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Biomedical subjects

J A Adams

Publications and source records attributed to J A Adams.

At least 19 recordsLinked to original sources
PubMed2006

Effect of gemtuzumab ozogamicin on acute myeloid leukemia blast cells in vitro, as a single agent and combined with other cytotoxic cells.

The effect of gemtuzumab ozogamicin (GO) alone, or combined with low-dose cytarabine or etoposide, on the proliferation of acute myeloid leukaemia blast cells in vitro was investigated. GO alone induced a dose-dependent inhibition of proliferation although an increase in apoptosis was only seen in a minority of patients. A correlation was found between PgP function and GO sensitivity but not between CD33 or PgP expression and GO. Combinations of GO with varying concentrations of cytarabine or etoposide were additive in inhibiting proliferation, reducing cell viability and increasing apoptosis.

Acute Disease↗
PubMed2004

Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma.

PURPOSE: To compare treatment plans from standard photon therapy to intensity modulated X-rays (IMRT) and protons for craniospinal axis irradiation and posterior fossa boost in a patient with medulloblastoma. METHODS: Proton planning was accomplished using an in-house 3D planning system. IMRT plans were developed using the KonRad treatment planning system with 6-MV photons. RESULTS: Substantial normal-tissue dose sparing was realized with IMRT and proton treatment of the posterior fossa and spinal column. For example, the dose to 90% of the cochlea was reduced from 101.2% of the prescribed posterior fossa boost dose from conventional X-rays to 33.4% and 2.4% from IMRT and protons, respectively. Dose to 50% of the heart volume was reduced from 72.2% for conventional X-rays to 29.5% for IMRT and 0.5% for protons. Long-term toxicity with emphasis on hearing and endocrine and cardiac function should be substantially improved secondary to nontarget tissue sparing achieved with protons. CONCLUSION: The present study clearly demonstrates the advantage of conformal radiation methods for the treatment of posterior fossa and spinal column in children with medulloblastoma, when compared to conventional X-rays. Of the two conformal treatment methods evaluated, protons were found to be superior to IMRT.

Cerebellar Neoplasms↗
PubMed2003

Normal studies are essential for objective medical evaluations of children who may have been sexually abused.

UNLABELLED: The findings of carefully conducted research studies of non-abused children should be used in medical evaluations for suspected sexual abuse if they are to be legally defensible. These studies have shown that a "wide" hymenal opening and a "narrow" rim of hymen should not be used as markers of abuse. CONCLUSION: The study by Myhre and associates is another addition to a growing collection of good science in a field of medicine where objectivity is essential.

Child↗
PubMed2001

Nucleotide release and associated conformational changes regulate function in the COOH-terminal Src kinase, Csk.

The COOH-terminal Src kinase (Csk) regulates a broad array of cellular processes via the specific phosphorylation and downregulation of Src family protein kinases. While Csk has been a topic for steady-state kinetic studies, the individual steps associated with substrate phosphorylation have not been investigated. To understand active-site phenomena, pre-steady-state and transient-state kinetic methods were applied to develop a catalytic pathway for substrate processing. Rapid quench flow techniques show that the phosphorylation of a substrate peptide, generated from a random library, occurs in two kinetic phases: a rapid, exponential "burst" phase followed by a slow, linear phase. The amplitude of the burst phase increases as a function of enzyme concentration, indicating that the biphasic kinetics are not the result of product inhibition. Analysis of the burst rate as a function of substrate concentration indicates that the phosphoryl transfer step is fast (k3 > or = 140 s(-1) and highly favorable (k3/k-3 > or = 6). The apparent dissociation rate constant for ADP (0.6 s(-1), measured using stopped-flow kinetic methods and a fluorescent trapping agent, mant-ATP, is close to kcat. Since the substrate dissociation constant is high, the release of phosphopeptide is not likely to limit turnover. These findings indicate that Csk rapidly delivers the gamma-phosphate of ATP to the substrate and rapidly releases the phosphoproduct. Overall rate limitation in the steady state is then attributed to the slow, net dissociation of ADP. Viscosometric studies suggest that this final event in the catalytic cycle is coupled with slow conformational changes.

Adenine Nucleotides↗
PubMed2001

Electrostatic environment surrounding the activation loop phosphotyrosine in the oncoprotein v-Fps.

Autophosphorylation of Tyr-1073 in the activation loop of the oncoprotein v-Fps enhances the phosphoryl transfer reaction without influencing substrate, ATP, or metal ion binding affinities [Saylor, P., et al. (1998) Biochemistry 37, 17875-17881]. A structural model of v-Fps, generated from the insulin receptor, indicates that pTyr-1073 chelates two arginines. Mutation of these residues to alanine (R1042A and R1066A) results in weakly phosphorylated enzymes, indicating that one electropositive center is insufficient for attaining maximum loop phosphorylation and concomitant high catalytic activity. While the turnover rate for R1066A is similar to that for a mutant lacking a phosphorylatable residue in the activation loop, the rate for R1042A is 50-fold slower. While solvent perturbation studies suggest that the former is due to a slow phosphoryl transfer step, the latter effect results from a slow conformational change in the mutant, potentially linked to motions in the catalytic loop. Binding of a stoichiometric quantity of Mg(2+) is essential for ATP binding and catalysis, while binding of an additional Mg(2+) ion activates further the wild-type enzyme. The affinity of the R1066A enzyme for the second Mg(2+) ion is 23-fold higher than that of the phosphorylated or unphosphorylated form of wild-type v-Fps, with substrate binding unaffected. Conversely, the affinity of R1066A for a substrate mimic lacking a phosphorylation site is 12-fold higher than that for the phosphorylated or unphosphorylated form of wild-type v-Fps, with binding of the second Mg(2+) ion unaffected. A comparison of these enzyme-independent parameters indicates that Arg-1042 and Arg-1066 induce strain in the active site in the repressed form of the enzyme. While this strain is not relieved in the phosphorylated form, the improvements in catalysis in activated v-Fps compensate for reduced metal and substrate binding affinities.

Adenosine Triphosphate↗
PubMed2001

Stimulation of autologous proliferative and cytotoxic T-cell responses by "leukemic dendritic cells" derived from blast cells in acute myeloid leukemia.

Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor alpha, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

Acute Disease↗
PubMed2001

Hypothalamic/pituitary function following high-dose conformal radiotherapy to the base of skull: demonstration of a dose-effect relationship using dose-volume histogram analysis.

PURPOSE: To evaluate the incidence and pattern of hypopituitarism from hypothalamic (HT) and pituitary gland (PG) damage following high-dose conformal fractionated proton-photon beam radiotherapy (PPRT) to the base of skull (BOS) region in adults. The relationship between dose, volume, and PG function is explored. METHODS AND MATERIALS: Between May 1982 to October 1997, 107 adults with non-PG and non-HT neoplasms (predominantly chordoma and chondrosarcomas) of the BOS were treated with PPRT after subtotal resection(s). The median age was 41.2 years (range, 17-75) with 58 males and 49 females. Median prescribed target dose was 68.4 cobalt gray equivalent (CGE) (range, 55.8-79 CGE) at 1.80-1.92 CGE per fraction per day (where CGE = proton Gy x 1.1). The HT and PG were outlined on planning CT scans to allow dose-volume histograms (DVH) analysis. All patients had baseline and follow-up clinical testing of anterior and posterior pituitary function including biochemical assessment of thyroid, adrenal, and gonadal function, and prolactin secretion. RESULTS: The 10-year actuarial overall survival rate was 87%, with median endocrine follow-up time of 5.5 years, thus the majority of patients were available for long-term follow-up. Five-year actuarial rates of endocrinopathy were as follows: 72% for hyperprolactinemia, 30% for hypothyroidism, 29% for hypogonadism, and 19% for hypoadrenalism. The respective 10-year endocrinopathy rates were 84%, 63%, 36%, and 28%. No patient developed diabetes insipidus (vasopressin deficiency). Growth hormone deficiency was not routinely followed in this study. Minimum target dose (Dmin) to the PG was found to be predictive of endocrinopathy: patients receiving 50 CGE or greater at Dmin to the PG experiencing a higher incidence and severity (defined as the number of endocrinopathies occurring per patient) of endocrine dysfunction. Dmax of 70 CGE or greater to the PG and Dmax of 50 CGE or greater to the HT were also predictive of higher rates of endocrine dysfunction. CONCLUSION: Radiation-induced damage to the HT & PG occurs frequently after high-dose PPRT to the BOS and is manifested by anterior pituitary gland dysfunction. Hyperprolactinemia was detected in the majority of patients. Posterior pituitary dysfunction, represented by vasopressin activity with diabetes insipidus, was not observed in this dose range. Limiting the dose to the HT and PG when feasible should reduce the risk of developing clinical hypopituitarism.

Adolescent↗
PubMed2001

Structural characterization of protein kinase A as a function of nucleotide binding. Hydrogen-deuterium exchange studies using matrix-assisted laser desorption ionization-time of flight mass spectrometry detection.

Transient state kinetic studies indicate that substrate phosphorylation in protein kinase A is partially rate-limited by conformational changes, some of which may be associated with nucleotide binding (Shaffer, J., and Adams, J. A. (1999) Biochemistry 38, 12072-12079). To assess whether specific structural changes are associated with the binding of nucleotides, hydrogen-deuterium exchange experiments were performed on the enzyme in the absence and presence of ADP. Four regions of the protein are protected from exchange in the presence of ADP. Two regions encompass the catalytic and glycine-rich loops and are integral parts of the active site. Conversely, protection of probes in the C terminus is consistent with nucleotide-induced domain closure. One protected probe encompasses a portion of helix C, a secondary structural element that does not make any direct contacts with the nucleotide but has been reported to undergo segmental motion upon the activation of some protein kinases. The combined data suggest that binding of the nucleotide has distal structural effects that may include stabilizing the closed state of the enzyme and altering the position of a critical helix outside the active site. The latter represents the first evidence that the nucleotide alone can induce changes in helix C in solution.

Adenosine Diphosphate↗
PubMed2001

Novel CPR with periodic Gz acceleration.

The effects of periodic Gz acceleration (pGz) on cardiovascular function and hemodynamics were determined in a pig model of acute cardiopulmonary resuscitation (CPR). The application of pGz (horizontal head-to-foot oscillations) at 2 Hz increased cardiac output in fibrillated animals proportional to the amplitude of the applied acceleration force that plateaued at 0.7 G. Cardiac output in fibrillating animals was restored to 20% of the values obtained before fibrillation with pGz-CPR and arterial blood gas values were normal during this period. The central vascular pressure gradient driving blood flow was only about 6 mmHg, suggesting low vascular resistance during pGz-CPR. In another study, capillary blood flow was determined before and after pGz-CPR using colored microspheres. Capillary perfusion was detected in all tissue beds studied during pGz-CPR. Significant capillary blood flow was detected in the endocardium and brain stem during pGz-CPR that represented 39 and 197% of control values before fibrillation, respectively. Thus, the cardiac output during pGz-CPR was preferentially distributed to the myocardial and brain tissues. In a final group, animals were successfully resuscitated with return of spontaneous circulation (ROSC) after pGz-CPR for 15 min following cardiac fibrillation with a 3-min non-intervention period. Following ROSC, blood pressure was maintained at pre-arrest values for 2 h without any pharmacological or mechanical support. Arterial blood gases during the pGz-CPR and the ROSC periods were normal and not different from values obtained before fibrillation. None of the control animals (18 min of fibrillation without pGz-CPR) survived the experimental protocol and only two of these six animals briefly returned to spontaneous circulation (<20 min). In conclusion, experimental pGz-CPR produces cardiac output, capillary blood flow, and ventilation sufficient to maintain fibrillating animals for 18 min with ROSC for 2 h without support.

Acceleration↗
PubMed2001

Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis.

Sympathetic neuronal death induced by nerve growth factor (NGF) deprivation requires the macromolecular synthesis-dependent translocation of BAX from the cytosol to mitochondria and its subsequent integration into the mitochondrial outer membrane, followed by BAX-mediated cytochrome c (cyt c) release. The gene products triggering this process remain unknown. Here, we report that BIM, a member of the BH3-only proapoptotic subfamily of the BCL-2 protein family, is one such molecule. NGF withdrawal induced expression of BIM(EL), an integral mitochondrial membrane protein that functions upstream of (or in parallel with) the BAX/BCL-2 and caspase checkpoints. Bim deletion conferred protection against developmental and induced neuronal apoptosis in both central and peripheral populations, but only transiently, suggesting that BIM--and perhaps other BH3-only proteins--serve partially redundant functions upstream of BAX-mediated cyt c release.

Alternative Splicing↗
PubMed2001

Adolescent sexual assault: documentation of acute injuries using photo-colposcopy.

OBJECTIVE: To document the frequency and types of genital injuries in adolescent women examined acutely following a sexual assault, and determine any historical correlates of injury. DESIGN: Retrospective chart review. SETTING: Sexual Assault Response Team services at a community hospital in an urban setting. PATIENTS: All female patients aged 14-19 yr who were referred by law enforcement for an acute sexual assault examination and were examined between May 1994 and May 1999. OUTCOME MEASURES: The frequency of signs of genital trauma at various anal and genital sites, as recorded by the examining clinician. RESULTS: Charts of 214 female subjects (mean age 16.3 yr) were reviewed. The most common findings were posterior fourchette tear (36%); erythema of the labia minora, hymen, cervix, or posterior fourchette (18%-32%); and swelling of the hymen (19%). Time to examination was highly correlated with the degree of injury noted (P =.000). The incidence of hymenal tears in self-described virgins was higher than in nonvirgins (19% vs. 3%, P =.008); however, the total number or severity of other injuries was not significantly higher in virgins. Victims reporting anal penetration had a higher frequency of anal injuries than those who denied such contact (14/31, 61% vs. 2/150, 1%; P =.000). CONCLUSIONS: Tears of the posterior fourchette or fossa were the most common findings (40%). Hymenal tears were uncommon, even in self-described virginal girls. Timely examination of adolescent victims is important to document injuries; however, many victims will still not have signs of bruising, abrasions, or tears.

Adolescent↗
PubMed2001

Comparison of megakaryopoiesis in vitro of paired peripheral blood progenitor cells and bone marrow harvested during remission in patients with acute myeloid leukaemia.

We have studied paired peripheral blood progenitor cells (PBPC) and bone marrow (BM) samples from 12 acute myeloid leukaemia (AML) patients following intensive chemotherapy, and assessed direct granulocyte-macrophage colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), megakaryocyte CFU (CFU-Mk) numbers and the production of CD61+ (platelet glycoprotein IIIa) cells in suspension culture in response to various haemopoietic growth factor combinations. We found that CFU-GM and BFU-E numbers per 105 mononuclear cells were similar in both AML PBPC and BM harvests; CFU-Mk numbers, however, were significantly higher in PBPC than BM. In addition, the higher total white cell count of the PBPC harvests meant that PBPC have much higher numbers of total progenitors per collection. CD61+ cell numbers in suspension cultures of AML PBPC and BM were lower than those of harvested normal marrow. However, response to pegylated recombinant human megakaryocyte growth and development factor (PEGrHuMGDF) both alone and in combination with other growth factors was qualitatively similar to that of normal BM. As with normal BM, response to PEGrHuMGDF alone did not increase further with addition of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin 6 (IL-6) or erythropoietin (EPO) in the AML PBPC and BM. Further responses over PEGrHuMGDF alone were seen when added with stem cell factor (SCF) or with a combination of SCF + IL-3 + EPO in both AML PBPC and BM cultures; however, the magnitude of the response was greater in the PBPC cultures. Response to PEGrHuMGDF + IL-3 was seen in the PBPC cultures but not in the AML BM. These data suggest that, in AML patients, there are proportionally more megakaryocyte progenitor cells in the mobilized PBPC than in the BM harvests, which would explain the more rapid platelet recovery following PBPC autografts.

Acute Disease↗
PubMed2001

Regional blood flow during periodic acceleration.

OBJECTIVE: To determine whether a motion platform that imparts noninvasive periodic acceleration (pGz) forces to the body causes systemic vasodilation and changes local organ blood flow. DESIGN: Prospective paired blocked design. SETTING: Medical center research laboratory. SUBJECTS: Juvenile Yorkshire pigs. INTERVENTIONS: Juvenile pigs (12 kg) were anesthetized, paralyzed, and placed on a motion platform that oscillated at a frequency of 4 Hz and a force of approximately 0.4 G. MEASUREMENTS AND MAIN RESULTS: Regional blood flows, as assessed by colored microspheres, increased during pGz relative to values obtained before pGz. Blood flow (mL.min-1.100 g-1) significantly increased to the epicardium (71%), endocardium (93%), cerebrum (183%), brain stem (177%), renal cortex (53%), ileal mucosa (69%), gastric antral mucosa (72%), and liver (86%). Spleen and skeletal muscle blood flow increased without statistical significance, 38% and 158% with pGz, relative to paired control values. Regional blood flows returned to baseline 10 mins after discontinuation of pGz, except in the myocardial layers, where blood flow remained significantly elevated. There was no difference compared with baseline in heart rate, arterial blood gases, and blood pressure, but serum nitrite concentration was significantly higher (58%) during pGz. In another series of animals, pGz increased pulmonary artery blood flow directly proportional to the magnitude of the applied acceleration force with frequency held constant. CONCLUSIONS: Periodic sinusoidal inertial forces in the spinal axis increase blood flow to tissues. The increased blood flow is reversible and may be caused by vasodilation secondary to local mediator release. These effects may be desirable in clinical conditions of low tissue oxygen delivery and perfusion.

Acceleration↗
PubMed2001

Evolution of a classification scale: medical evaluation of suspected child sexual abuse.

This article presents a revision of a system for classifying examination findings, laboratory findings, and children's statements and behaviors as to their possible relationship to sexual abuse. The revisions are based on published research studies and current recommendations from the American Academy of Pediatrics Committee on Child Abuse and Neglect, and the American Professional Society on the Abuse of Children. Part 1 of the classification system lists genital and anal findings that can be considered normal or nonrelated to abuse, nonspecific for abuse, concerning for abuse, and clear evidence of blunt force or penetrating trauma. Under Part 2, the overall classification of the likelihood of abuse is broken into four categories: no evidence of abuse, possible abuse, probable abuse, and definite evidence of abuse or penetrating trauma. Cautions in the use of the classification system, as well as controversies concerning a few medical findings, are discussed.

Anal Canal↗
PubMed2000

Catalytic assessment of the glycine-rich loop of the v-Fps oncoprotein using site-directed mutagenesis.

The three glycine residues in the glycine-rich loop of the oncoprotein, v-Fps, were mutated to determine the function of these highly conserved residues in catalysis. The kinase domains of six mutants (G928A,S, G930A,S, and G933A,S) and the wild-type enzyme were expressed and purified as fusion proteins of glutathione-S-transferase in Escherichia coli, and their catalytic properties were assessed using steady-state kinetic, inhibition, viscosity and autophosphorylation studies. Although both G928A and G930A had no detectable activity toward the substrate peptide (EAEIYEAIE), the other mutants had apparent, but varying activities. G930S lowered the rate of phosphoryl transfer by 130-fold while G928S and G933S had smaller (6-9-fold) reductions in this step. These effects on catalytic function parallel the reductions in turnover and autophosphorylation but, for G933S and G933A, net product release is still rate limiting at saturating substrate and ATP concentrations. On the basis of K(I) measurements, the effects on turnover for these mutants may be due to improved ADP affinity. While ADP affinity is reduced 2- and 3-fold for G928S and G930S, the affinity of this product is increased by 22- and 7-fold for G933S and G933A. In contrast, ATP affinity is enhanced by 5-fold for G928S and G933S and is reduced by less than 2-fold for G930S. These complex, differential effects on nucleotide binding indicate that the glycines influence the relative affinities of ADP and ATP. On the basis of the results of serine replacements, Gly-928 and Gly-930 enhance ADP affinity by 9- and 2-fold compared to ATP affinity whereas Gly-933 diminishes ADP affinity by approximately 4-fold compared to ATP affinity. These findings demonstrate that the functions of the loop lie not only in modulating the rate of the phosphoryl transfer step but also in balancing the relative affinities of ATP and ADP. These effects on nucleotide specificity may be a contributing element for the stabilization of the phosphoryl transition state and may also facilitate quick release of bound products.

Adenosine Diphosphate↗