely to be men (p < 0.01). Victims of intentional injury had a higher probability of alcohol use (p < 0.01) and admitted illicit drug use (p < 0.001) than either nonintentional injury victims or elective surgery patients. Victims of intentional injury were more likely to be unemployed than those in the other two groups (p < 0.02), whereas elective surgery patients were more likely to be retired (p < 0.05) or to be disabled (p < 0.0001). The average intelligence score was slightly above the median in the nonintentional trauma group and in the control group (55th percentile and 54th percentile, respectively), compared with a mean intelligence score equivalent to the 35th percentile in the victims of intentional trauma (p < 0.001). Thirty percent of elective surgery patients met diagnostic criteria for at least one category of psychopathology, compared with 50% of nonintentional trauma patients, and 63% of intentional trauma patients (p < 0.01, trauma vs. elective surgery). Logistic regression analysis identified six variables that were independently associated with an increased tendency to be a victim of trauma: younger age, lower intelligence, antisocial personality, mental retardation, depression, and low income.
Victims of trauma, both nonintentional, and especially intentional, have a high incidence of psychopathology. Victims of intentional trauma have significantly lower intelligence scores than either nonintentional injury or elective surgery patients. The high incidence of unemployment, alcohol abuse, and illicit drug use in victims of intentional injury might provide several opportunities for trauma prevention programs. Underlying psychological disorders will have to be addressed to reduce the likelihood of becoming a victim of trauma.
The Journal of trauma 04/1997; 42(4):711-5. · 2.48 Impact Factor
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ABSTRACT: Clinical trauma suppresses immunity and experimental wound fluids have been shown to be immunosuppressive. To ascertain whether human wounds contain immunosuppressive cytokines, we assayed serum from fracture/soft-tissue hematomas (FSTH) of 22 patients for interleukin (IL)-10, transforming growth factor (TGF)-beta 1, and IL-4. Results were correlated to concurrent plasma cytokine concentrations in the same patients and in volunteer plasma. IL-10 was present in high concentration (1376 +/- 539 pg/mL) in all (7/7) FSTH < 24 h old. In FSTH > 24 h old, IL-10 was found intermittently and at lower levels (239 +/- 106 pg/mL, p = .011 vs. FSTH < 24 h old). IL-10 was rarely detectable in fracture patient plasma and never detectable (< 20 pg/mL) in normal plasma. No significant variations of IL-4 or total TGF-beta 1 were found in FSTH or plasma. FSTH are significant potential sources of IL-10 activity in trauma patients, which may be overlooked when only plasma is assayed. The potential for a relationship between cytokines found locally at sites of injury and clinical immune modulation in trauma requires further study.
Shock 08/1996; 6(1):3-6. · 2.85 Impact Factor
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ABSTRACT: Giving glucose before hypoxic ischemia worsens brain injury in piglets. Does giving glucose after hypoxic ischemia affect severity of injury?
Forty-three 0- to 3-day-old pigs were used. All piglets received 2 U/kg insulin before injury to prevent stress-induced hyperglycemia. Hypoxic ischemic brain damage was induced by clamping both carotid arteries and reducing arterial blood pressure to two thirds of normal by hemorrhage at time 0. At 15 minutes the fraction of inspired oxygen (FIO2) was reduced to 6%. At 30 minutes FIO2 was increased to 100%, the carotids were released, and the withdrawn blood was reinfused. The piglets were then randomized to receive either 2 mL/kg of 50% dextrose followed by 2 mL/kg per hour for 2 hours or an equal volume of saline.
Neurological examination scores (20 is normal, 5 is brain dead, by blinded observer) at 1 day postinjury were similar in the two groups: glucose, median 15.5 (25th percentile, 12.2; 75th percentile, 18); controls, 15.6 (9.3, 18). Piglets were killed at 3 days with brain preservation at death. Pathological examination scores (sum of scores from cortex, hippocampus, and basal ganglia: 30 is normal, 3 is total necrosis) by blinded observer were similar in the two groups: glucose, 26 (18, 28); controls, 25 (16.5, 28); NS.
Although elevated glucose levels during hypoxic ischemic injury worsen brain injury in the piglet, elevated glucose levels after injury do not affect the severity of the injury.
Stroke 08/1994; 25(7):1443-7; discussion 1448. · 5.73 Impact Factor
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ABSTRACT: We discuss a generalization of the logistic response function of the form Pr(y = 1/x) = [1 + exp(- theta - beta'x)]-alpha, where alpha > 0. This function coincides with the usual logistic response when the shape parameter alpha is equal to one. We describe the use of this model for analysing cancer rates in mice for low-dose exposure to a known carcinogen. When estimating the low-dose responses, the errors associated with extrapolation are reduced when a priori knowledge about the rates among unexposed individuals is incorporated into the fitting procedures.
Statistics in Medicine 05/1993; 12(9):881-92. · 1.88 Impact Factor
