Biomedical subjects
J B Davis
Publications and source records attributed to J B Davis.
Purification of multiple forms of glial growth factor.
Glial growth factors (GGFs) were purified from bovine pituitaries using an in vitro rat Schwann cell mitogenesis assay. In addition to an approximately 34-kDa species termed GGF-I, similar in molecular mass to a previously identified molecule (Lemke, G. E., and Brockes, J. P. (1984) J. Neuroscience 4, 75-83), two species named GGF-II and GGF-III were characterized with apparent molecular masses of approximately 59 and approximately 45 kDa, respectively. Highly purified preparations of all species share a similar dose-dependent stimulation of Schwann cell DNA synthesis at nanomolar concentrations. Forskolin synergizes with all three GGFs, shifting their dose dependence 3-8-fold into the sub-nanomolar range. The GGFs, which contain N-linked carbohydrate groups not essential for their in vitro mitogenic effects, are three distinct members of a novel family of glial cell mitogens.
Osteomyelitis of the spine in a burn patient due to Candida albicans.
A 38-year-old white-skinned male was burned in an ultralight plane crash and sustained a 59 per cent body surface area burn, mostly full thickness skin loss. A fracture of the first lumbar vertebra was noted at admission which was treated without surgery. Candida septicaemia was diagnosed and treated during the acute phase of injury. Extensive grafting was required. Following discharge, the patient began experiencing low-grade back pain which was aggravated on postburn day 277 by a fall down a flight of stairs. Spinal radiographs obtained following this fall revealed osteomyelitis at the level of the eighth and ninth vertebrae with an intervertebral abscess. Following evacuation of the disc space during surgery, the organism was identified as Candida albicans. Treatment with amphotericin B and later fluconazole was initiated. Recovery was uneventful. The infection, probably of a haematogenous origin, is the first such case reported in the literature to our knowledge.
A small molecular mass inhibitor of growth of 3T3 cells and porcine aortic smooth muscle cells released from the macrophage cell line P388D1.
Murine peritoneal macrophages and the macrophage-like cell line, P388D1, were found to release both mitogenic and inhibitory modulators of growth of cells in culture. These growth factors were effective against both murine Swiss 3T3 fibroblasts and porcine aortic smooth muscle cells as assessed by [3H]thymidine incorporation into DNA and by measurement of cell number. Partial characterisation of the inhibitory activity demonstrated it to be lost on dialysis using a membrane with a 10 kDa cut-off, trypsin sensitive, heat stable, and slightly sensitive to freeze-thawing. The inhibitory activity not only affected cell growth but was found to change the morphology of porcine aortic smooth muscle cells. Gel permeation studies showed an estimated molecular mass in the range 2.5 to 6.5 kDa. The inhibitory activity could be partially purified using ion-exchange chromatography. Experiments with a neutralising antibody against transforming growth factor beta (TGF-beta) showed that TGF-beta is not responsible for the activity observed. Indomethacin had no effect on the production of inhibitor suggesting that it is not an inhibitory prostanoid. The inhibitory activity was not due to a non-specific toxic mechanism as confirmed by a [3H]adenine release assay. Incubation of P388D1 cells with cycloheximide prevented the release of inhibitory activity.
The amyloid beta-protein of Alzheimer's disease is chemotactic for mononuclear phagocytes.
The cellular pathology of Alzheimer's disease includes an accumulation of microglia surrounding the amyloid plaques. We report that human amyloid beta-protein is chemotactic for murine resident peritoneal macrophages and rat microglia, which may account for the increased density of microglia in plaques. A maximal chemotactic response was observed at 1-10nM, with a 2.5 fold increase in activity over controls for both classes of mononuclear phagocytes. The neurotoxic peptide fragment (25-35) of amyloid beta-protein is similarly chemotactic, while a control scrambled version and the precursor protein are not chemotactic. These results indicate that beta-protein may influence plaque formation via the recruitment of phagocytes, with consequent implications for the future development of treatments for Alzheimer's disease.
Output factors for blocked fields.
This study investigates the output from blocked treatment fields with 6 MV and 18 MV photons. Square fields, defined by collimators, were blocked down to smaller symmetrical square, rectangular and asymmetrical rectangular fields using blocks on a tray beneath the collimators. Up to 7.5% difference was found between the output measured for the blocked field and the output calculated using a collimator output factor for the surface field size. A method is described by which output factors for the blocked fields can be measured and used in practice. Three methods of approximating these output factors are also presented.
The axon may control Schwann cell responses to growth factors.
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The variation of wedge factors with field size on a linear accelerator with wedge tray beneath secondary collimators.
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Platelet-derived growth factors and fibroblast growth factors are mitogens for rat Schwann cells.
Rat sciatic nerve Schwann cells in culture respond to a limited range of mitogens, including glial growth factor, transforming growth factors beta-1 and beta-2 (TGF-beta 1, TGF-beta 2), some cell membrane-associated factors, and to agents such as cholera toxin and forskolin which raise intracellular levels of cAMP. These responses require the presence of FCS, which exhibits little or no mitogenic activity in the absence of other factors. However, we recently found that forskolin greatly potentiates the mitogenic signal from TGFs-beta 1 and beta 2, raising the possibility that cAMP might couple other factors to mitogenesis. We have therefore screened a range of candidate mitogens using DNA synthesis assays. Other than TGFs-beta and glial growth factor, none of the factors tested were mitogenic in the presence of 10% serum alone. With the addition of forskolin, however, porcine PDGF, human PDGF, acidic and basic FGF were potent mitogens for rat Schwann cells, stimulating DNA synthesis and increasing cell number. Cholera toxin and dibutyrylcyclicAMP, but not 1,9-dideoxyforskolin, can substitute for forskolin indicating that the mitogenic effect is mediated via adenylyl cyclase activation. Porcine PDGF gave half-maximal stimulation at 15 pM, and human PGDF an equivalent response at 1 nM. Basic FGF was half maximal at 5 pM, acidic FGF at 1 nM. The recognition of PDGFs and FGFs as mitogens for Schwann cells has many implications for the study of Schwann cell proliferation in the development and regeneration of nerves, and in Schwann cell tumorigenesis.
Percutaneous endoscopic gastrostomy. Do surgeons and gastroenterologists get the same results?
Numerous investigators have reported the safety, cost effectiveness, and low morbidity and mortality of percutaneous endoscopic gastrostomy (PEG) but not studies compare the results of gastroenterologists and surgeons performing PEG. In a retrospective review of PEG performed at our institution, morbidity and mortality were compared between these two groups. The procedure was performed by either the surgical service (n = 49) or gastroenterology service (n = 51). One hundred PEGs were successfully placed in 92 patients. Three placement failures occurred in the gastroenterology group. Major complications were defined as conditions requiring operative intervention or resulting in death. Minor complications, using a defined list (13 different complications), were those not serious or life-threatening, which were managed medically or resolved without treatment. Twenty-nine minor (17 patients) complications and 3 major (3 patients) complications occurred in the gastroenterology group. Thirteen minor (11 patients) complications and 4 major (4 patients) complications occurred in the surgery group. Overall 30-day mortality was 14 per cent (13 patients), two of which were probably procedure-related in the gastroenterology group. In both groups, there was no difference in the numbers of patients who had complications (P greater than 0.05). The complication rate (numbers of complications/number of patients) doubled in the gastroenterology group compared with the surgery group for minor (P less than 0.04) and total complications (minor and major--P less than 0.06). Since PEG is a procedure frequently performed by gastroenterologists, it is imperative that surgeons, particularly those not performing endoscopy, be aware of the potential morbidity associated with PEG.
Macrophages modify beta-VLDL by proteolysis and enhance subsequent lipid accumulation in arterial smooth muscle cells.
Murine resident peritoneal macrophages (MRPM), incubated with beta-very low density lipoprotein (beta-VLDL), modify the beta-VLDL, producing an increase in the mobility of the lipoprotein. The modification does not result in an increase of thiobarbituric acid-reactive substances (TBARS) in the lipoprotein, and is not inhibited by butylated hydroxyanisole (BHA), EDTA, removal of copper and iron from the medium, or by diphenyliodonium (DPI), suggesting that the mechanism of modification is independent of oxidation. Macrophage conditioned medium performed the modification in the absence of cells, and phenylmethylsulphonyl fluoride (PMSF) inhibited beta-VLDL modification, whereas other protease inhibitors did not, suggesting that a secreted neutral serine protease may possibly be involved in the mechanism. The modified beta-VLDL enhanced the accumulation of cholesterol esters by smooth muscle cells (SMC).
Transforming growth factors-beta 1 and beta 2 are mitogens for rat Schwann cells.
Transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 2 were found to be potent mitogens for purified rat Schwann cells, each stimulating DNA synthesis in quiescent cells and also increasing their proliferation rate. Half-maximal stimulation of DNA synthesis occurred at approximately 0.1 ng/ml TGF-beta 1 or TGF-beta 2. Mitogenic stimulation by TGF-beta 1 and TGF-beta 2 was enhanced by forskolin, which activates adenylate cyclase, at concentrations up to 0.5 microM forskolin. However, at 5 microM forskolin, the synergistic interaction between forskolin and TGF-beta 1 was abolished. These results are in contrast to the observed synergy between forskolin and another Schwann cell mitogen, glial growth factor (GGF). Both 0.5 and 5 microM forskolin were found to enhance the stimulation of DNA synthesis by partially purified GGF (GGF-CM). As well as being functionally distinct, TGF-beta 1 and GGF-CM activities were also physically separable by chromatography on a Superose 12 gel permeation column. Thus, TGF-beta 1 and beta 2 are rat Schwann cell mitogens, and Schwann cells are one of the few normal cell populations to respond mitogenically to TGF-beta.
Myoglobinuria exacerbates ischemic renal damage in the dog.
The effects of intramuscular glycerol on ischemic acute renal failure was investigated in dogs. Anesthetized dogs received a bilateral 120-min renal artery obstruction (RAO) alone, RAO plus 5 ml/kg of 50% glycerol or RAO plus 5 ml/kg of 75% glycerol. Control groups received the glycerol injection, but not RAO. Renal histopathology was minimal in dogs receiving glycerol alone. In RAO dogs, those receiving 50% glycerol showed diffuse acute tubular necrosis (ATN), while those receiving 75% glycerol had severe ATN with extreme mortality. Changes in serum creatinine, creatinine clearance, and fractional excretion of sodium were consistent with the histopathologic changes. We conclude that myoglobinuria, of a degree insufficient to cause renal failure itself, can interact with renal ischemia to significantly exacerbate the renal damage produced.
Successful gastrorrhaphy on ECMO.
From April 1985 to November 1987, over 100 infants were evaluated for extracorporeal membrane oxygenation (ECMO) in the treatment of respiratory failure. Of these infants, 40 underwent ECMO after failure of conventional treatment. Four developed gastroduodenal perforations. One developed a perforation prior to going on ECMO and died after several hours on ECMO, one developed a perforation while being treated conservatively for respiratory failure that never required ECMO, and two developed perforations requiring laparotomy while on ECMO. These two infants constitute the first report of successful gastrorrhaphy in infants while being supported by ECMO and anticoagulation with heparin. Particular measures helpful in the management of these infants included near-total cardiopulmonary bypass, reduction of the activated clotting time to 170 to 200, transverse abdominal incision for exposure, use of electrocautery, appropriate drainage of the operative site, insertion of a gastrostomy for gastric decompression and irrigation, rapid weaning from ECMO as soon as respiratory support could be provided by conventional methods, and the use of massive blood and platelet transfusions. In summary, 33 of 40 infants undergoing ECMO survived. Furthermore, two of the three infants with intestinal perforation who underwent ECMO have survived without significant short-term sequelae, and are 24 and 30 months of age, respectively. Therefore, we believe that despite severe respiratory failure requiring ECMO and anticoagulation with heparin, infants with intestinal perforation can be managed surgically with anticipated survival and good long-term prognosis.
A look at Indiana's Medical Malpractice Act.
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Growth factors and corneal epithelium.
Regeneration of corneal epithelium following injury is essential for visual rehabilitation. A limited number of approaches are available for treating patients who fail to heal epithelial injuries adequately. The presence of specific receptors for epidermal growth factor (EGF) on epithelial cells suggests that this potent mitogen may play a role in normal epithelial wound healing. Topical application of biosynthetic human EGF significantly accelerated epithelial regeneration in primates following epikeratophakia surgery. Epidermal growth factor alone and with fibronectin accelerated epithelial regeneration of rabbits following mild alkali burns. Since prolonged exposure of cells to EGF is necessary to induce mitosis, the dynamics of EGF in the eye and with various lenses was studied. When applied in methylcellulose-based eye drops, 90% of the EGF was lost from tear film within 10 min, while a small amount (10%) remained associated with conjuctival tissue. Soft contact lenses or epikeratophakia lenticles took up substantial amounts of EGF (50 micrograms) and released 85% of the EGF within 24 h, with a half-life of 4 h in vitro. Epidermal growth factor did not diffuse through corneas or lenticles and did not promote epithelial downgrowth along sutures in primate corneas. These results suggest that biosynthetic growth factors may be useful in the treatment of some epithelial injuries.
Selective intraoperative cholangiography. A case for its use on an anatomic basis.
The routine use of intraoperative cholangiography has vastly improved the results of common duct exploration by reducing the number of negative explorations. The controversy surrounding the use of routine versus selective intraoperative cholangiography has centered on the incidence of unsuspected common-duct stones. A prospective study was designed to examine both preoperative clinical data and intraoperative anatomical information to determine criteria that would identify patients who would not require cholangiography. One hundred consecutive patients undergoing cholecystectomy were included in the study. When considering patients without preoperative clinical data suspicious for common duct stones three anatomical conditions were identified in which common duct stones would not be present: cystic duct less than 3 mm; smallest stone size greater than 6 mm; a single stone. Using intraoperative criteria as a basis for cholangiography, 44 per cent of patients without clinical suspicion of common duct stones would be spared an intraoperative cholangiogram. It is the authors' opinion that the addition of anatomic findings to preoperative clinical data can further reduce or eliminate the risk of unsuspected stones while sparing a large number of patients the risk and expense of routine intraoperative cholangiography and possible negative duct exploration.