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Biomedical subjects

M Wahl

Publications and source records attributed to M Wahl.

At least 109 records · Page 6Linked to original sources
PubMed1989

Failure of hepatitis B immune globulin to protect against exp infection in chimpanzees.

To study experimentally the protective effect of post-exposure prophylaxis against hepatitis B (HB), a special preparation of hepatitis B immune globulin (HBIG) was injected intravenously (i.v.) into three chimpanzees simultaneously with, or at different time intervals after, intravenous injection of a titred inoculum of hepatitis B virus (HBV). The HBIG was given either simultaneously with the HBV inoculum, at 4 hours after, or at both 4 hours and 4 weeks after the HBV injection. A fourth chimpanzee received a standard preparation of HBIG intramuscularly (i.m.) at both 4 hours and 4 weeks after receiving the HBV injection. A fifth animal received HBIG i.v. 4 hours after the HBV inoculum and at the same time received its first of three HB vaccine injections. All chimpanzees were followed for 1 year. The animals which received HBIG simultaneously with HBV or received HBIG plus vaccine had no serological or biochemical sign of HB during follow-up. The three animals which received HBIG after HBV inoculation all developed HBs-antigenemia and serum aminotransferase (ALT) elevations. HBsAg did however appear in serum several weeks later than expected for the HBV inoculum used. Post-exposure prophylaxis with HBIG did protect the HBV-exposed chimpanzees, only if HBIG was combined with HB-vaccination or if HBIG was given simultaneously with the HBV inoculum.

Animals↗
PubMed1989

Immune status and booster effects of low doses of diphtheria toxoid in Swedish medical personnel.

During a diphtheria outbreak among Swedish alcoholics in 1984-1985, only 60% of 328 medical staff at risk for exposure had diphtheria antitoxin titers greater than or equal to 0.01 IU/ml, which is usually considered to give relative protection. 21% had levels between 0.01-0.09 IU/ml and the remaining 39% had titers greater than or equal to 0.1 IU/ml. Booster doses of 0.5 Lf-12.5 Lf of diphtheria toxoid were given to 450 vaccinees. Of 72 individuals with low pre-immunization titers, who were immunized with less than or equal to 2.5 Lf diphtheria toxoid, 40% failed to reach greater than or equal to 0.1 IU/ml when analyzed 4 weeks after vaccination. Local tenderness and swelling greater than 5 cm at the site of injection or general discomfort was found in 11% of those immunized with low dose diphtheria toxoid (less than or equal to 2.5 Lf). When the dose 0.5 Lf of diphtheria toxoid was combined with tetanus toxoid (3.75 Lf) the frequency of adverse reactions increased to 34% (p less than 0.001). The study shows that vaccination status in medical personnel must also be continuously examined in countries where diphtheria is rare and that low booster doses of diphtheria toxoid may not achieve an adequate immune response.

Adolescent↗
PubMed1989

Cerebrovascular effects of nimodipine in cats.

The effects of nimodipine on feline pial arteries were studied before and after cortical spreading depression (CSD) using perivascular microapplication. Vessel diameter was measured by image splitting technique. Nimodipine was used as liposome suspension. Before CSD nimodipine induced a dilatation of 23.3 +/- 2.7% (mean +/- SEM) at 2.4 x 10(-7) M, while the empty liposomes elicited a nonsignificant constriction of 1.3%. After CSD the nimodipine-induced dilatation was significantly diminished to an average of 15%. This attenuated response to nimodipine is discussed and thought to be due to a more general decrease in cerebrovascular reactivity after CSD.

Animals↗
PubMed1988

Regulation of epidermal growth factor-stimulated formation of inositol phosphates in A-431 cells by calcium and protein kinase C.

Epidermal growth factor (EGF) treatment of A-431 cells induces a biphasic increase in the levels of inositol phosphates. The growth factor produces an initial, rapid increase in the level of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) due to hydrolysis of phosphatidyl-inositol-4,5-bisphosphate (Wahl, M., Sweatt, J. D., and Carpenter, G. (1987) Biochem. Biophys. Res. Commun. 142, 688-695). The level of inositol 1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4) also rises rapidly in response to treatment with EGF. The initial formation (less than 1 min) of Ins-1,4,5-P3 and Ins-1,3,4,5-P4 does not require Ca2+ present in the culture medium. However, the addition of Ca2+ to the medium at levels of 100 microM or greater potentiates the growth factor-stimulated increases in the levels of all inositol phosphates at later times after EGF addition (1-60 min). The data suggest that EGF-receptor complexes initially stimulate the enzyme phospholipase C in a manner that is independent of an influx of extracellular Ca2+. The presence of Ca2+ in the medium allows prolonged growth factor activation of phospholipase C. Treatment of A-431 cells with Ca2+ ionophores (A23187 and ionomycin) did not mimic the activity of EGF in producing a rapid increase in the formation of the Dowex column fraction containing Ins-1,4,5-P3, Ins-1,3,4,5-P4, and inositol 1,3,4-trisphosphate (InsP3). However, the initial EGF-stimulated formation of inositol phosphates was substantially diminished in cells loaded with the Ca2+ chelator Quin 2/AM. EGF receptor occupancy studies indicated that maximal stimulation of InsP3 accumulation by EGF requires nearly full (75%) occupancy of available EGF binding sites, while half-maximal stimulation requires 25% occupancy. 12-O-Tetradecanoylphorbol-13-acetate (TPA), an exogenous activator of Ca2+/phospholipid-dependent protein kinase (protein kinase C), causes a dramatic, but transient, inhibition of the EGF-stimulated formation of inositol phosphates. Tamoxifen and sphingosine, reported pharmacologic inhibitors of protein kinase C activity, potentiate the capacity of EGF to induce formation of inositol phosphates. Neither TPA nor tamoxifen significantly affects the 125I-EGF binding capacity of A-431 cells; however, TPA appeared to enhance internalization of the ligand. Ligand occupation of the EGF receptor on the A-431 cell appears to initiate a complex signaling mechanism involving production of intracellular messengers for Ca2+ mobilization and activation of protein kinase C.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

IgG subclass-associated affinity differences of specific antibodies in humans.

Human IgG subclasses differ in their biologic functions and are restricted as specific antibodies to certain Ag. The basis for this restriction is unknown but in order to characterize it further, we obtained serum preparations containing one single subclass by using subclass-specific mAb in affinity chromatography. Subsequently we determined the affinity of antibodies in the four IgG subclasses for gp30/p25, a hepatitis B surface Ag (HBsAg) complex, for a nine-amino acid cyclical peptide representing residues 139 to 147 of HBsAg, and for a peptide representing residues 126 to 140 of the hepatitis B virus pre-S2 region and the relative avidity of IgG1 and IgG2 antibodies for purified pneumococcal polysaccharide type 3. Affinities to the HBsAg showed a clear pattern of decreasing affinity in the order IgG1 greater than IgG2 greater than IgG3 greater than IgG4 both in sera from vaccinated and from naturally infected individuals. The relative avidities of antibodies to the polysaccharide Ag had a reverse pattern, IgG2 greater than IgG1. In individuals with or without Ig H chain gene deletions where the anti-HBsAg response was restricted to one subclass, the affinity was similar to that observed for the same subclass in sera from individuals who in addition possessed high or low affinity antibodies of other subclasses.

Adult↗
PubMed1988

Cerebrovascular reactivity to angiotensin and angiotensin-converting enzyme activity in cerebrospinal fluid.

The purpose of the present study was to test the vasomotor effect of angiotensin I (A I) and angiotensin II (A II) in feline cerebral arteries and to examine the presence of angiotensin converting enzyme (ACE) activity in the vessel wall and cerebrospinal fluid (CSF). A II (10(-8) -10(-5) M) induced concentration-dependent contractions of feline pial arteries (resting diameter, 98-286 microns) in situ with a maximum of 34% at 10(-4) M A II. A I produced dose-related contractions being approximately 20 times less potent than A II. The action of A I was significantly attenuated by the ACE inhibitor captopril (10(-5) M). These findings demonstrate the presence of ACE activity in the vessel wall and/or its surroundings. ACE activity was also found in feline CSF sampled from the cisterna cerebellomedullaris. Bradykinin (BK) was broken down and A I converted to A II by CSF, both effects being inhibited by captopril. This was demonstrated using bioassay and high-performance liquid chromatography. Considering the present and previous studies we conclude that the presence of ACE in the vessel wall and CSF is necessary for the conversion of A I to A II. Although ACE in CSF is able to degrade BK it appears not to be important for the metabolism of BK acting from the perivascular side of pial arteries in situ.

Angiotensin II↗
PubMed1988

Successful postexposure vaccination against hepatitis B in chimpanzees.

To study the effect of postexposure vaccination, four chimpanzees were vaccinated with hepatitis B (HB) vaccine 4, 8, 48, and 72 hr, respectively, after intravenous injection of an infectious hepatitis B virus (HBV) inoculum. The second and third vaccine inoculations were given 2 and 6 weeks later, i.e., at considerably shorter intervals than recommended either for ordinary prophylactic vaccination or for postexposure vaccination in combination with hepatitis B immune globulin (HBIG). The chimpanzees were followed for 1 year. None showed HBs-antigenemia, liver enzyme elevation (ALT), or histopathological alterations in liver biopsies. Late appearance of anti-HBc was observed only in the serum of the animal whose series of vaccination started 72 hr after HBV inoculation. An unvaccinated control chimpanzee, which received the HBV inoculum only, developed clinical hepatitis B with ALT-elevations and HBs-antigenemia within 2 months of the experimental HBV inoculation. These results indicate that postexposure vaccination against hepatitis B begun within 48 hr after HBV exposure, with short intervals between the vaccine injections, can protect against hepatitis B infection also when concomitant HBIG-prophylaxis is not given.

Animals↗
PubMed1988

Effects of free radicals on permeability and vasomotor response of cerebral vessels.

To obtain further evidence on the role of free radicals as mediators of secondary brain damage, blood-brain barrier (BBB) function and vasomotor response of pial vessels were studied during cortical superfusion of a free radical-generating system of xanthine-oxidase (XO) and hypoxanthine (HX). Intravenously administered Na+-fluorescein (mol. wt. 376), or fluorescein isothiocyanate (FITC)-dextran (mol. wt. 62,000) served as low- and high-molecular weight BBB indicators. Since undialyzed XO considerably increased the osmolarity of artificial cerebrospinal fluid, XO was subjected to equilibrium dialysis, which did not affect enzyme activity. Cortical superfusion with either HX (4 mM) or dialyzed XO alone (0.5 U/ml; osmolarity, 310 mosmol/l) did not induce a vasomotor response. Cortical superfusion with the free radical-generating system under normotonic conditions (HX plus dialyzed XO), led to moderate arterial dilation only with a maximum of +13%. The venous diameters remained unaffected. Moderate extravasation of the low molecular weight indicator Na+-fluorescein was seen in only 33% of the experiments, leakage of FITC-dextran was never observed. To assess the role of hypertonicity of the superfusate, the same experiments were performed with undialyzed XO. When superfusing the cortex with undialyzed XO (0.5 U/ml; osmolarity, 420 mosmol/l), the pial arteries dilated to 146%-168% of normal. Similarly, simultaneous superfusion with undialyzed XO (0.25 U/ml) and HX (2 mM) elicited arterial dilatation to 161%-178% of normal. Even the pial veins were significantly dilated to 108% of normal. In this series a moderate extravasation of Na+-fluorescein occurred in 75%, with leakage of FITC-dextran in 25%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Decreased insulin secretory response of pancreatic islets during culture in the presence of low glucose is associated with diminished 45Ca2+ net uptake, NADPH/NADP+ and GSH/GSSG ratios.

In isolated rat pancreatic islets maintained at a physiologic glucose concentration (5.6 mM) the effect of glucose on parameters which are known to be involved in the insulin secretion coupling such as NADPH, reduced glutathione (GSH), 86Rb+ efflux, and 45Ca++ net uptake were investigated. The insulinotropic effect of 16.7 mM glucose was decreased with the period of culturing during the first 14 days being significant after 2 days though in control experiments both protein content and ATP levels per islet were not affected and insulin content was only slightly decreased. Both NADPH and GSH decreased with time of culture. 86Rb+ efflux which is decreased by enhancing the glucose concentration from 3 to 5.6 mM in freshly isolated islets was not affected by culturing whatsoever, even not after 14 days of culture when there was no longer any insulin responsiveness to glucose. The 45Ca++ net uptake was decreased during culturing. The data indicate (1) that the diminished glucose-stimulated release of insulin during culturing is not due to cell loss or simple energy disturbances, (2) that more likely it is the result of a diminished 45Ca++ net uptake as a consequence of the inability of islet cells to maintain proper NADPH and GSH levels, and (3) that potassium (86Rb+) efflux may not be related to changes of NADPH and GSH.

Adenosine Triphosphate↗
PubMed1988

Mediators of brain edema and secondary brain damage.

Progress is our understanding of the roles of vasogenic and cytotoxic brain edema in secondary brain damage can be expected from studies of the ability of biochemical factors to open the blood-brain barrier, derange the microcirculation, and cause cell swelling and necrosis. Mediator compounds are considered to form or to become released in an area of primarily damaged brain (necrosis) and to enter the cerebral parenchyma through the broken blood-brain barrier from the intravascular space. Many biochemical factors must be considered. We suggested three criteria for determining the roles of mediators: a) they must inflict brain tissue damage, b) they must occur in pathologic concentrations or in compartments not normally present, and c) specific inhibition should attenuate secondary brain damage. These requirements are met by the kallikrein-kinin system and by glutamate. In the case of arachidonic acid and its many metabolites, the concept is difficult to test because fatty acids may be active only if not bound to proteins, and therapeutic inhibition might be difficult. A variety of mediators may enhance each other in a cascade manner by various initiating reactions that might be amenable for pharmacologic inhibition.

Animals↗
PubMed1988

IgG subclass deficiency in patients with Down's syndrome and aberrant hepatitis B vaccine response.

Seventeen adult patients with Down's syndrome (DS) and 19 adult healthy references were vaccinated with a hepatitis B vaccine in order to study the IgG subclass response. An enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies specific for IgG subclasses was employed. In spite of normal levels of total IgG1 and normal or even high levels of IgG3 in the DS patients, a significantly lower IgG1 response to the vaccine was observed in trisomic patients than in the references.

Antibody Formation↗
PubMed1987

Change of cerebrovascular reactivity after cortical spreading depression in cats and rats.

The purpose of the present study was to examine the pial arteriolar diameter and evoked vascular responses after single episodes of cortical spreading depression (CSD) in rats and cats in order to elucidate the mechanisms of the persistent change of cortical perfusion which succeeds CSD. This problem is of potential clinical interest also since CSD may be involved in migraine pathophysiology. Using an open cranial window technique, pial arteriolar diameters were measured with an image splitting method. Vascular reactivity was tested by local perivascular microapplication of mock cerebrospinal fluid (CSF) containing high and low levels of K+, high and low pH, adenosine and bradykinin before and after CSD which was triggered by intracortical injection of KCl. During CSD a monophasic vasodilatation of 26.0 +/- 3.7% (mean +/- S.E.M.; cat) or 64.6 +/- 3.9% (rat) was observed. Following CSD, the cat developed persistent vasodilatation (16.7 +/- 1.9%) while the rat exhibited vasoconstriction (12.1 +/- 1.8%). Both species displayed a severely impaired responsiveness to constrictor and dilating stimuli as compared to pre-CSD values. The responses were reduced by 28-84%, dependent on the substance tested. It is concluded that vascular reactivity is severely impaired after CSD (15-75 min) and that this might explain the impaired coupling between flow and metabolism after CSD.

Adenosine↗
PubMed1987

Permeability and vasomotor response of cerebral vessels during exposure to arachidonic acid.

Release of arachidonic acid (AA) in brain tissue is found in various cerebral insults. Blood-brain barrier function and vasomotor response were studied during cerebral administration of the fatty acid to obtain further evidence on its role as mediator of secondary brain damage under pathological conditions. Na+-fluorescein or fluorescein isothiocyanate (FITC)-dextran were i.v. administered as low- and high-molecular weight blood-brain barrier indicators. Cortical superfusion of arachidonic acid led to moderate constriction of ca. 90% of normal of pial arteries of 60-220 micron phi, whereas the venous diameters remained unaffected. On the other hand, AA caused opening of the blood-brain barrier not only for Na+-fluorescein but also for FITC-dextran (mol.wt. 62,000). Extravasation of Na+-fluorescein started at AA concentrations of 3 X 10(-5) M. Concentrations of 3 X 10(-4) to 3 X 10(-3) M always sufficed to induce barrier opening for fluorescein, whereas 3 X 10(-3) M was required for FITC-dextran. Leakage of the blood-brain barrier indicators started around venules. Pretreatment with indomethacin, or with BW 755 C, a dual inhibitor of both the cyclo- and lipoxygenase pathway did not prevent barrier opening by arachidonate for Na+-fluorescein. However, in the presence of indomethacin higher concentrations of AA were required to open the barrier for Na+-fluorescein, whereas BW 755 C did not influence the dose-effect relationship of AA and barrier opening observed in untreated animals. The latter findings imply that the pathophysiological effects induced by AA are likely to be attributed to the acid itself, rather than to its metabolites, a conclusion which might be in conflict with earlier observations reported in the literature. Electron microscopy revealed marked alterations of the venous endothelium, such as an attachment and eventual penetration of polymorphonuclear granulocytes through the endothelial barrier, while the small arteries and arterioles were unaffected. The findings may indicate that opening of the barrier by AA is mediated by granulocytes and/or their products. Taken together, our findings support the concept that release of AA in primarily damaged brain tissue enhances secondary processes, such as a failure of the blood-brain barrier function. The limited potency or even ineffectiveness, respectively, of indomethacin or BW 755 C provides evidence for a direct involvement of the fatty acid rather than of its metabolic degradation products. Therefore, therapeutic prevention of AA formation under these circumstances might be superior to mere inhibition of its metabolism.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

Adverse reactions and immunogenicity in adults to regular and increased dosage of diphtheria vaccine.

Booster doses of 3 Lf or 7.5 Lf of a regular diphtheria vaccine were given to 200 previously immunized adult volunteers. The toxoid was prepared from toxin with a purity of 2100 Lf/mg protein nitrogen and adsorbed to aluminium phosphate. Systemic reactions were rare and no severe symptoms were observed. Local reactions occurred in 40-50% of the vaccinees, but in only 7.5% were they of clinical significance, i.e. an area of redness/swelling greater than 5 cm. The two doses did not cause significant differences in reaction rates, and the 7.5 Lf dose elicited a better antitoxin response. Thus, a dose of 7.5 Lf diphtheria toxoid of similar purity can safely be given to adults in vaccines.

Adult↗
PubMed1987

Intradermal, subcutaneous or intramuscular administration of hepatitis B vaccine: side effects and antibody response.

The immune response after vaccination with a plasma-derived hepatitis B unit vaccine (MSD) administered intradermally or subcutaneously in 2 microgram doses was compared to the recommended 20 microgram dose administered intramuscularly. The trial was performed in 58 healthy volunteers 20-43 (mean 30) years old. No statistically significant difference in seroconversion rate was observed when the intradermal (i.d.) (2 micrograms) and intramuscular (i.m.) (20 micrograms) routes were compared (100% and 96% seroconversion, respectively). The 2 microgram dose administered subcutaneously gave a seroconversion rate of only 63%. The intradermal and i.m. routes also gave significantly higher mean titers of anti-HBs than the subcutaneous route (p less than 0.005). No severe reactions occurred and local reactions were seen almost exclusively in those vaccinated intradermally. These reactions included mainly discoloration, itching and nodule formation at the site of injection. The intradermal route ought to be considered for administration of hepatitis B vaccine since the dosage can be reduced to 1/10 without affecting the antibody response. Correct intradermal deposition of the vaccine is, however, crucial for an adequate immune response. This is probably the main disadvantage if large-scale vaccination programs should be carried out in developing countries using i.d. immunization.

Adult↗