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Biomedical subjects

D Small

Publications and source records attributed to D Small.

At least 55 records · Page 3Linked to original sources
PubMed1996

Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias.

Normal expression of the hematopoietic growth factor receptor FLT3 (STK-1@Flk2) is limited to CD34+ stem/progenitor cells. We have evaluated the expression of FLT3 by RNase protection assay and Western blotting in 161 primary bone marrow (BM) samples from patients with leukemia. FLT3 RNA was found to be expressed at a higher level than in normal BM controls in 33 of 33 B-lineage acute leukemias, 11 of 12 acute myeloid leukemias (AMLs), and 3 of 11 T-cell acute leukemias (T-ALLs). Expression of FLT3 RNA was also observed in some cases of blast crisis CML. The FLT3 signal resulted from expression on the leukemic blasts, and was not caused by increased FLT3 expression on normal CD34+ stem/progenitor cells in the leukemic samples. To determine if FLT3 protein was also overexpressed, proteins were extracted from leukemic BM samples and screened by Western blotting with anti-FLT3 antisera. FLT3 protein was not detected in normal BM controls, but was found in 14 of 14 B-lineage ALLs, 36 of 41 AMLs, and 1 of 4 T-ALLs. Stimulation of patient samples with FLT3 ligand resulted in autophosphorylation of the FLT3 receptor, suggesting the receptor is functional in these cells. These data show that FLT3 RNA and protein are aberrantly expressed by AML and ALL cells in that CD34 expression and FLT3 expression are no longer synchronous, and suggest the possibility that overexpression of FLT3 could play a role in the survival and/or proliferation of malignant clones in acute myeloid and lymphoid leukemias.

Antigens, CD34↗
PubMed1995

Purification and expansion of human hematopoietic stem/progenitor cells.

CD34 monoclonal antibodies bind selectively to the most immature 1.5% of low-density human bone marrow mononuclear cells, including terminal deoxynucleotidyl transferase-positive lymphoid precursor cells, all types of in vitro assayed hematopoietic progenitor cells, and lymphohematopoietic stem cells capable of reconstituting myeloablated humans in clinical transplantation. Positive selection of highly enriched CD34+ stem and progenitor cells is widely used in research and is now being investigated in many applications of autologous and allogeneic clinical transplantation. More highly purified stem cells are also desired in research and may have clinical use. Immunoaffinity isolation of CD34+ cell subsets using antibodies against CD38 permits 10-100-fold further purification of stem cells. It will be valuable to be able to expand stem and progenitor cells from small marrow and blood samples. We are now identifying the genes expressed in stem and progenitor cells to eventually allow the control of stem and progenitor cell survival, proliferation, and differentiation.

Antibodies, Monoclonal↗
PubMed1995

Localization of the human stem cell tyrosine kinase-1 gene (FLT3) to 13q12-->q13.

We have previously reported the cloning of stem cell tyrosine kinase-1 (STK-1, gene symbol FLT3), the human homolog of the mouse Flk2/Flt3 gene (Small et al., 1994). This growth factor receptor is expressed in CD34+ human bone marrow (stem/progenitor) cells. We have mapped the gene for STK-1 using PCR screening of a human-rodent somatic cell hybrid panel, and fluorescence in situ molecular hybridization (FISH) of STK-1 genomic probes to mitotic chromosomes of normal human lymphocytes. The results of both analyses show that the gene for STK-1 (FLT3) localizes to chromosome 13q12-->q13.

Animals↗
PubMed1995

Pore properties of Lymnaea stagnalis neuron stretch-activated K+ channels

In many neurons, variations in membrane excitability are determined by a resting K+ conductance whose magnitude is modulated via neurotransmitters. The S-channel in Aplysia californica mechanosensory neurons is such a conductance, but it has also been shown to be a stretch-activated K+ channel. In this, it resembles stretch-activated K+ channels common to all molluscan neurons. Comparable channels are widespread, having been reported in molluscan and insect muscle and various vertebrate cells. The pore properties of the S-channel and similar stretch-activated K+ channels have received only sporadic attention. Here we examine, at the single-channel level, the permeation characteristics of a stretch-activated K+ channel from neurons of the mollusc Lymnaea stagnalis. Michaelis­Menten constants (Km) for the conductance, obtained separately for inward (28 mmol l-1) and outward (91 mmol l-1) K+ currents, suggest that the channel presents to the external medium, where [K+] is lower, a higher-affinity site than it presents to the cytoplasmic medium. This may help to ensure that influx is not diffusion-limited at potentials near the resting potential, i.e. near the K+ equilibrium constant. Anomalous mole fraction behavior, observed when the ratio of permeant ion (K+ and Rb+) was varied, indicated that the stretch-activated K+ channel is a multi-ion pore. The ion selectivity sequence determined using reversal potentials under bi-ionic conditions was Cs+>K+>Rb+>NH4+>Na+>Li+, and using relative conductance in symmetrical solutions, the sequence was Tl+=K+>Rb+>NH4+>>Na+=Li+=Cs+. Extreme variations in extracellular pH from 4.7 to 11.4 had no effect on stretch-activated K+ channel conductance, whereas normal concentrations of extracellular Mg2+ reduced inward K+ current. Intracellular, but not extracellular, Ba2+ produced a slow, open channel block with an IC50 of 140±80 µmol l-1. These pore properties are compared with those of other stretch-activated K+ channels and of K+ channels in general. In spite of a greater than half order of magnitude difference in the cytoplasmic [K+] in marine (Aplysia californica) and freshwater (Lymnaea stagnalis) molluscs, the conductances of stretch-activated K+ channels from the two groups are very similar.

Journal Article↗
PubMed1995

Clarithromycin versus cefaclor in lower respiratory tract infections. The Canadian Bronchitis Study Group.

A randomized study was done to compare the efficacy of clarithromycin 250 mg or 500 mg b.i.d., vs. cefaclor 250 mg or 500 mg t.i.d. for 7-14 d in 197 evaluable patients with lower respiratory tract infection. Ninety-five patients received clarithromycin, 88 with acute bronchitis or exacerbation of chronic bronchitis, and 7 with pneumonia. One hundred and two patients received cefaclor, 86 with bronchitis and 16 with pneumonia. Ten patients (10.5%) in the clarithromycin group did not complete the trial, 5 (5.3%) because of adverse event, and 3 (3.2%) because of clinical failure. Similarly, 11 patients (10.8%) did not complete cefaclor, 2 (2%) because of adverse event, and 7 (6.9%) because of clinical failure. Clinical cure or improvement was observed in 90 (94.7%) of patients on clarithromycin vs. 92 (90.2%) on cefaclor, p = 0.66. Bacteriologic cure was seen in 26/36 patients (72.2%) on clarithromycin vs. 28/40 patients (70%) on cefaclor, p = 0.28. Clarithromycin is just as effective as cefaclor for lower respiratory tract infections and is well tolerated.

Bronchitis↗
PubMed1994

Acute myocardial infarction in angiographically normal coronary arteries following induction of general anesthesia.

Coronary spasm may occur with angiographically normal and diseased coronary arteries. General anesthesia has been described only rarely as a triggering event for coronary artery spasm, and only once before in the presence of angiographically normal coronary arteries. We have now seen three patients presenting with acute ST-segment elevation following induction of general anesthesia with enzyme evidence of myocardial necrosis in two patients. Cardiac catheterization was performed in all three patients with one of the procedures performed on an emergency basis owing to hemodynamic compromise. All three patients demonstrated angiographically normal coronary arteries. The electrocardiograms and coronary arteriograms are presented, and possible mechanisms for the injury pattern seen on the electrocardiogram are discussed. Coronary vasospasm causing an acute injury pattern on the electrocardiogram can be caused by general anesthesia and has to be recognized promptly and treated appropriately to prevent more serious complications.

Anesthesia, General↗
PubMed1994

STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells.

We cloned the cDNA for stem cell tyrosine kinase 1 (STK-1), the human homolog of murine Flk-2/Flt-3, from a CD34+ hematopoietic stem cell-enriched library and investigated its expression in subsets of normal human bone marrow. The cDNA encodes a protein of 993 aa with 85% identity and 92% similarity to Flk-2/Flt-3. STK-1 is a member of the type III receptor tyrosine kinase family that includes KIT (steel factor receptor), FMS (colony-stimulating factor 1R), and platelet-derived growth factor receptor. STK-1 expression in human blood and marrow is restricted to CD34+ cells, a population greatly enriched for stem/progenitor cells. Anti-STK-1 antiserum recognizes polypeptides of 160 and 130 kDa in several STK-1-expressing cell lines and in 3T3 cells transfected with a STK-1 expression vector. Antisense oligonucleotides directed against STK-1 sequences inhibited hematopoietic colony formation, most strongly in long-term bone marrow cultures. These data suggest that STK-1 may function as a growth factor receptor on hematopoietic stem and/or progenitor cells.

Amino Acid Sequence↗
PubMed1994

Jejunobronchial fistula: case report and brief discussion of the literature.

Enterobronchial fistulas are extremely rare. Herein we describe a 69-year-old man who had previously undergone resection of a gastric adenocarcinoma. He was hospitalized because of a fever, cough that produced brown sputum, dyspnea at rest, and an 18-kg weight loss during the previous year. A jejunobronchial fistula was diagnosed when methylene blue, which had been added to an enteric feeding, was detected in a bronchus during bronchoscopy. In addition to the current case, we include a brief review of the literature.

Aged↗
PubMed1993

Mutation of the cyclin-dependent kinase phosphorylation site in simian virus 40 (SV40) large T antigen specifically blocks SV40 origin DNA unwinding.

A mutant simian virus 40 (SV40) large tumor (T) antigen bearing alanine instead of threonine at residue 124 (T124A) failed to replicate SV40 DNA in infected monkey cells (J. Schneider and E. Fanning, J. Virol. 62:1598-1605, 1988). We investigated the biochemical properties of T124A T antigen in greater detail by using purified protein from a baculovirus expression system. Purified T124A is defective in SV40 DNA replication in vitro, but does bind specifically to the viral origin under the conditions normally used for DNA replication. The mutant protein forms double-hexamer complexes at the origin in an ATP-dependent fashion, although the binding reaction requires somewhat higher protein concentrations than the wild-type protein. Binding of T124A protein results in local distortion of the origin DNA similar to that observed with the wild-type protein. These findings indicate that the replication defect of T124A protein is not due to failure to recognize and occupy the origin. Under some conditions T124A is capable of unwinding short origin DNA fragments. However, the mutant protein is almost completely defective in unwinding of circular plasmid DNA molecules containing the SV40 origin. Since the helicase activity of T124A is essentially identical to that of the wild-type protein, we conclude that the mutant is defective in the initial opening of the duplex at the origin, possibly as a result of altered hexamer-hexamer interactions. The phenotype of T124A suggests a possible role for phosphorylation of threonine 124 by cyclin-dependent kinases in controlling the origin unwinding activity of T antigen in infected cells.

Alanine↗
PubMed1992

Uses and misuses of oxygen in hospitalized patients.

PURPOSE: To document the use/misuse of oxygen therapy as compared with antibiotics in internal medicine inpatients. To determine whether the same care was being taken in the prescription and administration of both forms of therapy. PATIENTS: Ninety-six eligible patients at a university teaching hospital were entered into a study examining the use of oxygen. They were compared with 60 patients for whom antibiotics were prescribed. MATERIAL AND METHODS: Three hundred thirty consecutive newly admitted patients were screened for the presence of either (1) oxygen apparatus at the bedside, (2) physician orders for oxygen, or (3) oxygen orders noted in nursing kardex. Those meeting one of these three criteria were observed on up to four occasions over 48 hours following study entry. Similarly, patients were screened for medical orders or nursing medication kardex notation for antibiotics and were also observed for proper prescription and administration of medication. Procedural errors, determined by kardex audit and direct patient observation, were compared for the individuals with specific oxygen orders and those receiving antibiotics. RESULTS: Oxygen delivery apparatus was found in the room in 17 of 96 patients without it ever having been ordered by the physician or noted in the nursing kardex. In 27 of 96 patients, oxygen was noted in the nursing kardex and administered to patients without a physician order. There were no cases of antibiotic therapy without a physician order. Observations of 47 patients with specific orders for oxygen revealed the following errors: (1) physician order incorrectly transcribed to nursing kardex (16%), (2) flow meter off (34%), (3) oxygen delivery apparatus improperly worn (57%), (4) wrong fractional inspired oxygen concentration (58%). Improper transcription of antibiotic orders occurred on only one occasion (2%), and antibiotics were improperly administered in 5%. Arterial blood gas determinations preceded oxygen orders in 61%, whereas microbiologic cultures preceded antibiotic orders in 87% of the patients. CONCLUSIONS: We conclude that oxygen therapy is neither prescribed nor administered with the same attention that is given to other drugs such as antibiotics. Oxygen prescription and/or delivery is associated with significantly greater error than that seen with antibiotics. Education of medical personnel should stress more prudent prescription and use of oxygen in hospitalized patients.

Anti-Bacterial Agents↗
PubMed1992

The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth.

The beta A4 protein, the major component of the amyloid deposition characterizing Alzheimer's disease, derives from the amyloid protein precursor (APP), an integral membrane protein with soluble derivatives. The function of APP is unknown. Both soluble and membrane-associated human brain APP (10(-10) M) significantly increased (P less than 0.025) neurite length and branching in pheochromocytoma PC12 cells, but did not affect the number of neurites per cell. At higher concentrations, APP was cytotoxic, with a half-maximal concentration of 5 x 10(-9) M. Nerve growth factor (NGF) is known to affect APP expression in vivo and in vitro. Antibodies to APP specifically diminished the effects of NGF on neurite length and branching. Thus APP may act to mediate neurite outgrowth promotion by NGF.

Alzheimer Disease↗
PubMed1992

Exertional dyspnea and ventilation in hyperthyroidism.

Dyspnea is recognized to be an important feature in patients with hyperthyroidism at rest and during exercise. However, its etiology is not well-understood. Since dyspnea is thought to be related to the perception of excessive ventilatory effort, we explored the possibility that dyspnea in these patients might be related to an inappropriate ventilatory response to the increased metabolic rate. We studied 11 hyperthyroid patients and 11 age- and sex-matched controls, performing spirometry, lung volumes, mouth pressure measurements, and incremental exercise test. Central drive was estimated by measuring P0.1 and sensation of dyspnea by the Borg scale. We found that hyperthyroid patients (1) have higher ventilation than normal subjects during exercise even when corrected for VCO2 levels; (2) this increased ventilation is secondary to increased central drive which is correlated to the T3ria level (r = 0.85, p less than 0.01); (3) hyperthyroid patients are more dyspneic than controls; and (4) the increased drive can be normalized by beta-blockade. We conclude that the main ventilatory abnormality in hyperthyroid patients is an inappropriate increase in respiratory drive, possibly secondary to increased adrenergic stimulation.

Adult↗
PubMed1990

Coronary artery spasm induced by anesthesia: a case report and review of the literature.

Anesthesia-induced coronary vasospasm has been reported only rarely. We report a case, without previous cardiac history, in which immediately after anesthesia induction a marked ST elevation was noted on the EKG monitor. Premature ventricular contractions as well as non-sustained ventricular tachycardia were noted. These changes resolved immediately after nitroglycerin infusion and 75 mg of lidocaine were given. A coronary angiogram revealed normal coronary arteries and left ventriculogram. Ergonovine stimulation was not performed. The patient was discharged home on calcium entry blockers and nitrates. Exercise stress test two weeks after discharge was negative for ischemia. Induction of anesthesia triggering coronary spasm has been reported rarely, and to our knowledge never in the presence of angiographically normal coronary anatomy. Coronary vasospasm with typical EKG changes--namely, ST elevation and ventricular arrhythmias--has to be included as a possible complication of general anesthesia. Recognition of this syndrome allows prompt treatment and prevention of future episodes.

Anesthesia, General↗
PubMed1988

Characterization of N-myc amplification units in human neuroblastoma cells.

A set of DNA clones comprising 48 independent HindIII fragments (215 kilobases of sequence) was derived from the N-myc amplification unit of the neuroblastoma cell line NGP. These clones were used to investigate N-myc amplification units in NGP cells and 12 primary neuroblastoma tumors. Three parameters were evaluated: (i) the number of rearrangements from germ line configuration that had occurred during the amplification process; (ii) the homogeneity of amplification units within individual tumors; and (iii) the conservation of amplified sequences among different tumors. The results indicated that remarkably few rearrangements had occurred during amplification, that the amplification units within any one tumor were quite homogeneous, and that although each tumor contained a unique pattern of amplified DNA fragments, there was considerable similarity between the amplification units of different tumors. In particular, the amplification units were strikingly similar over a contiguous domain of at least 140 kilobases surrounding the N-myc structural gene.

Cell Line↗
PubMed1986

Oral herpes simplex infection in bullous pemphigoid.

A case of recurrent oral herpes simplex virus infection complicating bullous pemphigoid is described. The possibility of herpesvirus infection should always be considered in immunosuppressed patients with oral ulceration, including those patients with bullous disorders.

Aged↗
PubMed1985

The anatomy of supercoiled loops in the Drosophila 7F locus.

The genome in eucaryotes is organized into a series of supercoiled loops, topologically anchored at their bases by components of the nuclear matrix. Previous studies have shown that active genes are associated with the nuclear matrix. We wished to know whether loops in general were solely organized by active genes. We therefore examined a locus of the Drosophila X-chromosome comprising 163,000 bp of continuous DNA sequences and devoid of known active genes. Of the 52 EcoRI restriction fragments comprising this region, we found 5 anchored fragments which non-randomly organized this region into 4 DNA loops. Each of the 5 anchored fragments contained a transcribed sequence. These results strongly suggest that supercoiled loops are organized in a specific fashion with respect to DNA sequence, with the anchorage points exclusively demarcated by transcriptionally active genes.

Animals↗