Comparison of left ventricular performance in healthy young women and men during exercise

Background

Previous studies show sex-related differences in left ventricular (LV) response to exercise. It is not clear, however, whether these differences are also seen in younger healthy subjects.

Methods and Results

This study examined the changes in LV performance during dynamic upright exercise in 11 healthy men and 19 healthy young women according to the Bruce protocol and an individualized ramp protocol. There were no significant differences between the two protocols for either men or women in heart rate, blood pressure, LV ejection fraction (EF) (measured by ambulatory nuclear detector), and measured oxygen consumption. The peak oxygen consumption was higher in men than in women (44±13 vs 36±9 ml/kg/min; p<0.05), but the peak heart rate, systolic blood pressure, and EF were similar. The change in EF (from rest to exercise) was 19%±8% in men and 19%±11% in women with the Bruce protocol (difference not significant) and 26%±9% in men and 19%±6% in women with the ramp protocol (difference not significant). At peak exercise, both men and women showed an increase in end-diastolic volume (29%±14% vs 23%±11%; difference not significant) and a decrease in end-systolic volume (41%±15% vs 43%±21%) (difference not significant). The increase in cardiac output during exercise was due to an increase in heart rate and stroke volume in both men and women. At submaximal exercise, however, the decrease in end-systolic volume was less in women than in men (p<0.05).

Conclusions

There are no sex-related differences in compensatory mechanism during dynamic execise in healthy subjects. The changes in contractility and LV volume are not affected by the exercise protocol.     

Outcomes of a randomized trial of hyperfractionated cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic efficacy and neurotoxicity.

PURPOSE: We evaluated 8-year survival and late neuropsychologic toxicity in children with acute lymphoblastic leukemia treated in a randomized clinical trial to test whether hyperfractionated (twice daily) cranial radiation therapy (CRT) can reduce incidence and severity of late toxicities associated with 18 Gy of CRT. PATIENTS AND METHODS: Between 1987 and 1995, 369 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for high-risk acute lymphoblastic leukemia were randomly assigned to conventionally fractionated CRT (CFX) or hyperfractionated CRT (HFX) to a total dose of 18 Gy. Neuropsychologic testing was completed for 125 of 287 children in continuous complete remission. Event-free and overall survival, as well as neuropsychologic function, were compared for the two arms of the protocol. RESULTS: Eight-year event-free survival (+/- SE) was 80% +/- 3% for children randomly assigned to CFX and 72% +/- 3% for HFX (P =.06). Overall survival was 85% +/- 3% for CFX and 78% +/- 3% for HFX (P =.06). CNS relapses occurred in 2.8% of patients receiving CFX and 2.7% receiving HFX (P =.99). Cognitive function for both groups was solidly in the average range, with no group differences in intelligence, academic achievement, visuospatial reasoning, or verbal learning. Children on the HFX arm exhibited a modest advantage for visual memory (P <.05). CONCLUSION: HFX provides no benefit in terms of cognitive late effects and may compromise antileukemic efficacy. HFX should not be substituted for conventionally dosed CRT in children who require radiation therapy for treatment of acute lymphoblastic leukemia.     

Video-fluoroscopic study of swallowing in children with neurodevelopmental disorders

BACKGROUND: Children with neurodevelopmental disorders can have feeding problems. Malnutrition and recurrent aspiration pneumonia can increase the risk of morbidity and mortality. Video-fluoroscopic study of swallowing (VFSS) is essential in understanding the pathological mechanisms involved during swallowing. METHODS: The aim of the present study was to assess the role of VFSS in assessment and management of four children with various neurodevelopmental disorders in a multidisciplinary feeding team. We describe the team approach, with the participation of child neurologist, radiologist with the rehabilitation team including the speech therapist, occupational therapist and dietician, in the assessment and plan of management. RESULTS: Video-fluoroscopic study of swallowing had been useful in assessing the type of swallowing problems with treatment goals targeted to the basic underlying pathophysiological mechanism. CONCLUSION: A child neurologist should be involved in the multidisciplinary oromotor rehabilitation program for neurologically impaired children with feeding problems.     

A phase I clinical, pharmacologic, and biologic study of thrombopoietin and granulocyte colony-stimulating factor in children receiving ifosfamide, carboplatin, and etoposide chemotherapy for recurrent or refractory solid tumors: a Children's Oncology Group experience.

PURPOSE: Ifosfamide, carboplatin, and etoposide (ICE) are associated with grade III/IV dose-limiting thrombocytopenia. The Children's Oncology Group conducted a phase I dose escalation, pharmacokinetic, and biological study of recombinant human thrombopoietin (rhTPO) after ICE in children with recurrent/refractory solid tumors (CCG-09717) to assess the toxicity and maximum tolerated dose of rhTPO administered at 1.2, 2.4, or 3.6 microg/kg per dose. EXPERIMENTAL DESIGN: Children received ifosfamide 1,800 mg/m2 on days 0 to 4, carboplatin 400 mg/m2 on days 0 to 1, and etoposide 100 mg/m2 on days 0 to 4. rhTPO was administered i.v. on days +4, +6, +8, +10, and +12 at 1.2, 2.4, or 3.6 microg/kg per dose.RESULTS: rhTPO was well tolerated and maximum tolerated dose was not reached. Median time to platelet recovery > or =100,000/microL of rhTPO at 1.2, 2.4, and 3.6 microg/kg/d was 24 days (22-24 d), 25 days (23-29 d), and 22 days (16-37 d), respectively. Patients required a median of 2 days of platelet transfusions (0-7 days). Mean (+/- SD) rhTPO maximum serum concentrations were 63.3 +/- 9.7 and 89.3 +/- 15.7 ng/mL and terminal half-lives were 47 +/- 13 and 64 +/- 42 hours after 2.4 and 3.6 microg/kg/d, respectively. There was a significant increase in colony-forming unit megakaryocyte upon WBC count recovery. CONCLUSIONS: rhTPO was well tolerated. Time to hematologic recovery and median number of platelet transfusions seem to be improved compared with historical controls receiving ICE + granulocyte colony-stimulating factor (CCG-0894).     

Mapping molecular networks using proteomics: a vision for patient-tailored combination therapy.

Mapping tumor cell protein networks in vivo will be critical for realizing the promise of patient-tailored molecular therapy. Cancer can be defined as a dysregulation or hyperactivity in the network of intracellular and extracellular signaling cascades. These protein signaling circuits are the ultimate targets of molecular therapy. Each patient's tumor may be driven by a distinct series of molecular pathogenic defects. Thus, for any single molecular targeted therapy, only a subset of cancer patients may respond. Individualization of therapy, which tailors a therapeutic regimen to a tumor molecular portrait, may be the solution to this dilemma. Until recently, the field lacked the technology for molecular profiling at the genomic and proteomic level. Emerging proteomic technology, used concomitantly with genomic analysis, promises to meet this need and bring to reality the clinical adoption of molecular stratification. The activation state of kinase-driven signal networks contains important information relative to cancer pathogenesis and therapeutic target selection. Proteomic technology offers a means to quantify the state of kinase pathways, and provides post-translational phosphorylation data not obtainable by gene arrays. Case studies using clinical research specimens are provided to show the feasibility of generating the critical information needed to individualize therapy. Such technology can reveal potential new pathway interconnections, including differences between primary and metastatic lesions. We provide a vision for individualized combinatorial therapy based on proteomic mapping of phosphorylation end points in clinical tissue material.     

The selective serotonin-2A receptor antagonist M100907 reverses behavioral deficits in dopamine transporter knockout mice.

A hyperdopaminergic state in humans has been hypothesized to contribute to the pathology of a number of psychiatric illnesses, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Mice that display elevated synaptic levels of dopamine due to a genetically engineered deletion of the dopamine transporter (DAT) model behavioral deficits that simulate the above conditions. As novel treatment strategies for these disorders have focused on the serotonin (5-HT) 2A receptor, we determined the capacity of the highly selective 5-HT(2A) receptor antagonist M100907 to reverse behavioral deficits in DAT knockout (KO) mice. Prior to drug treatment, DAT KO mice exhibited increased levels of locomotor activity and highly linearized movement in a novel environment, as well as reduced prepulse inhibition (PPI) of acoustic startle, compared to wild-type littermates. Treatment with M100907 (0.3-1.0 mg/kg, but not 0.1 mg/kg) reversed locomotor deficits in DAT KO mice. Similarly, treatment with 1.0 mg/kg M100907 reversed the PPI deficits in DAT KO mice. These data indicate that selective 5-HT(2A) receptor antagonists, such as M100907, may represent a class of drugs that can be used to treat conditions in which a chronic, elevated dopaminergic tone is present and contributes to abnormal behavior and sensorimotor gating deficits.     

Molecular cloning of the guinea pig CYP1A2 gene 5'-flanking region: identification of functional aromatic hydrocarbon response element and characterization of CYP1A2 expression in GPC16 cells.

Aromatic hydrocarbon (AH) effects are mediated by binding of the AH receptor and its heterodimeric partner aromatic hydrocarbon nuclear translocator to specific response elements on DNA (AHREs). CYP1A2 expression is induced by AHs, yet AHREs have been identified in CYP1A2 genes of only two species and their functional role assessed only in the human gene. There have been few analyses of CYP1A2 gene regulation in nonhepatic cells. To gain further insight into CYP1A2 regulation, we cloned the initial 1.2 kilobases (kb) of the guinea pig CYP1A2 gene 5'-flanking region and characterized CYP1A2 expression in guinea pig colon adenocarcinoma cells (GPC16). Two putative AHRE sites were identified (-830 and -575 bp). They are considerably more proximal than the functional AHRE found in the human CYP1A2 gene (-2.5 kb). GPC16 cells expressed CYP1A2 after treatment with AH, enabling characterization of the putative AHRE sites in a homologous cell line. Double-stranded oligonucleotide probes, corresponding to each putative AHRE, bound in an AH-induced and specific manner to nuclear proteins prepared from GPC16 cells. In transfection analyses, only the distal site mediated AH-induced reporter gene activity. Mutation of this site suppressed AH-induced activity, supporting the concept that it is involved in AH-mediated induction of CYP1A2. However, the low level of AH-induction by the wild type suggests that other factors modulate AH-response by the CYP1A2 gene.