Biomedical subjects

F Alexander

Publications and source records attributed to F Alexander.

At least 73 records · Page 4Linked to original sources

PubMed1987

Proteolytic processing of avian sarcoma and leukosis viruses pol-endo recombinant proteins reveals another pol gene domain.

Three pol gene products have been identified in avian retroviral particles: the full-length 95-kilodalton (kDa) beta chain of reverse transcriptase and two proteolytic cleavage products of beta, a 63-kDa reverse transcriptase alpha chain derived from the amino terminus of beta and a 32-kDa (pp32) endonuclease from its carboxy terminus. By using molecularly cloned retroviral DNA and synthetic oligonucleotides to introduce initiator ATGs and codons corresponding to the authentic N termini, we constructed two bacterial-expression clones; one clone contains the entire pol gene, and the other contains the region encoding the pp32 domain. A 99-kDa protein was synthesized in Escherichia coli by the full-length clone, and a 36-kDa protein was synthesized by the endonuclease domain clone. The recombinant proteins exceeded the size of both the mature viral beta chain and the pp32, respectively, by approximately 4 kDa. These larger sizes, however, are consistent with predictions from the DNA sequence of the pol gene. Processing of the recombinant pol proteins was examined by using p15 protease purified from virus particles and antisera directed against synthetic peptides corresponding to three domains in pol. Proteolytic digestion of the 99-kDa product with p15 produced a 63-kDa protein that comigrated on polyacrylamide gels with the alpha chain of reverse transciptase and a 36-kDa fragment that comigrated with the endonuclease domain product. Further digestion of the 36-kDa protein yielded a 32-kDa protein that comigrated with viral pp32 endonuclease. Thus, we concluded that two p15-sensitive sites exist in pol. Cleavage at the previously identified site produces alpha, and cleavage at the newly discovered site removes approximately 4 kDa from the C terminus of the primary protein product. Since the 36-kDa protein was also detected in protein isolated from virus particles, it seems probable that processing at the C-terminal site is a normal step in the production of mature beta and pp32 endonuclease products.

Amino Acid Sequence↗

PubMed1987

Short term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects.

Short term variability in FEV1 and responsiveness to inhaled bronchodilator were measured in 150 patients with obstructive ventilatory defects. The range of initial FEV1 was 0.5-4.71 and the natural variability over a 20 minute period when expressed in absolute terms was similar over the entire range, and differed insignificantly from that found in normal subjects. The increase in FEV1 and vital capacity (VC) required to exclude natural variability with 95% confidence in these patients was 160 ml and 330 ml respectively. Natural variability when expressed in percentage terms was negatively correlated with the level of FEV1 recorded. The analysis of changes in FEV1 and VC after administration of bronchodilator used absolute and percentage criteria for response. The number of responders differed considerably according to the criterion used. In those defined by the absolute criterion as responders there was no evidence that size of response was related to level of FEV1. Percentage criteria have traditionally been used to identify responses to bronchodilator that may be clinically useful, while absolute criteria, although statistically valid, have not been favoured. Reappraisal of the criteria used and their limitations and implications is required.

Adolescent↗

PubMed1987

Effects of isoproterenol-induced tachycardia on myocardial blood flow and glycogen in the fetal lamb.

In utero tachycardia is a cause of fetal congestive heart failure and fetal hydrops. We investigated the effects of isoproterenol-induced tachycardia (IIT) on cardiac output and its distribution, on myocardial blood flow and intramyocardial blood flow distribution as well as on regional myocardial glycogen in 8 chronically prepared, near-term fetal lambs and 3 control twins (for myocardial glycogen only). Blood flows were measured by the radioactive microsphere method, myocardial glycogen by an enzymatic method. In animals with IIT (heart rate 200-280), cardiac output (excluding lung flow) increased from 0.399 to 0.544 ml/g/tissue/min (+36%), blood flow to the carcass increased from 0.19 to 0.32 ml/g/tissue/min (+68%) and myocardium increased from 2.31 to 7.72 ml/g/tissue/min (+234%), while kidney blood flow decreased from 1.34 to 0.72 ml/g/tissue/min (-46%). The normal intramyocardial blood flow distribution and predominance of flow to the endocardium of both ventricles was preserved during IIT. In the three sets of twins, glycogen was lower in the right (RV) and left (LV) ventricular walls of each animal stressed by IIT (mean RV = 0.19, mean LV = 0.44) than of its unstressed twin (mean RV = 0.75, mean LV = 0.70). Furthermore, a metabolic acidemia (mean pH 7.21, mean BE -8.4) developed in the stressed animals. Although we were unable to demonstrate regional myocardial ischemia at the maximal fetal heart rates achieved by isoproterenol infusion, our data suggest that metabolic acidemia and myocardial glycogen depletion are consequences of severe inotropic and chronotropic stress in the fetal lamb.

Animals↗

PubMed1986

Comparative pathology of prevalent and incident cancers detected by breast screening. Edinburgh Breast Screening Project.

In the Edinburgh Breast Screening Project 210 cancers were detected from commencement in 1979 up to December, 1984. By this time the full initial cohort had completed at least 3 visits and a proportion had attended for up to 5 visits, so pathological characteristics for prevalent and incident cancers could be compared. The main differences are in distribution of histological type of cancer, detection of occult invasive disease, and lymph-node positivity among incident tumours. Only the first of these was statistically significant. This evaluation shows that cancer detection by screening in Edinburgh conforms with screening theory, in which detection of good prognosis tumours is favoured at the prevalence screens, and faster growing, aggressive tumours are found at the incidence screens. Qualitative histopathology may provide a better measure than standard quantitative judgments of size and lymph node status to compare the varieties of cancer detected by screening programmes and to understand the biology of the disease.

Aged↗

PubMed1986

Cyclo-oxygenase products mediate hypoxic pulmonary hypertension.

High-risk infants with a fetal pattern of circulation demonstrate hyperactivity of the pulmonary vascular bed in response to stimuli including mucous plugging, atelectasis, and endotrachial tube suctioning. The resultant increase in pulmonary vascular resistance (PVR) leads to pulmonary hypertension, severe right-to-left shunting, and hypoxemia. Stimuli that trigger pulmonary hypertension cause hypoxia, suggesting the importance of hypoxic pulmonary vasoconstriction (HPV). Although many humoral mediators of HPV have been hypothesized, none have been proven. This study investigates the possible role of the cyclo-oxygenase derivatives thromboxane A2 and prostacyclin as determinants of hypoxic pulmonary hypertension. Open-chested lambs were ventilated with 13% O2 prior to and following treatment with OKY 046, a selective thromboxane inhibitor. In untreated lambs, the partial pressure of arterial oxygen fell from 80 +/- 27 (mean +/- SD) to 35 +/- 13 mm HG (P less than .01). The mean arterial pressure (MAP) remained at 50 +/- 7 mm HG, and the cardiac output (CO) was unchanged at 0.8 +/- 0.2 L/min. The mean pulmonary arterial pressure (MPAP) rose from 11 +/- 4 to 20 +/- 4 mm HG (P less than .01) whereas the PVR increased 70% (P less than .01). TxB2 rose from 147 +/- 85 to 271 +/- 154 pg/mL (P less than .05), and 6-keto-PGF1 alpha rose from 105 +/- 96 to 142 +/- 110 pg/mL. These substances are the hydrolysis products of TxA2 and prostacyclin respectively. In animals treated with OKY 046 prior to ventilation with 13% O2, values for MAP, CO, and PVR were similar to those of the nontreatment period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Anal continence following Soave procedure. Analysis of results in 100 patients.

The Soave procedure is an increasingly popular procedure for the definitive therapy of patients with ulcerative colitis. The authors present their experience with 100 patients in whom total proctocolectomy, rectal mucosal stripping, and ileoanal anastomosis (generally using an S-pouch) were carried out. The physiological and anatomical basis of continence is presented, and anastomosis at the top of the columns of Morgagni is recommended. Of the 100 patients in whom this procedure was performed, there was no mortality either in-hospital or later. Of the 12 patients in whom the anastomosis was done 1 cm above the top of the columns (and thus columnar epithelium was retained), six have recurrent anorectal disease, but all are continent both day and night. Three patients in whom the anastomosis was done at the dentate line have had difficulty with continence; two are now continent, but one, after being totally incontinent for 4 years, has required a permanent ileostomy. Of the 69 patients in whom the anastomosis was done at the top of the columns of Morgagni, five are incontinent at night only and two have seepage during both day and night. Thus, if the anastomosis is done at the level recommended, namely, at the top of the columns of Morgagni, retaining no columnar epithelium and anastomosing the ileal pouch to transitional epithelium (which the authors believe not to be subject to the disease of ulcerative colitis), daytime continence will be achieved in 97% and total day and night continence in 90%. The evidence presented suggests that a properly done pull-through procedure with ileoanal anastomosis is the procedure of choice for ulcerative colitis.

Adolescent↗

PubMed1986

Effect of cationic proteins on the glomerular deposition of anionic proteins and immune complexes.

When 3 mg of cationized human IgG (cIgG, pI greater than 9) was injected intravenously into mice and followed 15 min later by 3 mg anionized bovine serum albumin (aBSA, pI = 4), deposits were detected along the capillary loops and in the mesangium. Additional infusion of immunoaffinity-purified rabbit anti-BSA antibodies 1 h later led to their deposition at the same location. Intravenous injection of an equivalent amount of preformed BSA-anti-BSA or aBSA-anti-BSA immune complexes into mice with glomerular planted cIgG gave rise to few deposits. Similarly, the perfusion of preformed aBSA-anti-BSA complexes in isolated rat kidneys with planted cIgG led to granular deposition of both, but the intensity of staining was less than when sequential perfusions were used. Cationic macromolecules bound to the glomerulus may lead to the deposition of anionic macromolecules and anionic immune complexes.

Animals↗

PubMed1986

Temelastine, a new H1-receptor antagonist.

Temelastine is a selective, competitive histamine H1-receptor antagonist which does not penetrate the central nervous system. The effect of varying doses of temelastine was compared in a randomized, double-blind, controlled study by measuring the inhibition of cutaneous histamine wheals. In twelve subjects single oral doses of 50, 100 and 200 mg of temelastine produced dose-dependent reductions in wheal areas. The inhibition of wheal size was maximal by 2 hr after dosing and was present at 8 hr. At 2 hr the 50, 100, and 200 mg doses reduced the wheal size by 53, 64, and 78%, respectively. Chlorpheniramine, 4 mg, reduced wheal size by 32% at the same period. The ability of temelastine to antagonize the histamine-induced skin reaction over 20 hr was evaluated in a second randomized, double-blind study. Eight subjects participated. Temelastine, 100 mg, produced reductions of 64, 49, 56 and 51% in histamine wheal area at 8, 12, 16 and 20 hr, respectively. Plasma concentrations at these times were 4.04, 2.77, 1.88, and 1.44 mumol/l, respectively. These data suggest that blood levels as low as 1.44 mumol/l may be sufficient to produce an antihistaminic effect, and that daily or twice daily dosing with 100 mg may be adequate to control allergic symptoms.

Adult↗

PubMed1986

Reduction of polymorphonuclear leukocyte accumulations by inhibition of cyclooxygenase and thromboxane syntase in the rabbit.

Thromboxane (Tx) inhibition prevents pulmonary leukostasis after acid aspiration. This observation prompted study of polymorphonuclear leukocyte (PMN) accumulations and products of cyclooxygenase. Experiments were conducted with a skin abrasion preparation. Five groups of six rabbits were pretreated intravenously with: (1) placebo, (2) ibuprofen, (3) imidazole and two other Tx syntase inhibitors, (4) OKY 1555, or (5) OKY 046. Zymosan-activated serum (ZAS) and leukotriene B4 were used as chemotaxins and balanced salt solution as control. After pretreatment with placebo, PMN accumulation in leukotriene B4 sites was 2130 +/- 874 PMN/mm3 (mean +/- SD). Pretreatment with ibuprofen, imidazole, or OKY 046 decreased (p less than 0.05) accumulations to 205 +/- 139 PMN/mm3, 485 +/- 387 PMN/mm3, and 504 +/- 260 PMN/mm3, respectively. In ZAS sites, placebo pretreatment led to 2006 +/- 866 PMN/mm3, while the ibuprofen, imidazole, and OKY 046 groups had decreased (p less than 0.05) responses of 295 +/- 218 PMN/mm3, 444 +/- 477 PMN/mm3, and 386 +/- 151 PMN/mm3, respectively. Pretreatment with OKY 1555 did not produce significant reductions in response. Six animals in each group received intradermal injections of the two chemotaxins or Hank's balanced salt solution. Reduction in PMN accumulations after cyclooxygenase and Tx inhibition were similar to those observed in the skin abrasion preparation. Pretreatment with either ibuprofen, imidazole, or OKY 046 resulted in a decreased concentration of Tx in abrasion fluid exudate in response to leukotriene B4, 275 +/- 164 pg/ml, 460 +/- 144 pg/ml, and 440 +/- 260 pg/ml, respectively, as compared with 1168 +/- 380 pg/ml in the placebo group. The reduced responses were not the result of a decrease in regional perfusion as measured by 133Xe washout. The in vitro chemotactic response of PMN to leukotriene B4 and ZAS was unchanged after incubation in either ibuprofen, imidazole, OKY 1555, or OKY 046. These data show that cyclooxygenase and Tx syntase are integrally associated with PMN accumulations.

Animals↗

PubMed1986

Pulmonary and systemic consequences of localized acid aspiration.

Acid aspiration may recruit a generalized inflammatory reaction that can potentiate the local injury. After surgical isolation of bronchi in a group of 15 dogs, 1 milliliter per kilogram of 0.37 normal hydrochloric acid was instilled into either side. After five minutes, platelet and white blood cell counts fell to 10,000 and 1,000 per cubic millimeter (p less than 0.05). Platelet aggregates were noted in blood smears. 111Indium-platelet activity doubled over both the aspirated and nonaspirated lung (p less than 0.05). Physiologic dead space rose from 18 to 67 per cent and to 46 per cent in the aspirated and nonaspirated lung (p less than 0.05). Physiologic shunt increased from 12 to 47 per cent and to 43 per cent (p less than 0.05) on the two sides. Plasma thromboxane B2 levels at 30 minutes rose from 0.28 to 0.93 nanograms per milliliter (p less than 0.05). Edema fluid from the aspirated lung had thromboxane B2 values of 2.87 nanograms per milliliter, indicating pulmonary synthesis. Within five minutes of aspiration, systemic effects were prominent; mean arterial pressure fell from 114 to 46 milliliters of mercury (p less than 0.05), and the cardiac index fell 24 per cent from 106 to 81 milliliters per kilogram per minute (p less than 0.05) along with an 18 per cent decrease in contractility of a rat papillary muscle bathed in plasma from the aspirated dog. Mean pulmonary arterial pressure rose from 12 to 18 millimeters of mercury (p less than 0.05). Despite fluid infusion at 36 milliliters per kilogram per hour to keep wedge pressure constant at 5.5 millimeters of mercury, and sampling of one-third the blood volume, hemoglobin concentration rose 0.9 grams per cent (p less than 0.05) indicating increased microvascular permeability. At autopsy, the aspirated and nonaspirated lung were indistinguishable with congestion, interstitial hemorrhage, and white blood cell infiltrates. Systemic organs showed vascular congestion and edema. These data demonstrate that local aspiration leads to generalized inflammatory sequelae with cardiopulmonary failure.

Animals↗

PubMed1985

The critical level for preservation of continence in the ileoanal anastomosis.

Mucosal proctectomy with ileoanal anastomosis was performed for 90 patients with ulcerative colitis or polyposis over the past 18 years. In three, the anastomosis was at the dentate line. All three had varying degrees of soilage necessitating permanent ileostomy in one. For 12 patients with the anastomosis 1.0 cm proximal to the top of the columns, all were totally continent, but six experienced recurrent disease. For 75 in the third group, the anastomosis was at the top of the columns. Five await ileostomy closure. Of the other 70, none experienced recurrent disease and three have mild nighttime soilage, two of which are less than 1 year following operation. We recommend that the transitional epithelium of the anorectal columns be preserved.

Anal Canal↗

PubMed1985

Esophageal atresia.

Esophageal anomalies present a challenge to the pediatric surgeon and demand close attention and care from the nursing staff as well as the surgical staff. We have encountered a survival rate of 96 per cent for all infants undergoing operation for esophageal atresia. An emergency gastrostomy is recommended as an immediate procedure when the diagnosis is established. In many instances, it can be performed with local anesthesia if the infant is particularly small or has developed aspiration pneumonia. The definitive operation is delayed until the infant is in optimum condition to permit a general anesthetic and thoracotomy. Staging is recommended for all infants with a birth weight of less than 2000 gm. Once the infant has recovered from the operative correction of the malformation, significant late complications are rare, and the great majority of individuals lead completely normal lives.

Dilatation↗

PubMed1985

Thromboxane A2 moderates permeability after limb ischemia.

Reperfusion after limb ischemia results in muscle edema as well as excess secretion of thromboxane A2 (TxA2), an agent associated with permeability increase in other settings. This study tests whether TxA2 moderates the permeability following limb ischemia. A tourniquet inflated to 300 mmHg was applied for 2 hours around the hind limb of four groups of dogs. In untreated animals (N = 25), 2 hours following tourniquet release, plasma TxB2 values rose from 320 pg/ml to 2416 pg/ml (p less than 0.001), and popliteal lymph values rose from 378 pg/ml to 1046 pg/ml (p less than 0.001). Platelet TxB2 was unaltered and plasma 6-keto-PGF1 alpha levels did not vary. Following ischemia, lymph flow (QL) increased from 0.07 to 0.37 ml/h (p less than 0.05), while the lymph/plasma (L/P) protein ratio was unchanged at 0.41. These measurements indicate increased permeability since increase in hydrostatic pressure in a second group by tourniquet inflation to 50 mmHg (N = 7) led to a rise in QL from 0.07 to 0.22 ml/h, but a fall in the L/P ratio to 0.32, a value lower than the ischemic group (p less than 0.05). Pretreatment with the imidazole derivative ketoconazole (N = 11) reduced platelet Tx synthesis from 42 ng to 2 ng/10(9) platelets, but lymph TxB2 levels rose to 1703 pg/ml after ischemia, indicating an extravascular or vessel wall site of synthesis not inhibited by ketoconazole. Pretreatment with a lower molecular weight imidazole derivative OKY 046 (N = 9) inhibited all Tx synthesis after ischemia. Prior to tourniquet inflation, both OKY 046 and ketoconazole lowered plasma TxB2 levels as well as the L/P ratio (p less than 0.05). After ischemia, OKY 046, but not ketoconazole, maintained the L/P ratio at 0.33, a value below that of untreated animals (p less than 0.05). These results indicate that nonplatelet-derived TxA2 modulates both baseline and ischemia-induced increases in microvascular permeability in the dog hind limb.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Membranous glomerulonephritis in a patient with Crohn's disease of the small bowel.

A 12-year-old girl presented with concurrent onset of membranous glomerulonephritis and Crohn's disease of the small intestine. Subsequent investigations failed to implicate any other systemic disease as a cause of the glomerulonephritis. Membranous glomerulonephritis is an immune complex--mediated glomerulopathy frequently associated with underlying systemic disease. The association of immune complex phenomenon with Crohn's disease and the variation of renal abnormalities in parallel with activity of bowel disease in this patient suggest that the glomerulonephritis may be due to the underlying Crohn's disease.

Child↗

PubMed1985

Prostacyclin and thromboxane A2 moderate postischemic renal failure.

Since prostacyclin (PGI2) is known to regulate renal cortical blood flow and since ischemia stimulates thromboxane (Tx) A2 synthesis, the role of these prostanoids in moderating the response to renal ischemia was studied in the rat. At baseline, plasma TxB2 concentration in untreated animals (n = 13) was 357 pg/ml. The left renal pedicle was clamped for 45 minutes after a right nephrectomy (n = 16), which led after 5 minutes of reperfusion to a rise in TxB2 to 2825 pg/ml (p less than 0.001), but there was no change in 6-keto-PGF1 alpha. After 24 hours creatinine levels rose from 0.4 to 3.0 mg/dl (p less than 0.001), and left renal weight rose from 94% to 117% (p less than 0.001) relative to the weight of the right kidney. In nephrectomized but nonischemic sham control rats (n = 7), creatinine level was 0.9 mg/dl and kidney weight 91% after 24 hours. Pretreatment with OKY 046 (n = 13) (2 mg/kg administered intravenously) blocked ischemia-induced TxB2 synthesis, while 6-keto-PGF1 alpha levels rose from 96 to 302 pg/ml (p less than 0.001). There was no increase in creatinine levels or kidney weight relative to the sham group. Pretreatment with ibuprofen (n = 10) (12 mg/kg) or OKY 046 and ibuprofen (n = 9) inhibited TxB2 and 6-keto-PGF1 alpha synthesis, but creatinine levels and renal weight rose (p less than 0.001). Renal histology in OKY 046-pretreated animals was equal to that in nephrectomized controls, while all other ischemic groups showed tubular necrosis. Results indicate that a high PGI2/TxA2 ratio protects against renal ischemia.

6-Ketoprostaglandin F1 alpha↗

PubMed1984

Evolution of the albumin: alpha-fetoprotein ancestral gene from the amplification of a 27 nucleotide sequence.

The genes for alpha-fetoprotein and albumin arose by duplication of an ancestral gene that contained three genetic domains. These domains were generated by the triplication of a primordial genetic domain composed of five exons or subdomains. That the primordial domain itself arose by amplification of a simpler sequence is suggested by nucleotide sequence homologies among the subdomains of the mouse alpha-fetoprotein gene. A detailed analysis of these homologies reveals that each of the five subdomain families contains remnants of a 27-base-long repeat from which the entire alpha-fetoprotein coding sequence has been assembled. A consensus sequence for the 27 nucleotide repeat is derived, and the positions of the repeats within each subdomain are described. A model is proposed for the evolution of the primordial domain by the amplification and divergence of the 27 base-pair sequence, along with the condensation of the repeats into subdomains separated by intervening sequences. It is postulated that the role of intervening sequences may be to limit sequence amplification in genes such as alpha-fetoprotein and albumin whose protein products cannot tolerate size variation.

Albumins↗

PubMed1984

Biliary carcinoma. A review of 109 cases.

One hundred nine patients operated on for bile duct carcinoma were reviewed. Herein, we reported 83 proximal duct tumors, 12 mid-duct tumors, and 14 distal third tumors. Resectability was 10 percent, 33 percent, and 100 percent, respectively, with an operative mortality of 0 percent, 25 percent, and 23 percent. The median survival time and 5 year survival rate for these resected groups were 21 months and 25 percent for proximal duct tumors, 8 months and 0 percent for mid-duct tumors, and 16 months and 20 percent for distal third tumors. Eighty-three patients were treated with strictly palliative procedures with an operative mortality of 19 percent, an adjusted median survival rate of 10.9 months, and a 5 year survival rate of 0. The 2 and 5 year survival rates of patients with well-differentiated tumors were 73 percent and 15 percent, respectively, whereas for patients with poorly differentiated lesions, it was 6 percent and 0. Although most patients require palliative decompressive procedures, resection should be attempted whenever possible. It is expected that nonoperative techniques will have an increased role in the treatment of poor-risk patients or those who have unresectable disease.

Adenocarcinoma↗

PubMed1984

Arachidonic acid metabolites mediate early burn edema.

Standard burns were sequentially produced on the backs of Sprague-Dawley rats at 0, 1, 2, and 2 1/2 hr, followed by the IV injection of Evans blue dye. All animals were killed at 3 hr, and burns evaluated by wet/dry weight ratios, and Evans blue extravasation scored 1-4 by two observers. Five groups of rats were compared to controls. Rats made neutropenic by exposure to 137cesium showed no significant difference in wet/dry weight ratio or Evans blue extravasation compared to controls. At 1 1/2 hr four other groups were treated with various inhibitors of arachidonic acid metabolism including ibuprofen, a cyclo-oxygenase inhibitor; FPL 55712, a leukotriene (LT) receptor antagonist; ketoconazole, an inhibitor of thromboxane (Tx) synthetase; and lodoxamide, a calcium channel inhibitor. All treated groups showed significant reduction of Evans blue dye extravasation. Wet/dry weight ratios were significantly reduced in rats treated with FPL 55712 and ketoconazole before or after burning. These data support the postulate that oxygenation products of arachidonic acid, particularly Tx and LT, are important mediators in early burn edema.

Animals↗