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Biomedical subjects

G Heller

Publications and source records attributed to G Heller.

At least 37 records · Page 2Linked to original sources
PubMed2001

Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging.

PURPOSE: To examine the potential for visual acuity loss, and its relation to extent and location of optic pathway gliomas in a cohort of children with neurofibromatosis type 1 studied with magnetic resonance imaging. METHODS: We reviewed the neuro-ophthalmologic records and brain/orbital magnetic resonance imaging scans for 43 consecutive pediatric patients with neurofibromatosis type 1 and optic pathway gliomas who were followed at the Children's Hospital of Philadelphia. The presence of visual loss, defined as abnormal visual acuity for age in one or both eyes, was determined. Optic pathway gliomas were classified by tumor extent and location according to involvement of the optic nerves, chiasm, and postchiasmal structures by magnetic resonance imaging. RESULTS: Involvement of the optic tracts and other postchiasmal structures at tumor diagnosis was associated with a significantly higher probability of visual acuity loss (P =.048, chi-square test). Visual loss was noted in 20 of 43 patients (47%) at a median age of 4 years; however, three patients developed visual acuity loss for the first time during adolescence. CONCLUSIONS: In pediatric patients with neurofibromatosis type 1 and optic pathway gliomas, the likelihood of visual loss is dependent on the extent and location of the tumor by magnetic resonance imaging and is particularly associated with involvement of postchiasmal structures. Furthermore, older age during childhood (adolescence) does not preclude the occurrence of visual loss. Close follow-up beyond the early childhood years, particularly for those with postchiasmal tumor, is recommended.

Adolescent↗
PubMed2001

Validation of NACB and IFCC guidelines for the use of cardiac markers for early diagnosis and risk assessment in patients with acute coronary syndromes.

BACKGROUND: International guidelines have been established for the use of cardiac markers in the early diagnosis and risk assessment of patients with acute coronary syndromes. METHODS: A single center, prospective observational study was conducted in a tertiary care university hospital on 200 consecutive patients with suspected acute myocardial infarction (AMI). Blood was drawn on admission and after 2, 4, 8, 12 and 24 h for the measurement of CK-MB/CK activity, myoglobin, CK-MB mass and troponin I. A 6-week follow-up was undertaken for the combined end point of acute coronary syndrome and death. RESULTS: Myoglobin showed an early diagnostic sensitivity of 0.65 on admission, 0.90 after 2 h and 0.92 after 4 h compared with 0.46, 0.74 and 0.88 for CK-MB/CK activity. The combination of myoglobin and cTnI increased the diagnostic value compared with myoglobin alone on admission, 2 and 4 h later. In multivariate analysis, cTnI and CK-MB/CK mass, but not myoglobin and CK-MB/CK activity, were shown to be independent predictors on the 6-week follow-up. CONCLUSIONS: Repetitive myoglobin measurements within 4 h of admission, combined with at least one early troponin test, was shown to be the strategy of choice in early AMI diagnosis and prognosis assessment.

Adult↗
PubMed2001

The Cox proportional hazards model with a partly linear relative risk function.

The conventional Cox proportional hazards regression model contains a loglinear relative risk function, linking the covariate information to the hazard ratio with a finite number of parameters. A generalization, termed the partly linear Cox model, allows for both finite dimensional parameters and an infinite dimensional parameter in the relative risk function, providing a more robust specification of the relative risk function. In this work, a likelihood based inference procedure is developed for the finite dimensional parameters of the partly linear Cox model. To alleviate the problems associated with a likelihood approach in the presence of an infinite dimensional parameter, the relative risk is reparameterized such that the finite dimensional parameters of interest are orthogonal to the infinite dimensional parameter. Inference on the finite dimensional parameters is accomplished through maximization of the profile partial likelihood, profiling out the infinite dimensional nuisance parameter using a kernel function. The asymptotic distribution theory for the maximum profile partial likelihood estimate is established. It is determined that this estimate is asymptotically efficient; the orthogonal reparameterization enables employment of profile likelihood inference procedures without adjustment for estimation of the nuisance parameter. An example from a retrospective analysis in cancer demonstrates the methodology.

Humans↗
PubMed2001

Platelet activation through triathlon competition in ultra-endurance trained athletes: impact of thrombin and plasmin generation and catecholamine release.

The aims of this study were to evaluate whether platelets are activated during strenuous exercise in healthy athletes. Also, to determine the impact of plasmin and thrombin activity and catecholamine release. Previous studies have shown activation of the hemostatic system after competitive exercise, but platelet activation was thought to be absent in trained athletes. The impact of thrombin and other potent platelet activators is still a matter for debate. We examined 30 healthy triathletes during a triathlon competition. Flow cytometric detection of CD62p (P-selectin) was used to measure in vivo activation of platelets. Platelet-leukocyte aggregates were also determined. Thrombin concentration was assessed by the thrombin-antithrombin III complex (TAT) and the fibrinolytic state was characterised by the plasmin-alpha2-antiplasmin complex (PAP). Catecholamines were measured by means of high-pressure liquid chromatography. CD62p rose from baseline (2.3%) to 3.4% and was still elevated after 2 hours (3.1%, p = 0.0133). Platelet-leukocyte aggregates were elevated 30 min after exercise (4.3 % vs 3.6%) and decreased significantly after 60 min (2.9 %, p = 0.008). TAT increased from 3.9 microg/l to 8.3 microg/l after competition and to 5.4 microg/l 2 hours later (p < 0.001). PAP increased 10-fold from 350 microg/l to 3,267 microg/l after the triathlon and was still elevated after 2 hours (1,074 microg/l, p<0.001). No linear correlation was found between the hemostatic markers, catecholamines and platelet activation. Platelets, coagulation and fibrinolysis are activated by competitive exercise in athletes, whereby fibrinolytic changes are pronounced. Mechanisms of platelet activation during exercise include phenomena other than plasmatic hemostatic factors and catecholamines.

Adult↗
PubMed2001

Human epidermal growth factor receptor 2 as a prognostic indicator in osteogenic sarcoma.

Prognostic biologic factors that can be assessed at the time of diagnosis for patients with osteogenic sarcoma have not been identified. The current study was designed to evaluate the prognostic significance of the human epidermal growth factor receptor 2 as it relates to histologic response to preoperative chemotherapy and event-free survival. A retrospective immunohistochemical study was performed on material from patients who were newly diagnosed with osteogenic sarcoma who were treated according to the T12 protocol from the authors' institution between 1986 to 1993. Staining for HER2/erbB-2 was accomplished using standard monoclonal antibodies and methods. At the time of initial biopsy, 42.6% of the samples showed HER2/erbB-2 overexpression. Higher levels of expression were observed in samples from patients with clinically detectable metastases at initial presentation and at relapse. Expression of HER2/erbB-2 correlated with inferior event-free survival in patients with nonmetastatic disease (47% versus 79% at 5 years). In addition, HER2/erbB-2 expression was associated with significantly less tumor necrosis after preoperative chemotherapy as determined by the Huvos grading system. These data suggest that HER2/erbB-2 should be evaluated prospectively as a prognostic indicator and clinical trials using antibodies that target this receptor should be considered for the treatment of patients with osteogenic sarcoma.

Adolescent↗
PubMed2001

Pairwise rank-based likelihood for estimation and inference on the mixture proportion.

We consider the problem of estimation and inference on the mixture parameter in the two-sample problem when sample data from the two distributions as well as from a third population consisting of a mixture of the two are used. Under a general nonparametric model, where the relationship between the two populations is unspecified, we develop a pairwise rank-based likelihood. Simultaneous inference on the mixture proportion and a parameter representing the probability an observation from one population is greater than an observation from the other population is based on this likelihood. Under some regularity conditions, it is shown that the maximum pairwise rank likelihood estimator is consistent and has an asymptotic normal distribution. Simulation results indicate that the performance of this statistic is satisfactory. The methodology is demonstrated on a data set in prostate cancer.

Biometry↗
PubMed2000

Granulocyte-colony stimulating factor and multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy in children with neuroblastoma.

BACKGROUND: The authors assessed key effects of granulocyte-colony stimulating factor (G-CSF) used prophylactically with multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy. To the authors' knowledge, no large study has focused on G-CSF in this setting, yet this kind of treatment has recently become standard for poor risk pediatric solid tumors such as neuroblastoma. PATIENTS AND METHODS. Children with neuroblastoma received cyclophosphamide 140 mg/kg (i.e., 4200 mg/m(2)), doxorubicin 75 mg/m(2), and vincristine (CAV) in cycles 1, 2, 4, and 6 and cisplatin 200 mg/m(2) and etoposide 600 mg/m(2) (P/VP) in cycles 3, 5, and 7. To maximize dose intensity, chemotherapy was begun as soon as the absolute neutrophil count (ANC) was > or = 500/microL and platelet count was > or = 100,000/microL. No cytokines were used during 1990-1994 (control group; n = 28), but G-CSF was used from 1995 to 1998 (G-CSF group; n = 30) at 5 microg/kg/day subcutaneously from 1 day after chemotherapy until the ANC was > or = 500/microL on 2 successive days or was > or = 1000/microL. RESULTS: Each cycle of CAV decreased ANCs to < 200/microL in all 58 patients; recovery to 200/microL and to 500/microL was significantly sooner with G-CSF. In contrast, P/VP did not invariably cause severe neutropenia: similar numbers of patients in each group maintained ANCs > or = 200/microL and > or = 500/microL; recovery to 500/microL (but not to 200/microL) was significantly faster in the G-CSF group. G-CSF had no impact on rates of febrile episodes. Bacterial/fungal infections were slightly less frequent in the G-CSF group with CAV (P = 0.11) but not with P/VP. Dose intensity through cycle 4 was the same in both groups. Beginning with cycle 3, G-CSF patients had slower recovery to platelet counts > or = 100,000/microL. Response rates were similar in the two groups. CONCLUSIONS: With multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy, prophylactic use of G-CSF hastened ANC recovery but did not reduce the incidence of febrile episodes, had little impact on infection rates, did not yield augmented dose intensity, was associated with prolonged thrombocytopenia, and had no effect on response rates of neuroblastoma. The data support more limited use of G-CSF.

Antineoplastic Agents, Alkylating↗
PubMed2000

Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin.

The stable introduction of a functional beta-globin gene in haematopoietic stem cells could be a powerful approach to treat beta-thalassaemia and sickle-cell disease. Genetic approaches aiming to increase normal beta-globin expression in the progeny of autologous haematopoietic stem cells might circumvent the limitations and risks of allogeneic cell transplants. However, low-level expression, position effects and transcriptional silencing hampered the effectiveness of viral transduction of the human beta-globin gene when it was linked to minimal regulatory sequences. Here we show that the use of recombinant lentiviruses enables efficient transfer and faithful integration of the human beta-globin gene together with large segments of its locus control region. In long-term recipients of unselected transduced bone marrow cells, tetramers of two murine alpha-globin and two human betaA-globin molecules account for up to 13% of total haemoglobin in mature red cells of normal mice. In beta-thalassaemic heterozygous mice higher percentages are obtained (17% to 24%), which are sufficient to ameliorate anaemia and red cell morphology. Such levels should be of therapeutic benefit in patients with severe defects in haemoglobin production.

Animals↗
PubMed2000

Induction of posterior vitreous detachment in rabbits by intravitreal injection of tissue plasminogen activator following cryopexy.

The purpose of this study was to generate intravitreal plasmin after intravitreal injection of tissue plasminogen activator (TPA) and cryopexy, and to assess its proteolytic effect on the vitreoretinal border region.Twenty-four hr after a mild cryopexy, 25 microg recombinant tissue plasminogen activator (TPA) was injected into the vitreous cavity, the fellow eye received an intravitreal injection of the same volume of buffered salt solution. Light, scanning and transmission electron microscopy was performed in 24 eyes that underwent vitrectomy 1 week later. Plasmin was measured prior and 2 hr after intravitreal TPA injection (4 eyes). Hyaluronic acid (8 eyes) and vitronectin (4 eyes) were measured 1 week after TPA- or BSS-injection and compared to untreated controls. In all eyes treated with TPA, histopathologic examination by scanning and transmission electron microscopy demonstrated a complete detachment of the vitreous from the surface of the retina as well as from the posterior surface of the lens. After BSS-injection, vitreous cortex attachment to the retina was demonstrated in all eyes. Two hr after TPA-injection, plasmin increased to 9.75 mU ml(-1)(s.d.+/-2.3). Neither a decrease of hyaluronic acid nor an increase of transglutaminase, that might alter the vitreous structure leading to a collapse of the vitreous, were detected in treated eyes. There was no increase of vitronectin indicating proliferative activity.A temporary breakdown of the blood-retinal barrier by cryopexy combined with intravitreal injection of TPA is a sufficient technique to induce a posterior vitreous detachment enzymatically. The method may be useful prior to mechanical vitrectomy.

Animals↗
PubMed2000

[C-reactive protein as an independent marker of prognosis in acute coronary syndrome: comparison with troponin T].

BACKGROUND: It has been suggested that inflammatory processes play a role in the pathogenesis of acute coronary syndromes (ACS). C-reactive protein (CRP) is a classic acute phase protein. It is yet unclear whether, in addition to established markers as troponin T (TnT), determination of CRP in patients admitted for ACS contributes significantly to the diagnosis and prognosis of ACS. PATIENTS AND METHODS: We investigated 50 patients with ACS (59.4 SD 13.9 years) in the first hour after admission and 4-24 h later with respect to TnT (Elecsys, Roche Diagnostics) and CRP (biokit, modified Quantex CRP plus, analytical sensitivity 0.02 mg/dL). Fifty percent of the patients were classified as having unstable angina retrospectively. All patients were followed in the 6 weeks post discharge regarding death and recurrent ACS. RESULTS: The cumulative event rate at 6 weeks after discharge was 62.5% for patients being CRP and TnT positive compared to 35.3% in TnT positive and CRP negative patients. In TnT negative patients a positive CRP test predicted 33.3% of events and 28.8% of patients negative for CRP and TnT had events at 42 days post discharge. Logistic regression analysis regarding the primary endpoint including TnT and CRP (4-24 h values), age, gender and diagnosis resulted in independent prediction of ACS or death by TnT (cutoff 0.1 microgram/L, p = 0.048, odds ratio = 7.5) and CRP (cutoff 0.862 mg/dL, p = 0.026, odds ratio = 5.3). Sensitivity/specificity for AMI diagnosis were 69.6%/75% for TnT and 12%/72% for CRP in the first hour and 91.3%/68.2% for TnT and 68%/72% for CRP 4-24 h later. CONCLUSIONS: Besides TnT, high sensitivity CRP determination has no additional value for early AMI diagnosis. The prognosis of these patients during the first 24 hours is significantly and independently predicted by CRP measurements in addition to troponin T.

Acute Disease↗
PubMed2000

The acute coronary syndrome diagnosis and prognostic evaluation by troponin I is influenced by the test system affinity to different troponin complexes.

It was suggested recently that cardiac troponins are released as T-I-C complexes and then further degraded to T and I-C. It is not known whether the various affinity to the T-I-C and I-C complex of different troponin I test systems influence the diagnostic and prognostic value of the test results in clinical practice. We studied 162 patients (61.3 S.D. 11.1 years) with suspected acute myocardial infarction (AMI) in a single center study. AMI was confirmed in 109 patients. Blood samples were taken at admission, after 1, 2, 4, 8, 12 and 24 h. Troponin I (TnI) was measured using the OPUS plus (TnI-O, cut-off 1.6 microg/l) and the Stratus II (TnI-S, cut-off 1.5 microg/l) analyzers. TnI-O has high affinity to the binary (I-C) and TnI-S to the ternary (T-I-C) troponin complex. A 6-month follow-up with respect to death and recurrent AMI was performed. The sensitivity (SE) and specificity (SP) for AMI diagnosis were 82.6 and 86.8% for TnI-S; 75.2 and 92.5% for TnI-O 0-2 h after admission. The ROC analysis showed a slightly better curve for TnI-S at 4 h (P<0.05). Logistic regression analysis shows prediction of 6 months outcome by 0-24 h serial TnI-S measurements (odds ratio 5.21, P=0.0356), and serial TnI-O measurements (odds ratio 4.92, P=0.0186). High affinity to the ternary troponin complex enhances the diagnostic but not the prognostic value of a test system. Indeed, the resulting differences are small but underline the need for standardization of biochemical markers.

Acute Disease↗
PubMed2000

The phase II/III transition. Toward the proof of efficacy in cancer clinical trials.

Few phase III investigations show a benefit for an experimental treatment when compared to a standard therapy or placebo. This illustrates the need for more reliable estimates of treatment effects from the phase II investigations used to design the more definitive phase III trials. In this manuscript, we examine four aspects of phase II clinical trial designs: (1) selecting endpoints; (2) defining the patient population for evaluation; (3) determining a level of activity that would justify a phase III trial; and (4) estimating sample sizes. In each area, problems with the conventional approaches are discussed and alternatives for the successful transition of phase II results to a phase III setting are suggested. An application of the design for patients with androgen-independent prostate cancer is illustrated.

Antineoplastic Agents↗
PubMed2000

Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p.

Deletion of the short arm of chromosome 1 is frequently observed in neuroblastoma (NB). We performed loss of heterozygosity (LOH) analysis of 120 well characterized NB to better define specific regions of 1p loss and any association with clinical and biological prognostic features (DNA index, MYCN, age, and stage). All categories of disease were represented including 7 ganglioneuromas, 8 stage 4S, 33 local-regional (stages 1, 2, and 3), and 72 stage 4 NB according to the International Neuroblastoma Staging System. Patients were consistently treated with stage-appropriate protocols at a single institution. Sixteen highly informative, polymorphic loci mapping to chromosome 1 were evaluated using a sensitive, semi-automated, fluorescent detection system. Chromosome arm 1p deletions were detected in all categories of tumor except ganglioneuroma. Frequent LOH was detected at two separate regions of 1p and distinct patterns of losses were associated with individual clinical/biological categories. Clinically aggressive stage 4 tumors were predominantly diploid with extensive LOH frequently detected in the region of 1ptel to 1p35 (55%) and at 1p22 (56%). The shortest region of overlap for LOH at 1p36 was between D1S548 and D1S1592 and for 1p22 was between D1S1618 and D1S2766. Local-regional tumors were mostly hyperdiploid with short regions of loss primarily involving terminal regions of 1p36 (42%). Most spontaneously regressing stage 4S tumors (7/8) were hyperdiploid without loss of 1p36 or 1p22. These findings suggest that genes located on at least two separate regions of chromosome arm 1p play a significant role in the biology of NB and that distinct patterns of 1p LOH occur in individual clinical/biological categories.

Alleles↗
PubMed2000

[Management concept for acute traumatic aortic rupture based on a case report].

Acute traumatic rupture of the thoracic aorta (ATRRA) is mainly a consequence of high-speed travel or fall from great altitude. Most of the victims die at the accident scene. Only 10-20% reach the hospital alive. Because of the extremely high mortality, emergency repair seems to be indicated. Taking into consideration that the hemorrhage into the mediastinum may remain constained and the patient usually suffers from a wide variety of life-threatening causes of injury the aforementioned option is probably not the best one. We report on a patient whose "stable" aortic rupture was surgically corrected after stablization of the circulation, coagulation and respiratory problems.

Aortic Rupture↗
PubMed2000

Quantitative effect of intravitreally injected tissue plasminogen activator and gas on subretinal hemorrhage.

PURPOSE: To quantify the effect of intravitreally injected tissue plasminogen activator (TPA) and an expanding gas on freshly formed subretinal hemorrhage (SRH). PATIENTS AND METHODS: Thirteen patients with acute (1 week or less) SRH due to age-related macular degeneration (ARMD) were treated with an intravitreal injection of 50 microg TPA, and 24 hours later, with an expanding gas. Fundus photographs taken before and 24 hours after each injection were digitized and calibrated. Area, geometric center, and shift of the SRH were measured at each time point using NIH image analysis software. Elevation of the SRH was assessed by echography. RESULTS: Compared to the preoperative size, SRH enlarged significantly 24 hours after TPA injection (P < 0.001). A significant shift of the geometric center toward the inferior retinal periphery out of the macula was found after gas injection (P < 0.001). Significant horizontal displacement of the SRH was not noted after TPA or gas injection. More elevated subretinal blood clots showed a larger increase in size after TPA injection than flat clots (P < 0.05). CONCLUSION: Enlargement of SRH in a gravity-dependent manner indicates subretinal liquefaction of the clot after TPA treatment. An intravitreal injection of gas 24 hours later can significantly displace the SRH inferiorly.

Acute Disease↗
PubMed2000

Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide.

PURPOSE: Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena. PATIENTS AND METHODS: Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg. RESULTS: Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/microL (range, 1,200 to 72,300 cells/microL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/microL; range, 500 to 5,400 cells/microL; P =.01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P <.001), and no patient without a peak leukocyte count greater than 10,000 cells/microL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P =.37). CONCLUSION: Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.

Antineoplastic Agents↗