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Biomedical subjects

J L Harper

Publications and source records attributed to J L Harper.

18 recordsLinked to original sources
PubMed2000

Effect of calmidazolium analogs on calcium influx in HL-60 cells.

The structure-activity relationships of calmidazolium analogs with respect to intracellular calcium levels were investigated in HL-60 cells. Quaternized derivatives of miconazole and clotrimazole, known inhibitors of store-operated calcium (SOC) channels, were synthesized. The quaternary N-methyl derivatives of miconazole (3) and clotrimazole (6) had no effect on intracellular calcium levels, alone or after elevation of calcium induced by ATP. Calmidazolium alone induced a large increase in intracellular calcium levels in HL-60 cells (EC(50) 3 microM). Similar effects were observed for miconazole derivatives 1 (EC(50) 15 microM) and 2 (EC(50) 10 microM), wherein the diphenylmethyl group in calmidazolium was replaced by a 3,5-difluorobenzyl or cyclohexylmethyl group, respectively. The analogous clotrimazole derivatives 4 and 5 had no effect on intracellular calcium levels. The elevation of calcium levels by calmidazolium, 1, and 2 appears to be comprised of a calcium release component from inositol trisphosphate (IP(3))-sensitive stores followed by a large calcium influx component. Calcium influx was greater than that normally observed due to depletion of IP(3)-sensitive calcium stores and activation of SOC channels. In addition, only a small component of the calmidazolium-elicited influx was inhibited by the SOC channel blocker miconazole. Thus, certain quaternized imidazoles substituted with large residues at both nitrogens of the imidazole ring caused both release and influx of calcium, the latter in part through SOC channels but mainly through an undefined cationic channel. Quaternized imidazoles, unlike the parent nonquaternary imidazole miconazole, did not block SOC channels. Inhibitory effects on calmodulin-activated phosphodiesterase did not correlate with effects on calcium release and influx.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Store-operated calcium channels in HL-60 cells effects of temperature, differentiation and loperamide.

The effect of temperature on calcium release and influx has been compared in differentiated and undifferentiated HL-60 cells. Receptor-mediated release of intracellular calcium by ATP was little affected by temperature in HL-60 cells. In differentiated HL-60 cells the store-operated calcium (SOC) channel-dependent sustained elevation of calcium levels after ATP was maximal at 25-29 degrees C; at higher temperatures calcium levels returned relatively rapidly towards basal levels. In undifferentiated cells, a SOC channel-dependent sustained elevation of calcium levels was not observed with levels returning to basal levels much more rapidly than in differentiated cells. The initial thapsigargin-initiated elevation of calcium did not become maximal until about 25 degrees C in both differentiated and undifferentiated HL-60 cells. In differentiated cells, the SOC channel-dependent sustained elevation of calcium after thapsigargin was maximal at 30-37 degrees C, while in undifferentiated cells, the sustained elevation was maximal at 25-30 degrees C. Loperamide, which augments the SOC channel-dependent sustained elevation of calcium, showed a temperature-dependent response that was maximal at about 22 degrees C after either ATP or thapsigargin and was minimal at 37 degrees C. In contrast, inhibition of SOC channel-dependent elevation of calcium by miconazole or trifluoperazine was not greatly affected by temperature.

Adenosine Triphosphate↗
PubMed1999

Pediatric clerkship experience and performance in the Nebraska Education Consortium: a community vs university comparison.

OBJECTIVE: To compare the reported experiences and performance on end-of-course examinations of students completing their pediatric clerkship at the University of Nebraska Medical Center (UNMC), Omaha, with that of students completing their clerkship in a community pediatrician's practice (CPP) outside the Omaha metropolitan area. DESIGN: Cohort study. SETTING: Private and/or institutional practices with both ambulatory and hospital components. PARTICIPANTS: For the academic year 1996-1997, all 113 students completing the 8-week third-year pediatric clerkship returned a questionnaire detailing their opinions of the experience. They also completed written (multiple-choice and essay questions) and oral (standardized parent interview) examinations, locally prepared and based on clerkship curriculum objectives provided to the students at orientation. Prior to student placement in the CPP, the clerkship goals, content, and evaluation methods as well as techniques for teaching in a busy office practice were reviewed with the CPP physicians. Eighty-one students performed their clerkship at UNMC while 31 spent all but the first week of the clerkship in the CPP. MAIN OUTCOME MEASURES: The students' opinions about their experiences and their performances on the end-of-course examinations were compared. Statistical analysis of the questionnaire was done using the Fisher exact test and the Mantel-Haenszel chi2 test while examination performance was compared using the t test and the Wilcoxon rank sum test. RESULTS: The UNMC and CPP groups reported similar opinions of their experiences in the newborn nursery and the inpatient portion of the clerkship, but the CPP students were much more positive about their learning experience in the clinic (P=.001). The CPP students reported more involvement in the patient's overall care (P<.001) and in other aspects of clinic operation (P<.001). The UNMC and CPP students had similar opinions of curriculum content, reading material, and didactic instruction. No group differences were found regarding interest in pediatrics as a career. Most importantly, no group differences were found in performance on any portion of the end-of-course examinations. CONCLUSIONS: Community-based education at the third-year clerkship level can be accomplished without a significant effect on student examination performance if students and faculty are aware of and adhere to a common set of goals. The end result is a much more robust experience for students who spend the clerkship in the practice of a community-based pediatrician.

Clinical Clerkship↗
PubMed1998

Signal transduction mechanisms involved in angiotensin-(1-7)-stimulated arachidonic acid release and prostanoid synthesis in rabbit aortic smooth muscle cells.

This study investigated the signal transduction mechanisms of angiotensin-(1-7) [Ang-(1-7)]- and Ang II-stimulated arachidonic acid (AA) release for prostaglandin (PG) production in rabbit aortic vascular smooth muscle cells. Ang II and Ang-(1-7) enhanced AA release in cells prelabeled with [3H]AA. However, 6-keto-PGF1 alpha synthesis produced by Ang II was much less than that caused by Ang-(1-7). In the presence of the lipoxygenase inhibitor baicalein, Ang II enhanced production of 6-keto-PGF1 alpha to a greater degree than Ang-(1-7). Angiotensin type (AT)1 receptor antagonist DUP-753 inhibited only Ang II-induced [3H]AA release, whereas the AT2 receptor antagonist PD-123319 inhibited both Ang II- and Ang-(1-7)-induced [3H]AA release. Ang-(1-7), receptor antagonist D-Ala7-Ang-(1-7) inhibited the effect of Ang-(1-7), but not of Ang II. In cells transiently transfected with cytosolic phospholipase A2 (cPLA2), mitogen-activated protein (MAP) kinase or Ca(++)-/cal-modulin-dependent protein (CAM) kinase II antisense oligonucleotides, Ang-(1-7)- and Ang II-induced [3H]AA release was attenuated. The CaM kinase II inhibitor KN-93 and the MAP kinase kinase inhibitor PD-98059 attenuated both Ang-(1-7)- and Ang II-induced cPLA2 activity and [3H]AA release. Ang-(1-7) and Ang II also increased CaM kinase II and MAP kinase activities. Although KN-93 attenuated MAP kinase activity, PD-98059 did not affect CaM kinase II activity. Both Ang II and Ang-(1-7) caused translocation of cytosolic PLA2 to the nuclear envelope. These data show that Ang-(1-7) and Ang II stimulate AA release and prostacyclin synthesis via activation of distinct types of AT receptors. Both peptides appear to stimulate CaM kinase II, which in turn, via MAP kinase activation, enhances cPLA2 activity and release of AA for PG synthesis.

Angiotensin I↗
PubMed1997

Loperamide: a positive modulator for store-operated calcium channels?

The depletion of inositol trisphosphate-sensitive intracellular pools of calcium causes activation of store-operated calcium (SOC) channels. Loperamide at 10-30 microM has no effect on intracellular calcium levels alone, but augments calcium levels in cultured cells when SOC channels have been activated. In HL-60 leukemic cells, the apparent positive modulatory effect of loperamide on SOC channels occurs when these channels have been activated after ATP, thapsigargin, or ionomycin-elicited depletion of calcium from intracellular storage sites. Loperamide has no effect when levels of intracellular calcium are elevated through a mechanism not involving SOC channels by using sphingosine. Loperamide caused augmentation of intracellular calcium levels after activation of SOC channels in NIH 3T3 fibroblasts, astrocytoma 1321N cells, smooth muscle DDT-MF2 cells, RBL-2H3 mast cells, and pituitary GH4C1 cells. Only in astrocytoma cells did loperamide cause an elevation in intracellular calcium in the absence of activation of SOC channels. The augmentation of intracellular calcium elicited by loperamide in cultured cells was dependent on extracellular calcium and was somewhat resistant to agents (SKF 96365, miconazole, clotrimazole, nitrendipine, and trifluoperazine) that in the absence of loperamide effectively blocked SOC channels. It appears that loperamide augments influx of calcium through activated SOC channels.

3T3 Cells↗
PubMed1997

Cytodifferentiation of a Wilms' tumor pulmonary metastasis: theoretic and clinical implications.

BACKGROUND: Complete maturation (cytodifferentiation) of treated metastatic Wilms' tumor is an infrequent occurrence. In a large series of reports, Wilms' metastases have generally contained malignant blastemic elements admixed with lesser amounts of cytodifferentiated mesenchyme. The authors describe a patient in whom complete maturation of a pulmonary metastasis was documented after intensive chemoradiotherapy. METHODS: A MEDLINE search was employed to identify pertinent cases from 1966 to the present. Key words used in the search included Wilms' tumor, relapse, therapy, metastasis, maturation, and cytodifferentiation. Four patients were identified as having completely mature cytodifferentiated pulmonary metastases of Wilms' tumor after chemotherapy; one had also undergone irradiation of the pulmonary metastasis. RESULTS: The primary tumor was an extremely necrotic blastemic Wilms' tumor devoid of maturation, as studied after irradiation and chemotherapy. The lung metastases (examined 13 years later) were represented by a scar and a nodule comprised of bland epithelium and tubules admixed with mature smooth muscle. Immunohistochemical stains, used to assess the proliferative rate of these cells, revealed a nearly negligible proliferation index. CONCLUSIONS: This report suggests that therapy (chemotherapy and/or irradiation) may effect, on occasion, complete cytodifferentiation of Wilms' tumor pulmonary metastasis. Although this would appear to be an uncommon event, its true incidence is unknown, because few patients with metastatic pulmonary Wilms' tumor are subjected to biopsy. The findings of this study suggest that for children with radiologically stable Wilms' lung metastases (as determined by imaging studies) who are yet undergoing intensive chemoradiotherapy, the notion of a surgical biopsy should be entertained to determine the true nature of the radiologic images. For some, this might result in the cessation of further therapy that would be unnecessary and not without complications.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Allogeneic bone marrow transplantation for children with acute leukemia: long-term follow-up of patients prepared with high-dose cytosine arabinoside and fractionated total body irradiation.

High-dose therapy and allogeneic matched sibling bone marrow transplantation (BMT) is considered to be the treatment of choice for children with relapsed acute lymphoblastic leukemia (ALL), or for children with acute myeloid leukemia (AML) in first remission. However, the rate of bone marrow relapse after transplant for either of these diseases remains high. In this study, we assessed the efficacy and toxicity of high-dose cytosine arabinoside and total body irradiation (TBI) followed by allogeneic BMT, for children with acute leukemia or myelodysplastic syndrome (MDS). Sixty-five pediatric patients underwent allogeneic related (n = 57) or unrelated (n = 8) BMT. Twenty-seven were transplanted for ALL in second remission (CR2), and 16 for AML in first remission (CR1). The other 22 were high risk patients: six were transplanted for ALL in third remission (CR3), two for AML in CR2, two for myelodysplastic syndrome (MDS) and 12 for acute leukemia in relapse. Patients were prepared with cytosine arabinoside 3000 mg/m2 per dose twice daily for 6 days followed by 12000 cGy TBI as 200 cGy fractions twice daily for 3 days. Minimum follow-up is 21 months. Five-year event-free survival (EFS) and the actuarial relapse rate is 59 and 14% for patients with ALL in second remission, and 38 and 14+% for patients with AML in first remission. Twelve patients have relapsed (three are alive in remission after testicular or marrow relapse) and 28 have died of other causes. Acute GVHD with or without infection was the cause of death in 11 patients. Ten of the 11 patients who died of acute GVHD were considered at 'high risk' for GVHD (inadequate GVHD prophylaxis, or mismatched family donor or a matched unrelated donor). Toxicities in the immediate post-BMT period included diarrhea, oropharyngeal mucositis and conjunctivitis. Significant late toxicities included short stature, avascular necrosis of bone, and poor school performance (most often in patients who had received prior cranial irradiation). Our conclusions are that high-dose Ara-C and TBI followed by allogeneic bone marrow transplantation is effective therapy for children in second complete remission of their acute leukemia. However, significant late toxicities occur, and it is clear that more effective, less toxic therapies are necessary for these patients.

Acute Disease↗
PubMed1996

Mortality associated with cervicofacial necrotizing fasciitis.

Cervicofacial necrotizing fasciitis is a rare infection but still occurs and carries a mortality rate up to 60%. It is a polymicrobial infection that is characterized by diffuse necrosis of fascial planes and subcutaneous tissues. Diagnosing early stages of cervicofacial necrotizing fasciitis in relationship to other soft tissue infections of odontogenic origin is difficult and leads to less aggressive treatment with resulting increased morbidity and mortality. To prevent this significant mortality and morbidity associated with cervicofacial necrotizing fasciitis early presentation, recognition and treatment by health care provider is essential.

Candidiasis↗
PubMed1996

Treatment of veno-occlusive disease of the liver with bolus tissue plasminogen activator and continuous infusion antithrombin III concentrate.

Veno-occlusive disease (VOD) of the liver is a common complication of BMT and is accompanied by reduced levels of natural anticoagulants and by multi-organ dysfunction. We describe two cases of clinical VOD developing after autologous BMT and accompanied by ultrasonographic features of reversed portal venous flow. In both cases the patients had decreased levels of antithrombin (AT). Once the diagnosis of VOD was made, these patients were treated with tissue plasminogen activator (tPA) and continuous infusion AT. Each patient had radiographic and clinical resolution of VOD with the therapy. This novel treatment appears to have reversed the course of VOD without the increased risk of bleeding seen in the use of heparin therapy.

Adolescent↗
PubMed1995

A prospective study of the efficacy of various gloving techniques in the application of Erich arch bars.

PURPOSE: This is a prospective study of the efficacy of three different techniques of triple gloving during the application of Erich arch bars. Two different cut-resistant glove liners and three layers of latex gloves were compared with double gloving. METHODS AND MATERIALS: Thirty patients underwent Erich arch bar placement from first molar bilaterally on both arches. Two surgeons per case were arbitrarily placed into one of four groups that included double latex gloving, triple gloving with kevlar or stainless steel glove liners, or triple layer latex gloving, based on the availability of glove liners. All gloves were collected postoperatively and tested for perforation using water insufflation. RESULTS: One hundred eight of 120 outer gloves were perforated. There were 16 perforations in 11 inner gloves of the double latex glove group, but no perforations in the inner gloves of the triple latex glove group. There were two inner gloves with one perforation each in the stainless steel group and one glove with a perforation in the kevlar group. All techniques of triple gloving were found to be superior to double gloving. There was no difference between the techniques of triple gloving. CONCLUSION: During certain high-risk procedures greater protection to the surgeon can be obtained by triple gloving. The use of cut-resistant glove liners or triple layer latex gloving is superior to double layer latex gloving.

Equipment Design↗
PubMed1995

Induction of immune tolerance in a 7-year-old hemophiliac with an anaphylactoid inhibitor.

BACKGROUND: Anaphylactic reactions were a rare complication of low purity VIII concentrates, but not with high purity VIII concentrates. CASE: 7 y/o WM with severe hemophilia A, received only cryoprecipitate and monoclonally purified VIII concentrates; developed post-infusional urticaria. A 2-Bethesda-unit inhibitor was detected. Generalized urticaria and bronchospasm following factor developed as the titer increased. Skin tests demonstrated reactivity to plasma derived VIII, but not recombinant VIII (rhVIII). Attempts at desensitization using rhVIII failed. ELISA revealed an anti-VIII IgE antibody. He was treated with a modified tolerance regimen using rhVIII starting at 500 U/day with aggressive premedication. The dosage increased by 200 U weekly as tolerated to a maximum of 100 U/kg/d without symptoms. RESULTS: His antibody titer decreased rapidly once he started 100 U/kg/d. Six months later, the inhibitor was < 1 Bethesda unit. CONCLUSION: Immune tolerance induction using a graduated dosage of rhVIII was successful.

Anaphylaxis↗
PubMed1994

Biodiversity: measurement and estimation.

In introducing a series of 11 papers on the measurement and estimation of biodiversity, eight crucial questions are posed: What is 'biodiversity'? Is biodiversity just the number of species in an area? If biodiversity is more than the number of species how can it be measured? Are all species of equal weight? Should biodiversity measures include infraspecific genetic variance? Do some species contribute more than others to the biodiversity of an area? Are there useful indicators of areas where biodiversity is high? And can the extent of biodiversity in taxonomic groups be estimated by extrapolation? In addition, the modern concept of biological diversity is attributed to Elliot R. Norse and his colleagues.

Animals↗
PubMed1992

Severe refractory anemia with ringed sideroblasts and bone marrow aplasia in a child.

Sideroblastic anemia is an extremely rare disorder in children. This report describes a 9-year 4-month-old girl with severe refractory anemia with ringed sideroblasts (RARS) that progressed to severe bone marrow aplasia. Ultrastructural studies revealed the presence of abundant intramitochondrial deposits of iron in erythroblasts similar to that observed in adults with this disorder. Although acid ferrocyanide staining confirmed the ferric valence of the iron deposits, they lacked morphologic and cytochemical characteristics associated with ferritin and hemosiderin. Bone marrow culture showed decreased or absent CFU-GEMM, CFU-GM, CFU-E, and BFU-E. Erythrocyte uroporphyrinogen I synthase, aminolevulinic acid dehydratase, uroporphyrinogen decarboxylase, urinary porphyrins, porphobilinogen, and aminolevulinic acid were normal. Free red cell protoporphyrin was increased. Therapy with corticosteroid and androgens was totally ineffective. The aplastic bone marrow in this child appeared to represent the end stage of RARS and differed from adults with RARS, who more frequently demonstrate a chronic course, often with the onset of leukemia as a terminal sequela. Although this case documents the occurrence of RARS in a child, additional reports of children with this disorder will be required to determine the prognosis and natural history of RARS in children.

Anemia, Sideroblastic↗