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Biomedical subjects

J R White

Publications and source records attributed to J R White.

At least 37 records · Page 2Linked to original sources
PubMed2000

Dangerous and common drug interactions in patients with diabetes mellitus.

As more medications are made available to the prescriber, the likelihood of drug interactions will increase. The number of drug interactions encountered by the provider treating the patient with diabetes has increased over the past few years because the number of medications used in the management of hyperglycemia has dramatically increased during that time. These interactions are complex but can be predicted.

Adrenal Cortex Hormones↗
PubMed2000

Identification of SAF-2, a novel siglec expressed on eosinophils, mast cells, and basophils.

BACKGROUND: Eosinophils, basophils, and mast cells are believed to be the central tenet cells in allergic conditions including allergic rhinitis, asthma, and eczema. The molecular mechanisms underlying the recruitment of these cells to sites of allergic inflammation are poorly understood. OBJECTIVES: Our aim was to identify a common adhesion molecule that could potentially be responsible for mediating the recruitment of the allergic cell types to the lungs and other sites of allergy. METHODS: We have cloned a sialoadhesin molecule from a human eosinophil library with the use of expressed sequence tag technology and characterized its expression on allergic cells by the use of flow cytometry and specific mAbs. RESULTS: With the use of expressed sequence tag sequencing, we have identified a novel siglec molecule, SAF-2. SAF-2 has homology with other sialoadhesin family members (CD33 and siglec-5) and belongs to a subgroup of the Ig superfamily. SAF-2 is a 431-amino acid protein composed of 3 Ig domains with a 358-amino acid extracellular domain and a 47-amino acid tail. SAF-2 is highly restricted to eosinophils, basophils, and mast cells. Antibodies to SAF-2 do not modulate Ca(++) mobilization or chemotaxis of human eosinophils induced by eotaxin. CONCLUSION: SAF-2 is a highly restricted sialoadhesin molecule, which may be useful in the detection and/or modulation of allergic cells.

Antigens, CD↗
PubMed2000

Insulin aspart: a new rapid-acting insulin analog.

OBJECTIVE: To examine the pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, and drug interactions of insulin aspart, and summarize the clinical trials of efficacy and safety in patients with type or type 2 diabetes mellitus. DATA SOURCES: A MEDLINE database search (1985-May 2000) was performed to identify all applicable published articles and abstracts; in some cases, Novo Nordisk unpublished information was also obtained. Review articles on insulin analogs were also identified, as well as review chapters in medical textbooks. STUDY SELECTION: The majority of the studies identified were in abstract form. These studies reported information on the pharmacokinetics of insulin aspart in healthy volunteers and in those with diabetes, as well as the therapeutic utility, safety, and clinical efficacy in patients with diabetes. A limited number of randomized studies were reported as artices in the medical literature DATA EXTRACTION: All published clinical studies were reviewed. DATA SYNTHESIS: Insulin aspart, the second Food and Drug Administration-approved rapid-acting insulin analog, is produced by recombinant technology that replaces the proline at position 28 on the B chain of insulin with negatively charged aspartic acid. Insulin aspart exists as hexamers that rapidly dissociate into monomers and dimers on subcutaneous injection. When administered immediately prior to a meal, insulin aspart is at least as effective as regular human insulin in control of postprandial blood glucose concentrations. Insulin aspart achieves higher peak insulin concentrations in less time and with a shorter duration of action than regular human insulin. CONCLUSIONS: Insulin aspart is a convenient premeal insulin for use by patients requiring mealtime insulin. Furthermore, due to favorable pharmacokinetics, insulin aspart controls postprandial blood glucose concentrations at least as well as regular human insulin and contributes to improved quality of life.

Amino Acid Sequence↗
PubMed1999

Intravenous valproate associated with significant hypotension in the treatment of status epilepticus.

Intravenous valproate has been suggested for the treatment of status epilepticus in part because of its relatively good cardiovascular safety profile. We report a case of severe hypotension associated with intravenous valproate used to treat status epilepticus in an 11-year-old girl. Valproate 960 mg (30 mg/kg) was infused over 1 hour. The patient's blood pressure decreased from a baseline of 130/80 mm Hg to 70/55 mm Hg, 39 minutes into the infusion. Although her seizures stopped, her blood pressure fluctuated between 90/60 mm Hg and 60/30 mm Hg over the next several hours, requiring treatment with intravenous fluids and pressor therapy. Endotracheal intubation eventually was performed. Once her blood pressure stabilized, the patient improved clinically. To our knowledge, this is the first report of significant hypotension associated with intravenous valproate in the treatment of status epilepticus in the pediatric population.

Anticonvulsants↗
PubMed1999

Direct measurement of unfractionated heparin using a biochemical assay.

A number of investigations have noted that functional biological assays for heparin are not always reliable and may not reflect the actual biochemical level of heparin in patients receiving anticoagulant therapy. This creates the possibility that patients receiving anticoagulant treatment may have an excess or deficiency of circulating levels of heparin. To address this problem, we have developed a direct biochemical measurement of heparin. The heparin assay uses fluorophore-assisted carbohydrate electrophoresis (FACE) to directly measure the predominate disaccharide of unfractionated heparin. In this study, unfractionated heparin was measured in vitro throughout a wide range of heparin concentrations in plasma. Seven in vivo pharmacokinetic studies in five normal subjects given 3,000 USP units of unfractionated heparin intravenously showed a three-phase elimination process with higher peak plasma levels and shorter elimination times than predicted from previous studies. At these doses, heparin is largely eliminated intact through urinary excretion. Body weight has a significant effect on heparin kinetics. When we compared the direct biochemical assay with two biological clotting assays, we found the latter can overestimate biochemical heparin concentrations. The FACE assay, due to its sensitivity, is also able to measure circulating levels of endogenous heparin in plasma and urine. Direct heparin measurement using the FACE technique is practical and useful for studies of the correlation of biochemical and biological activities.

Animals↗
PubMed1999

Clinically significant drug interactions.

Ironically, pharmacotherapy can harm the very patients it is intended to help if clinically significant drug interactions occur. However, knowledge of the role of the hepatic cytochrome P-450 isoenzyme system in drug interactions has expanded greatly with advances in gene-mapping technologies, and an understanding of the system can aid physicians in preventing or minimizing complications from drug interactions mediated through that system. The authors summarize the role of important isoenzymes and drugs that induce and inhibit the P-450 system. They also discuss serious drug interactions mediated through the P-450 system and ways to predict and avoid them. As a special aid, they provide a reference guide which, when used faithfully in prescribing, should result in better drug therapy.

Cytochrome P-450 Enzyme System↗
PubMed1998

Identification of a truncated form of the CC chemokine CK beta-8 demonstrating greatly enhanced biological activity.

A new CC chemokine, designated CKbeta-8 or myeloid progenitor inhibitor factor-1, was recently identified in a large scale sequencing effort and was cloned from a human aortic endothelial library. CKbeta-8 cDNA encodes a signal sequence of 21 amino acids, followed by a 99-amino acid predicted mature form. CKbeta-8 was expressed and purified from a baculovirus insect cell expression system, which resulted in the identification of different N-terminal variants of the secreted chemokine. The three major forms (containing amino acids 1-99, 24-99, and 25-99 of the secreted chemokine) showed a large variation in potency. CKbeta-8 activated both monocytes and eosinophils to mobilize intracellular calcium; however, the shortest form of CKbeta-8 (25-99) was >2 orders of magnitude more potent than the longest form. Cross-desensitization experiments in both monocytes and eosinophils suggested that the CCR1 receptor was probably the predominant receptor that mediates this chemokine's physiologic response. However, incomplete desensitization was encountered in both cell systems, suggesting involvement of an additional receptor(s). Interestingly, the short form of CKbeta-8 was the most potent chemotactic chemokine that we have ever evaluated in the monocyte system (EC50 = 54 pM). However, in contrast to its action on monocytes, CKbeta-8 was a very poor chemotactic factor for eosinophils.

Amino Acid Sequence↗
PubMed1998

Macrophage-inflammatory protein-3 beta/EBI1-ligand chemokine/CK beta-11, a CC chemokine, is a chemoattractant with a specificity for macrophage progenitors among myeloid progenitor cells.

Chemoattractants are potential factors influencing cell migration. Stromal cell-derived factor-1, a CXC chemokine, is the only chemokine reported to have chemotactic activity for hemopoietic progenitor cells (HPC). We report in this work another chemokine of the CC subfamily, which is chemotactic for HPC. Macrophage-inflammatory protein (MIP)-3 beta/EBI1-ligand chemokine/CK beta-11 attracted bone marrow and cord blood CD34+ cells. In contrast to stromal cell-derived factor-1, which attracts multiple types of HPC, MIP-3beta attracted mainly CFU granulocyte macrophage, but not other HPC such as burst-forming unit erythrocyte or CFU granulocyte, erythrocyte, macrophage, and megakaryocyte. Chemoattracted CD34+ cells formed CFU granulocyte macrophage-like colonies, which were morphologically determined as large macrophages. These progenitors were selectively responsive to stimulation by macrophage CSF, demonstrating that MIP-3 beta attracts macrophage progenitors. Expression of CCR7, the receptor for MIP-3 beta, was detected at a mRNA level in the attracted CD34+ cells as well as input CD34+HPC. Expression of MIP-3 beta mRNA was not constitutive, but was inducible in bone marrow stromal cells by inflammatory agents such as bacterial LPS, IFN-gamma, and TNF-alpha. Taken together, our findings suggest that MIP-3 beta is expressed in the bone marrow environment after induction with certain inflammatory cytokines and LPS, and may play a role in trafficking of macrophage progenitors in and out of the bone marrow in inflammatory conditions.

Antigens, CD34↗
PubMed1998

Differential chemotactic behavior of developing T cells in response to thymic chemokines.

Differentiation-dependent thymocyte migration in the thymus may be important for T lymphopoiesis and might be regulated by thymic chemoattractants. We examined modulation of chemotactic responsiveness of thymocyte subsets during their early to late stages of development in response to 2 thymus-expressed chemokines, SDF-1 and CKbeta-11/MIP-3beta/ELC. SDF-1 shows chemotactic preference for immature thymocytes (subsets of triple negative thymocytes and double positive [DP] subset) over mature single positive (SP) thymocytes. CKbeta-11/MIP-3beta/ELC shows low chemotactic activity on the immature thymocytes, but it strongly attracts mature SP thymocytes, effects opposite to that of SDF-1. SDF-1-dependent chemoattraction of immature thymocytes is not significantly desensitized by a negative concentration gradient of CKbeta-11/MIP-3beta/ELC, and chemoattraction of mature SP thymocytes to CKbeta-11/MIP-3beta/ELC is not antagonized by SDF-1, demonstrating that these two chemokines have different chemoattractant preferences for thymocyte subsets and would probably not inhibit each other's chemotaxis in the event of microenvironmental coexpression. The chemotactic responsiveness of thymocytes and mature T cells to the 2 chemokines is respectively enhanced after selection process and migration to the spleen. These studies demonstrate the presence of thymocyte chemoattractants with differential chemotactic preference for thymocytes, a possible mechanism for thymocyte migration in the thymus.

Animals↗
PubMed1998

Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration.

Interleukin-8 (IL-8) and closely related Glu-Leu-Arg (ELR) containing CXC chemokines, including growth-related oncogene (GRO)alpha, GRObeta, GROgamma, and epithelial cell-derived neutrophil-activating peptide-78 (ENA-78), are potent neutrophil chemotactic and activating peptides, which are proposed to be major mediators of inflammation. IL-8 activates neutrophils by binding to two distinct seven-transmembrane (7-TMR) G-protein coupled receptors CXCR1 (IL-8RA) and CXCR2 (IL-8RB), while GROalpha, GRObeta, GROgamma, and ENA-78 bind to and activate only CXCR2. A chemical lead, which selectively inhibited CXCR2 was discovered by high throughput screening and chemically optimized. SB 225002 (N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea) is the first reported potent and selective non-peptide inhibitor of a chemokine receptor. It is an antagonist of 125I-IL-8 binding to CXCR2 with an IC50 = 22 nM. SB 225002 showed >150-fold selectivity over CXCR1 and four other 7-TMRs tested. In vitro, SB 225002 potently inhibited human and rabbit neutrophil chemotaxis induced by both IL-8 and GROalpha. In vivo, SB 225002 selectively blocked IL-8-induced neutrophil margination in rabbits. The present findings suggest that CXCR2 is responsible for neutrophil chemotaxis and margination induced by IL-8. This selective antagonist will be a useful tool compound to define the role of CXCR2 in inflammatory diseases where neutrophils play a major role.

Animals↗
PubMed1998

CK beta-11/macrophage inflammatory protein-3 beta/EBI1-ligand chemokine is an efficacious chemoattractant for T and B cells.

We examined the functional properties of CK beta-11/MIP-3 beta/ELC, a recently reported CC chemokine that specifically binds to a chemokine receptor, EBI1/BLR2/CCR7. CK beta-11/MIP-3 beta/ELC is distantly related to other CC and CXC chemokines in primary amino acid sequence structure. Recombinant human CK beta-11/MIP-3 beta/ELC expressed from a mammalian cell system showed potent chemotactic activity for T cells and B cells but not for granulocytes and monocytes. An optimal concentration of CK beta-11/MIP-3 beta/ELC attracted most input T cells within 3 h, a chemotactic activity comparable with that of stromal cell derived factor 1 (SDF-1), a highly efficacious CXC chemokine. CK beta-11/MIP-3 beta/ELC equally attracted naive CD45RA+ and memory type CD45RO+ T cells. CK beta-11/MIP-3 beta/ELC also strongly attracted both CD4+ and CD8+ T cells, but the attraction for CD4+ T cells was greater. CK beta-11/MIP-3 beta/ELC was also a more efficacious chemoattractant for B cells than MIP-1 alpha, a known B cell chemoattractant. CK beta-11/MIP-3 beta/ELC induced actin polymerization in lymphocytes, and chemotaxis was completely blocked by pertussis toxin showing its receptor, most likely EBI1/BLR2/CCR7, is coupled to a G(alpha i) protein. CK beta-11/MIP-3 beta/ELC induced calcium mobilization in lymphocytes, which could be desensitized by SDF-1, suggesting possible cross-regulation in their signaling. Human CK beta-11/MIP-3 beta/ELC attracted murine splenocytes suggesting functional conservation of CK beta-11/MIP-3 beta/ELC between human and mouse. The efficacy of chemoattraction by CK beta-11/MIP-3 beta/ELC and tissue expression of its mRNA suggest that CK beta-11/MIP-3 beta/ELC may be important in trafficking of T cells in thymus, and T cell and B cell migration to secondary lymphoid organs.

Actins↗
PubMed1998

Long term results with breast-conserving therapy for patients with early stage breast carcinoma in a community hospital setting.

BACKGROUND: Prospective randomized trials and retrospective reviews from academic centers have documented the success of breast-conserving therapy (BCT) for patients with early stage breast carcinoma. The authors retrospectively reviewed the outcome of BCT for early stage breast carcinoma to determine the success of BCT at the study institution, a 1000-bed community hospital. METHODS: Between January 1980 and December 1987, 400 cases of Stage I and II breast carcinoma were managed with BCT at the study institution. All patients were treated with an excisional biopsy. The axilla was surgically staged in 383 patients (96%). Postoperative treatment was composed of 45-50 gray (Gy) external beam irradiation to the whole breast and a boost to the tumor bed to at least 60 Gy in all patients. The median follow-up of the 292 surviving patients is 118 months. RESULTS: At last follow-up, there were 37 local recurrences for 5- and 10-year actuarial rates of 4% and 10%, respectively. Clinical, pathologic, and treatment-related factors were analyzed for an association with local recurrence. On univariate analysis, patient age < or = 35 years and positive surgical margins were associated with an increased risk of local recurrence. On multivariate analysis, only patient age < or = 35 years remained significant. The 10-year actuarial regional recurrence rate was 5%. The 10-year actuarial cause specific survival rate was 91% and 69% for Stage I and II patients, respectively. CONCLUSIONS: BCT for patients with early stage breast carcinoma in a community hospital setting produces excellent results comparable to contemporary series reported from academic institutions and multiinstitution trials.

Actuarial Analysis↗
PubMed1998

Performance of advanced resuscitation skills by pediatric housestaff.

OBJECTIVE: To describe pediatric housestaff resuscitation experience and their ability to perform key resuscitation skills. DESIGN: Cohort study of 63 pediatric residents in a university-based training program. PARTICIPANTS AND METHODS: Investigators observed, scored, and timed resident performance on 4 key resuscitation skills. Cognitive ability was tested with 4 written scenarios. Housestaff provided self-reports of the number of months since their last American Heart Association Pediatric Advanced Life Support course, number of mock and actual codes attended, number of times skills were performed, and self-confidence with respect to resuscitation. RESULTS: A total of 45 pediatric residents (71%) participated. Median cognitive score was 5 (range, 1-5). Of all residents, 44 (97%) successfully bag mask-ventilated the mannequin; 24 (53%) and 36 (80%) used the correct bag and mask size, respectively. Thirty-nine residents (87%) placed a tube in the mannequin trachea, 12 (27%) checked that suction was working prior to intubation, and 30 (67%) chose the correct endotracheal tube size. Forty residents (89%) discharged the defibrillator, and 25 (56%) and 32 (71%) correctly chose asynchronous mode and infant paddles, respectively. Thirty-eight residents (84%) inserted an intraosseous line; 35 (78%) had correct placement. Median times for successful skill completion were 83 seconds for bag mask ventilation, 136 seconds for intubation, 149 seconds for defibrillation, and 68 seconds for intraosseous line placement. CONCLUSION: Pediatric housestaff previously trained in pediatric advanced life support were generally able to reach the end point of 4 key resuscitation skills but less frequently performed the specific subcomponents of each skill. This poor performance and the prolonged time to skill completion suggest the need for greater attention to detail during training.

Adult↗
PubMed1997

Ductal carcinoma in situ detected in the mammographic era: an analysis of clinical, pathologic, and treatment-related factors affecting outcome with breast-conserving therapy.

PURPOSE: We reviewed our institution's experience treating predominantly mammographically detected ductal carcinoma in situ (DCIS) with breast-conserving therapy (BCT) to determine if any clinical, pathologic, or treatment-related factors affected outcome. METHODS AND MATERIALS: From January 2, 1980 to January 6, 1992, 107 breasts in 105 patients were treated with BCT at William Beaumont Hospital, Royal Oak, MI. All patients underwent at least an excisional biopsy and 70 patients (65%) were reexcised. All patients received whole-breast irradiation to a median dose of 50.4 Gy (range 43.1 to 56.0 Gy). Ninety-nine patients (93%) received a supplemental boost to the tumor bed for a median total dose of 60.4 Gy (range 59.1 to 71.8 Gy) using either photons (2 patients), electrons (69 patients), or an interstitial implant (28 patients). RESULTS: With a median follow-up of 78 months, 10 patients have failed in the treated breast for a 5- and 10-year actuarial local control rate of 91.2 and 89.8%, respectively. Thirteen percent of the population have been followed for 10 years or more. Three recurrences were pure DCIS, and seven were invasive. All patients were salvaged with mastectomy. Nine patients remain without evidence of disease a median of 30.6 months after surgery. One patient failed distantly 36 months after local recurrence for an ultimate cause specific survival of 99%. Potential clinical (age, mammographic findings, method of detection, etc.), pathologic (nuclear grade, margins, etc.), and treatment-related factors (dose, boost technique, reexcision status, etc.) affecting outcome were analyzed. No variable was found to be associated with an ipsilateral breast tumor recurrence. However, when only recurrences that occurred within or immediately adjacent to the lumpectomy cavity were analyzed, both margin status and the extent of cancerization of lobules (COL) near the surgical margin were associated with the development of a local recurrence. CONCLUSIONS: Patients treated with BCT for predominantly mammographically detected DCIS achieve excellent rates of local control and overall survival. Both margin status and the extent of COL near the surgical margin appear to be associated with recurrences within or immediately adjacent to the lumpectomy cavity. These data suggest that careful attention to the completeness of surgical resection of DCIS is an important determinant of outcome.

Adult↗
PubMed1997

Pulsed low dose rate brachytherapy in a rat model: dependence of late rectal injury on radiation pulse size.

PURPOSE: Clinical protocols utilizing pulsed low dose rate brachytherapy (PDR) to replace traditional continuous low dose rate brachytherapy (CLDR) employ irradiation in individual pulses given at intervals of a few hours. A critical factor in determining whether PDR will produce equivalent or greater late-occurring normal tissue toxicity is the dose per pulse. A rat rectal model was used to determine the role of pulse size in modifying dose effectiveness in producing late-occurring toxicity. METHODS AND MATERIALS: A rat model in which the rectum is irradiated with 192Ir sources was used in conjunction with an intracavitary applicator. A section of rectum 1.3 cm in length was irradiated with either 0.75 Gy/h CLDR or one of five schemes of PDR. The schemes applied 0.375, 0.75, 1.5, 3.0, or 6.0 Gy pulses at 0.5, 1.0, 2.0, 4.0, or 8.0 h intervals, respectively. Rats were observed for up to 300 days after completion of irradiation for rectal obstruction. Rectal specimens were taken at the time of sacrifice for obstruction or at the end of follow-up and analyzed histologically for injury. RESULTS: Effectiveness of irradiation was analyzed by calculating the ED50 for incidence of obstruction and severe histological injury. The ED50 for obstruction after treatment with CLDR and pulse sizes of 0.375, 0.75, and 1.5 Gy were 70.5, 68.0, 68.6, and 68.8 Gy, respectively. These values were not significantly different. Compared to CLDR, the ED50 for obstruction after pulse sizes of 3.0 and 6.0 Gy were significantly different at 60.9 and 46.3 Gy, respectively. The relative changes in ED50 for the different radiation schemes in producing ulceration, fibrosis, and vascular sclerosis injury were similar to that observed for obstruction. The endpoints of colitis cystica profunda and atypical epithelial regeneration varied less with increasing pulse size. CONCLUSIONS: We have demonstrated that for late rat rectal injury, dose responses to PDR pulse sizes up to 1.5 Gy at 2-h intervals are not distinguishable from that seen with CLDR at a dose rate of 0.75 Gy/h.

Animals↗
PubMed1997

Cloning, in vitro expression, and functional characterization of a novel human CC chemokine of the monocyte chemotactic protein (MCP) family (MCP-4) that binds and signals through the CC chemokine receptor 2B.

Here we describe the characterization of a novel human CC chemokine, tentatively named monocyte chemotactic protein (MCP-4). This chemokine was detected by random sequencing of expressed sequence tags in cDNA libraries. The full-length cDNA revealed an open reading frame for a 98-amino acid residue protein, and a sequence alignment with known CC chemokines showed high levels of similarity (59-62%) with MCP-1, MCP-3, and eotaxin. MCP-4 cDNA was cloned into Drosophila S2 cells, and the mature protein (residues 24-98) was purified from the conditioned medium. Recombinant MCP-4 induced a potent chemotactic response (EC50 = 2.88 +/- 0.15 nM) and a transient rise in cytosolic calcium concentration in fresh human peripheral blood monocytes but not in neutrophils. Binding studies in monocytes showed that MCP-4 and MCP-3 were very potent in displacing high affinity binding of 125I-MCP-1 (IC50 for MCP-4, MCP-3, and unlabeled MCP-1 of 2.1 +/- 1.4, 0.85-1.6, and 0.7 +/- 0.2 nM respectively), suggesting that all three chemokines interact with the CC chemokine receptor-2 (MCP-1 receptor). This was confirmed in binding studies with Chinese hamster ovary cells, stably transfected with the CC chemokine 2B receptor. Northern blot analysis in extracts of normal human tissues showed expression of mRNA for MCP-4 in small intestine, thymus, and colon, but the level of protein expression was too low to be detected in Western blot analysis. However, expression of MCP-4 protein was demonstrated by immunohistochemistry in human atherosclerotic lesion and found to be associated with endothelial cells and macrophages.

Amino Acid Sequence↗