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Biomedical subjects

F Hofmann

Publications and source records attributed to F Hofmann.

At least 19 recordsLinked to original sources
PubMed1992

Serum antibodies to L-type calcium channels in patients with amyotrophic lateral sclerosis.

BACKGROUND AND METHODS: Sporadic amyotrophic lateral sclerosis is a chronic, progressive degenerative disease of the motor neurons of the spinal cord and motor cortex. The cause is unknown. Recent electrophysiologic studies in animals indicate that immunoglobulins from patients with this disease alter presynaptic voltage-dependent calcium currents and calcium-dependent release of neurotransmitters. To determine whether similar interactions might be identified biochemically, we used an enzyme-linked immunosorbent assay (ELISA) to detect the reaction of serum IgG with purified complexes of L-type voltage-gated calcium channels from rabbit skeletal muscle. The results from patients with amyotrophic lateral sclerosis were compared with those obtained from patients with other types of motor neuron disease, patients with autoimmune and non-autoimmune neurologic diseases, and normal subjects. RESULTS: Serum samples from 36 of 48 patients with sporadic amyotrophic lateral sclerosis (75 percent) contained IgG that reacted with L-type calcium-channel protein, and serum reactivity on ELISA correlated with the rate of disease progression (Spearman rank-correlation coefficient, 0.62). Reactive serum was present in only 1 of 25 normal subjects and 1 of 35 control patients with no motor neuron disease. Antibodies to L-type voltage-gated calcium channels were identified in 6 of 9 patients with Lambert-Eaton syndrome, and in 3 of 15 patients with Guillain-Barré syndrome. CONCLUSIONS: Antibodies to L-type voltage-gated calcium channels are present in the serum of patients with amyotrophic lateral sclerosis, and antibody titers correlate with the rate of disease progression. Together with previous data, these results suggest a role for autoimmune mechanisms in the pathogenesis of sporadic amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed1992

Detection of cGMP dependent protein kinase isozymes by specific antibodies.

Two isozymes of cGMP-dependent protein kinase (cGMP kinase) have been identified. Polyclonal antibodies were developed which recognize both isozymes or specifically the I alpha and I beta isoform. The specificity of these antibodies was verified by using the recombinant or purified I alpha and I beta isozymes. The antibodies cross-reacted with the purified isozymes of cGMP kinase from bovine tracheal smooth muscle. The tissue concentration of cGMP kinase was determined by ELISA. High concentrations (greater than 10 pmol/g wet tissue) were present in bovine lung, rumen, trachea, aorta, uterus and stomach. The tissue distribution of the isozymes I alpha and I beta was investigated by immunoblots using crude extracts of the different tissues. The I beta-specific antibody yielded strong signals with extracts of trachea, aorta, stomach and uterus, whereas heart, cerebellum and lung apparently contain mainly the I alpha isozyme.

Amino Acid Sequence↗
PubMed1992

Modulation of cardiac Ca2+ channels in Xenopus oocytes by protein kinase C.

L-Type calcium channel was expressed in Xenopus laevis oocytes injected with RNAs coding for different cardiac Ca2+ channel subunits, or with total heart RNA. The effects of activation of protein kinase C (PKC) by the phorbol ester PMA (4 beta-phorbol 12-myristate 13-acetate) were studied. Currents through channels composed of the main (alpha 1) subunit alone were initially increased and then decreased by PMA. A similar biphasic modulation was observed when the alpha 1 subunit was expressed in combination with alpha 2/delta, beta and/or gamma subunits, and when the channels were expressed following injection of total rat heart RNA. No effects on the voltage dependence of activation were observed. The effects of PMA were blocked by staurosporine, a protein kinase inhibitor. beta subunit moderate the enhancement caused by PMA. We conclude that both enhancement and inhibition of cardiac L-type Ca2+ currents by PKC are mediated via an effect on the alpha 1 subunit, while the beta subunit may play a mild modulatory role.

Alkaloids↗
PubMed1992

A monoclonal antibody recognizes an epitope in the first extracellular loop of the plasma membrane Ca2+ pump.

A monoclonal antibody against the human erythrocyte Ca2+ pump (1E4) reacted with the enzyme in intact erythrocytes. Using trypsinized preparations of the pump the antibody only reacted with the N-terminal fragments of 33.5 and 35 kDa. The fragments span from the N terminus (35 kDa) or from residue 19 (33.5 kDa) to residue 314 of the hPMCA4 isoform of the pump. Exhaustive degradation with a number of agents produced smaller peptides which reacted with the antibody. Sequencing analysis on two chymotryptic fragments of 8.8 and 13.5 kDa identified the epitope in an approximately 80-residue domain beginning with Gly-81. Two peptides corresponding to the putative extramembrane portions of this region of the pump were synthesized. The antibody reacted with one of them, spanning residues Phe-121 to Gly-152 and containing the first putative external loop of the pump. Peptides corresponding to overlapping portions of this peptide were synthesized, leading to the location of the epitope in a 13-residue sequence (Glu-130 to Glu-142) in the first predicted extracellular loop (Verma, A. K., Filoteo, A. G., Stanford, D. R., Wieben, E. D., Strehler, E. E., Fischer, R., Heim, R., Vogel, G., Mathews, S., Strehler-Page, M-A., James, P., Vorherr, T., Krebs, J., Penniston, J. T., and Carafoli, E. (1988) J. Biol. Chem. 263, 14152-14159).

Amino Acid Sequence↗
PubMed1992

Calcium channel beta subunit heterogeneity: functional expression of cloned cDNA from heart, aorta and brain.

Complementary DNAs encoding three novel and distinct beta subunits (CaB2a, CaB2b and CaB3) of the high voltage activated (L-type) calcium channel have been isolated from rabbit heart. Their deduced amino acid sequence is homologous to the beta subunit originally cloned from skeletal muscle (CaB1). CaB2a and CaB2b are splicing products of a common primary transcript (CaB2). Northern analysis and specific amplification of CaB2 and CaB3 specific cDNAs by polymerase chain reactions showed that CaB2 is predominantly expressed in heart, aorta and brain, whereas CaB3 is most abundant in brain but also present in aorta, trachea, lung, heart and skeletal muscle. A partial DNA sequence complementary to a third variant of the CaB2 gene, subtype CaB2c, has also been cloned from rabbit brain. Coexpression of CaB2a, CaB2b and CaB3 with alpha 1heart enhances not only the expression in the oocyte of the channel directed by the cardiac alpha 1 subunit alone, but also effects its macroscopic characteristics such as drug sensitivity and kinetics. These results together with the known alpha 1 subunit heterogeneity, suggest that different types of calcium currents may depend on channel subunit composition.

Amino Acid Sequence↗
PubMed1992

Stable and functional expression of the calcium channel alpha 1 subunit from smooth muscle in somatic cell lines.

Voltage-activated calcium channels are membrane spanning proteins that allow the controlled entry of Ca2+ into the cytoplasm of cells. The principal channel forming subunit of an L-type calcium channel is the alpha 1 subunit. Transfection of Chinese hamster ovary (CHO) cells with complementary DNA encoding the calcium channel alpha 1 subunit from smooth muscle led to the expression of functional calcium channels which bind calcium channel blockers and show the voltage-dependent activation and slow inactivation and unitary current conductance characteristic of calcium channels in smooth muscle. The currents mediated by these channels are sensitive towards dihydropyridine-type blockers and agonists indicating that the calcium channel blocker receptor sites were present in functional form. The smooth muscle alpha 1 subunit cDNA alone is sufficient for stable expression of functional calcium channels with the expected kinetic and pharmacological properties in mammalian somatic cells.

Animals↗
PubMed1992

Immunogenicity, reactogenicity and consistency of a new, inactivated hepatitis A vaccine--a randomized multicentre study with three consecutive vaccine lots.

We investigated immunogenicity, reactogenicity and consistency of three consecutive lots of an inactivated hepatitis A vaccine in 204 seronegative volunteers. Each volunteer received a total of three doses of vaccine (720 EIU) according to a 0, 1 month primary vaccination schedule with a booster dose given at month 6. Mild, moderate and mostly local side effects were reported in 49.7% after the first and in less than 30% after the third injection. Seroconversion rate after one vaccine dose was as high as 91%. All subjects but one had already seroconverted by 1 month after the second injection, corresponding to a seroconversion rate of 99%. The geometric mean titres (GMT) increased with each dose of vaccine administered. Our results show that this inactivated hepatitis A vaccine is highly immunogenic, safe and well tolerated. Furthermore, there were no significant differences between the three vaccine lots in respect to seroconversion rate, size of antibody titre or reactogenicity.

Antibodies, Viral↗
PubMed1992

Hepatitis A as an occupational hazard.

Few studies have been carried out to evaluate the role of hepatitis A virus (HAV) as an occupational hazard. Our analysis of data on occupational diseases in Germany showed that hepatitis A ranks as third among infectious occupational diseases. Morbidity based on the frequency of compensation (15.2%) was in the same range as that observed for hepatitis B (19.7%). In another study, data were collected on anti-HAV prevalence among 2293 hospital workers in southwest Germany. Anti-HAV prevalence of hospital staff responsible for patient care and that of the general population were comparable, while food-handlers under the age of 30 years had a higher degree of anti-HAV prevalence. When an evaluation of anti-HAV prevalence data was carried out on persons younger than 30 years who comprised subsets of the medical staff, the relative risk was: charwomen 4.2, food-handlers 2.49, and paediatric nurses 1.84, showing that they had higher prevalence rates than nurses 1.25, physicians 1.09 and laboratory assistants 0.93. Vaccinations for the prevention of hepatitis A should therefore reach individuals that have an increased occupational risk: food-handlers, health care workers in infectious diseases and paediatrics, medical staff in laboratories handling stool samples, medical charwomen and, according to previously published work, staff of day care centres and sewerage workers.

Food Handling↗
PubMed1992

Hepatitis A vaccination: schedule for accelerated immunization.

Hepatitis A vaccine, strain HM175, was investigated for immunogenicity and tolerability in a prospective multicentre trial. The following vaccination schedules and antigen contents were evaluated: days 0 and 14 with 720 ELISA units (El.U) of antigen, days 0 and 28 with 720 El.U and days 0 and 28 with 360 El.U. In all study groups, the seroconversion rates following two vaccinations were between 95 and 100%. Higher geometric mean concentrations of antibody to hepatitis A virus (anti-HAV) were reached by the vaccine containing 720 El.U of HAV antigen. The vaccine was equally well tolerated in all groups. In addition, an abbreviated schedule, in which 720 El.U of HAV antigen was given on days 0 and 14, resulted in 100% seroconversion by day 28 and a level of anti-HAV that was substantially higher than that observed after passive immunization. This implies that such a vaccine could replace immune globulin administration if time permits.

Adult↗
PubMed1992

Reactogenicity and immunogenicity of three different lots of a hepatitis A vaccine.

To study the immunogenicity and reactogenicity of an inactivated hepatitis A vaccine, 204 healthy individuals were randomized into three equal groups, each to receive a different vaccine lot. Each subject received a total of three doses, each of 720 ELISA units of hepatitis A vaccine HM175, according to a 0 and 1 month primary vaccination schedule, with a booster dose given at month 6. Side effects were low and were < 30% after the second injection. All subjects but one had antibodies to hepatitis A virus two months after the first dose of vaccine. At month 6 all vaccinees had seroconverted. There were no differences between the three vaccine lots with respect to side effects, seroconversion rates and geometric mean titre of antibodies. We conclude that the three lots of inactivated hepatitis A vaccine are safe, well tolerated and equally immunogenic.

Adult↗
PubMed1992

Hormonal regulation of calcium current in freshly isolated airway smooth muscle cells.

Single freshly isolated smooth muscle cells of adult bovine trachea were voltage clamped, and the calcium inward current was separated from K+ currents by blocking the large outward currents with intra- and extracellular Cs+ and extracellular tetraethylammonium chloride. Isoproterenol stimulated peak calcium current (ICa) in a dose-dependent manner through the beta-adrenergic receptor. The isoproterenol effect was not mediated or caused by the stimulation of a K+ or Na+ current, a decrease in the intracellular concentrations of Ca2+ or H+, the stimulation of the Na(+)-H+ or the Na(+)-Ca2+ exchanger. Neither basal nor isoproterenol-stimulated ICa was affected by internal dialysis of the cell with adenosine 3',5'-cyclic monophosphate (cAMP), cAMP analogues, or the catalytic subunit of cAMP-kinase. Internal dialysis of the cells with guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) blocked the stimulation of isoproterenol whereas dialysis with guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) induced an isoproterenol-like maximal increase of ICa. These results show that the beta-adrenergic receptor stimulates the L-type calcium current of isolated tracheal smooth muscle cells independent of cAMP and cAMP-kinase through a GTP/GDP regulated protein.

Albuterol↗
PubMed1992

Cyclic GMP-dependent protein kinase and smooth muscle relaxation.

Cyclic guanosine monophosphate (cGMP)-dependent protein kinase has been cloned from bovine trachea. The isozymes I alpha and I beta, which differ only in their amino-terminal domains were expressed transiently in COS-7 cells. Both isozymes were activated by cGMP and cyclic adenosine monophosphate (cAMP). However, approximately 10-fold higher concentrations of cyclic nucleotides were needed to activate the I beta enzyme than the I alpha enzyme. The KA values for cAMP were 9.1 and greater than 20 microM for the I alpha and I beta isozymes, respectively. It is therefore unlikely that an unmodified I beta enzyme that occurs in high concentrations in vascular smooth muscle can be activated in vivo by cAMP.

Animals↗
PubMed1992

[The status of preventive medical examinations based on labor safety regulations for adolescents--results of a survey in 129 students].

The implementation of laws governing the protection of the health of adolescent workers has rarely been investigated scientifically. The paper presents results of an investigation probing into the opinions of 129 students of vocational schools regarding their expectations, experiences and assessments in respect of preventive medical examinations based on this legislation. The results are discussed with the consequence that improvements either in content and organisation of these examinations may increase the acceptance among the adolescents. This acceptance seems to be the crucial factor for a higher efficacy of the protective function of legislation.

Adolescent↗
PubMed1992

[Role of the school in vaccination and prevention of infection].

628 pupils from both the northern and southern parts of West Germany (Baden-Württemberg, Bavaria, Lower Saxony, Schleswig-Holstein) were interviewed via an "infectious diseases" questionnaire: 44 questions dealt with vaccination (vaccination history, opinions of efficiency of different vaccines), 38 with problems concerning AIDS/HIV. The results indicated significant lack in the acceptance of most of the common immunisations. Improvement of AIDS/HIV-information, especially on HIV-transmission and psychosocial, economical and political consequences seems to be necessary. Possibilities of future health education for pupils are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1991

The activation of expressed cGMP-dependent protein kinase isozymes I alpha and I beta is determined by the different amino-termini.

cDNA of bovine cGMP-dependent protein kinase (cGMP kinase) isozymes I alpha and I beta differ only in their amino-terminal domains (amino acids 1-89 and 1-104, respectively). Each recombinant isozyme (rI alpha and rI beta) was transiently expressed in COS-7 cells and its properties were compared with the cGMP kinase isozymes P-I and P-II purified from bovine trachea. The subunit of P-I, P-II, rI alpha and rI beta had a molecular mass of about 75 kDa. rI alpha and rI beta had S20,W values of 7.6 and 7.2, respectively, indicating that they were present as dimeric holoenzymes. Immunostaining with specific antibodies showed that P-I and rI alpha, and P-II and rI beta, were immunologically indistinguishable. P-I, P-II, rI alpha and rI beta had the same catalytic activity. However, rI alpha and rI beta were half-maximally activated at 0.1 microM and 1.3 microM cGMP, and 0.3 microM and 12 microM 8-bromoguanosine 3',5'-(cyclic)phosphate (Br8-cGMP), respectively. P-I and P-II had a similar shift in their apparent KA values. P-I and rI alpha bound 2 mol cGMP/mol subunit to high-affinity (site 1) and low-affinity (site 2) cGMP-binding sites. The exchange rates were 0.005-0.009 min-1 for site 1 and 3.7 min-1 for site 2. In contrast, P-II and rI beta bound and rI beta bound 2 mol cGMP/mol enzyme subunit at only two low-affinity binding sites (site 2) with k-1 values of 0.92 min-1 and 4.8 min-1. These results suggest that a change from the I alpha amino-terminal domain to that of I beta increases the apparent KA value for cGMP 10-fold by altering the binding properties of binding site 1. The differential expression of the cGMP kinase isozymes could be an important mechanism in vivo to dampen the effect of long-term elevation of cGMP level.

Animals↗