Biomedical subjects

J G Still

Publications and source records attributed to J G Still.

12 recordsLinked to original sources

PubMed2001

Spontaneous microdeletions and microinsertions in a transgenic mouse mutation detection system: analysis of age, tissue, and sequence specificity.

A total of 3497 independent spontaneous mutations were examined using the Big Blue transgenic mouse mutation detection system. Base substitutions predominate, although 16% of somatic and germline mutations are microdeletions, microinsertions, or deletions combined with insertions. The pattern of microdeletions and microinsertions is similar in both the lacI transgene and the human p53 gene. Single-base deletions (D1) and insertions (I1) are evenly distributed in the lacI transgene, whereas microdeletions from 2 to 50 bp are clustered at two regions (bp 129-228 and 529-628). The pattern of microdeletions and microinsertions is similar between young (< or =3 months) and old (25 months) mice. Brain tissue has a paucity of deletions combined with insertions when compared with that of thymus and nine other tissues (P = 0.01). A 16-bp deletion at lacI base position 272 is a tissue-specific hotspot preferentially occurring in brain. Approximately 68 and 93% of D1 and I1, respectively, occur at mononucleotide repeats. The frequencies of D1 and I1 in mononucleotide repeats increase in an exponential manner with the length of the repeat. The lacI transgene shows similarity to the human p53 gene in the pattern of microdeletions and microinsertions and the size distribution of microdeletions.

Age Factors↗

PubMed1995

Pretreatment of normal humans with monophosphoryl lipid A induces tolerance to endotoxin: a prospective, double-blind, randomized, controlled trial.

OBJECTIVES: Endotoxin is one of the principal mediators of Gram-negative septic shock. Pretreatment with monophosphoryl lipid A, a hydrolyzed derivative of endotoxin from Salmonella minnesota R595, induces endotoxin tolerance and nonspecific resistance to infection in experimental animals. The present clinical trial was undertaken to test the response to monophosphoryl lipid A in humans and the ability of monophosphoryl lipid A to attenuate the response of normal human volunteers to U.S. Reference Ec-5 endotoxin. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Clinical research center. PATIENTS: Forty-four healthy volunteers. INTERVENTIONS: In part 1 of the study, 29 volunteers were randomized in varying ratios to receive vehicle control or monophosphoryl lipid A intravenously in a double-blind dose escalation trial. In part 2 of the study, 12 volunteers were randomized to receive either monophosphoryl lipid A (20 micrograms/kg) or vehicle control and, 24 hrs later, all 12 volunteers were challenged with U.S. Reference Ec-5 endotoxin (20 units/kg intravenous, bolus injection). Systemic response to endotoxin challenge was evaluated and compared between the monophosphoryl lipid A and vehicle control-pretreated subjects. MEASUREMENTS AND MAIN RESULTS: In part 1 of the study, subjective effects and increases in cytokine levels were not observed until a dose of 10 micrograms/kg of monophosphoryl lipid A was administered. Six volunteers receiving a maximum dose of 20 micrograms/kg experienced mild-to-moderate symptoms that did not require therapy. Moderate increases in temperature, heart rate, and tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 release were observed. IL-1 alpha and IL-1 beta were not detected but a significant increase in IL-1 receptor antagonist was observed. In part 2 of the study, monophosphoryl lipid A pretreatment reduced the number of volunteers who experienced one or more subjective complaints after endotoxin administration (3/6 vs. 6/6; p = .09). The febrile response and tachycardic response to endotoxin were significantly reduced by pretreatment with monophosphoryl lipid A. Monophosphoryl lipid A-pretreated volunteers demonstrated significantly reduced concentrations of TNF-alpha after endotoxin challenge, as compared with subjects treated with vehicle control (84 +/- 76 vs. 244 +/- 128 pg/mL; p < .05). IL-6 concentrations (100 +/- 91 vs. 268 +/- 171 pg/ml; p < .05) and IL-8 concentrations (136 +/- 86 vs. 632 +/- 323 pg/mL; p < .05) elicited by endotoxin challenge were also significantly reduced by monophosphoryl lipid A pretreatment. CONCLUSIONS: Data indicate that monophosphoryl lipid A, in a dose 10,000 times that of endotoxin, used in experimental pyrogenicity trials, is well tolerated in human volunteers. Pretreatment of normal human volunteers with monophosphoryl lipid A attenuated the systemic response to bacterial endotoxin. These data support further clinical testing of monophosphoryl lipid A for the prevention or amelioration of the severe sequelae of sepsis.

Adolescent↗

PubMed1993

Comparative safety and efficacy of clarithromycin and cefadroxil suspensions in the treatment of mild to moderate skin and skin structure infections in children.

A prospective, randomized, single (investigator) blind multicenter study was performed to compare the safety and efficacy of clarithromycin and cefadroxil oral suspensions in the treatment of mild to moderate skin and skin structure infections in children. Male and female patients ages 6 months to 12 years were enrolled at 24 study centers in the United States. Patients had signs and symptoms consistent with mild to moderate skin or skin structure infections judged suitable for oral antimicrobial therapy. Clarithromycin oral suspension was given to 118 children in a dose of 7.5 mg/kg (maximum of 500 mg) twice daily; cefadroxil oral suspension was given to 113 children in a dose of 15 mg/kg (maximum of 1000 mg) twice daily. Among clinically evaluable patients clinical success rates (cure plus improvement) were 96% (71 of 74) for clarithromycin and 98% (83 of 85) for cefadroxil (P = 0.664). Bacteriologic cure rates in evaluable clarithromycin and cefadroxil patients were 96% (72 of 75) and 99% (89 of 90), respectively (P = 0.331). Pathogen eradication rates based on 204 evaluable pathogens were 97% in the clarithromycin group and 99% in the cefadroxil group (P = 0.326). Adverse events were mild or moderate and were reported in 25% of clarithromycin and 35% of cefadroxil patients (P = 0.085). In both groups adverse events involved primarily the digestive tract. No significant laboratory changes were noted. Clarithromycin oral suspension appears to be a safe and effective alternative to cefadroxil for the treatment of pediatric skin and skin structure infections.

Administration, Oral↗

PubMed1993

Comparison of clarithromycin and penicillin VK suspensions in the treatment of children with streptococcal pharyngitis and review of currently available alternative antibiotic therapies.

In a randomized investigator-blinded study, 506 children ages 6 months to 12 years with positive rapid direct antigen tests for Group A beta-hemolytic Streptococcus (GABHS) received treatment with either clarithromycin suspension, 7.5 mg/kg twice daily, or penicillin VK suspension, 13.3 mg/kg three times per day for 10 days. Signs and symptoms of pharyngitis or tonsillitis were evaluated and throat cultures were obtained before treatment, once during treatment and 4 to 6 days and 19 to 25 days posttreatment. All GABHS isolates were susceptible in vitro to clarithromycin. Successful clinical responses at the end of treatment were demonstrated in 169 of 176 (96%) evaluable clarithromycin-treated patients and 179 of 191 (94%) evaluable penicillin-treated patients. GABHS was successfully eradicated at end of treatment in 168 of 183 (92%) evaluable clarithromycin-treated patients compared with 162 of 199 (81%) evaluable penicillin-treated patients (P = 0.004). There were no significant changes in hematologic or serum chemistry parameters in either group. Both drugs were well-tolerated. The incidence and nature of adverse events were similar in the clarithromycin and penicillin groups, except for gastrointestinal complaints reported in 35 of 250 (14%) clarithromycin recipients compared with 12 of 256 (5%) penicillin recipients (P < or = 0.001). The results indicate that twice daily clarithromycin was as safe and effective as three times daily penicillin VK in the treatment of children with streptococcal pharyngitis or tonsillitis. Clarithromycin was statistically superior to penicillin VK in the eradication of GABHS.

Child↗

PubMed1982

Pulmonary artery sling: a new diagnostic tool and clinical review.

The pulmonary artery sling is a vascular anomaly that produces severe respiratory disease in infancy. The differential diagnosis is lengthy, and the diagnostic work-up frequently includes such invasive maneuvers as bronchography, bronchoscopy, and cardiac catheterization. In this paper the use of a new noninvasive diagnostic tool, computer tomography, to aid in the diagnosis of this form of vascular ring, is discussed and a review of salient features of this cardiovascular malformation is presented.

Female↗

PubMed1978

The effect of prostaglandins and other vasoactive substances on uterine blood flow and myometrial activity.

The effects of prostaglandins (PG's), bradykinin, and adenosine on uterine blood flow (UBF) and intrauterine pressure (IUP) were investigated in conscious oophorectomized ewes. PGE1 and adenosine increased UBF to levels comparable to those induced by estradiol-17beta, whereas PGE2 and PGA1 achieved only 20 and 36 per cent of peak estradiol-induced levels, respectively. PGE1, PGE2, and adenosine all caused transient increases in IUP while PGA1 had no effect on myometrial activity. Bradykinin increased UBF to 60 per cent of peak estradiol-induced levels, with concomitant increases in IUP tonus. PGE2 and PGF2alpha decreased peak estrogen-induced UBF by 50 and 70 per cent, respectively, while inducing related increases in IUP. When compared with oxytocin, the effects of PGE2 at high flow appeared to be mediated only my myometrial activity, whereas PGF2alpha apparently caused vasoconstriction as well. These findings support the concept that PGE1 could play a role in mediating estrogen-induced uterine vasodilatation.

Adenosine↗

PubMed1977

Differential reactivity of the gravid uterine vasculatures: effects of norepinephrine.

Norepinephrine dose-conductance-response relationships were determined for the placental and nonplacental vasculatures of ewes between 95 and 130 days of gestation with the use of radioactive-labeled microspheres injected under flow meter guidance. The regression line for the placental circulation differed significantly from that for the nonplacental circulation (P less than 0.01). The decrease in nonplacental conductance was 30 to 45% of control greater than the decrease in placental conductance. These responses are consistent with the hypothesis that the site of placental vascular resistance is in vessels of larger caliber than those which are usually the primary site of resistance to blood flow.

Animals↗

PubMed1977

Uterine blood flow and its distribution after chronic estrogen and progesterone administration.

The rates and distributions of uterine blood flow (UBF) were measured in conscious castrated ewes during estradiol, progesterone, and combined-hormone regimens. Supplemental progesterone decreased the magnitude of UBF observed on estradiol alone. Progesterone favored distribution of UBF to the uterine caruncles and estradiol favored distribution to the myometrium and uterine cervix. Proportionate endometrial blood flows were similar on all hormone regimens. These observations suggest that estradiol secretion may not be responsible for the definitive increase in UBF observed during ovine pregnancy.

Animals↗

PubMed1976

Uterine pressure-flow relationships during early gestation.

Placental and myoendometrial pressure-flow relationships were determined in 17 gravid ewes between 29 and 110 gestational days with the use of radioactive-labeled microsphere injections under flow meter guidance. Myoendometrial relationships were consistently curvilinear with convexity toward the flow axis. From 29 to 40 days, caruncular-cotyledonary relationships were similar to myoendometrial ones. After 50 days, the relationship was slightly but significantly curvilinear with convexity toward the pressure axis. From 42 to 50 days, responses were intermediate. The changes in caruncle-cotyledon vascular reactivity correlated with the onset and maturation of interdigitation of fetal and maternal tissues during definitive placentation. A hypothesis for these changes in vascular reactivity is presented.

Animals↗

PubMed1976

Effects of local anesthetic agents on the uterine vasculatures and myometrium.

Intravascular procaine, lidocaine, mepivacaine, and bupivacaine decrease blood flow to the placental and nonplacental vascular beds of gravid ewes by stimulating vasoconstriction and myometrial contractility. These effects appear to be direct ones since they are not affected by alpha-adrenergic blockade. Dose-response curves determined in nonpregnant ewes indicate that significant decreases in blood flow may occur at arterial blood concentrations encountered clinically. It is proposed that reduced placental blood flow is the cause of fetal bradycardia following paracervical block anesthesia. The implications of these findings in obstetric anesthesia are discussed.

Anesthesia, Conduction↗

PubMed1976

Effects of Cis- and trans-clomiphene on the uterine blood flow of oophorectomized ewes.

Changes in the left uterine artery blood flow (YBF) after intraarterial administration of estradiol-17beta and cis- and trans-clomiphene citrate to conscious, oophorectomized ewes were monitored by chronically implanted electromagnetic flow probes. Cis-clomiphene produced UBF increases comparable to or greater than those produced by estradiol-17beta but at dose levels 20 times greater. Comparison of UBF response curves for cis-clomiphene with those for estradiol-17beta showed a delayed onset of initial vasodilation and a delayed peak response. The duration of uterine vasodilation produced by cis-clomiphene was dose-dependent and exceeded that produced by estradiol-17beta. Similar reponses were observed with trans-clomiphene but at dose levels at least 1,000 times those of estradiol-17beta. The characteristics of clomiphene-induced UBF responses that differed from those after estradiol-17beta may reflect differences in estrogen receptor activation between the compounds.

Animals↗

PubMedDate not supplied

Evaluation of bivalent live attenuated influenza A vaccines in children 2 months to 3 years of age: safety, immunogenicity and dose-response.

1126 children, 2 months to 3 years old, received a single intranasal dose of 10(4), 10(6), or 10(7) TCID50 of cold adapted (ca) A/Kawasaki/9/86 (H1N1) and A/Beijing/352/89 (H3N2) or placebo, in a double blind, placebo-controlled, safety and immunogenicity trial. No reactogenicity attributable to vaccine was demonstrated. A single bivalent 10(6) or 10(7) dose produced high rates of seroconversion to H1N1 (77%) and H3N2 (92%) in seronegative children > 6 months old; serologic responses were lower to H1N1 (P < 0.001) and H3N2 (P = 0.01) in younger infants. A single 10(6) dose of bivalent ca influenza A vaccine can be immunogenic in children, but response is age dependent.

Antibodies, Viral↗