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Biomedical subjects

J Klein

Publications and source records attributed to J Klein.

At least 703 records · Page 39Linked to original sources
PubMed1985

Evolution of mouse major histocompatibility complex genes borne by t chromosomes.

Virtually all wild mouse populations carry t haplotypes that cause embryonic lethality or semilethality, distortion of segregation ratios, suppression of crossing-over, and male sterility. The t complex of genes is located on chromosome 17, closely linked to the H-2, the major histocompatibility complex of the mouse. The t haplotypes differ from each other not only in lethal genes they carry but also in their linked H-2 haplotypes. In this study, we compared the class II H-2 genes present on 31 t chromosomes extracted from wild populations in different parts of the world. The comparison was based on the analysis of DNA fragments obtained after digestion with restriction endonucleases. The results reveal the existence of three major groups of class II alleles representing main branches on the evolutionary tree of the t chromosomes. Alleles within each group are similar if not identical, although they are borne by chromosomes that have been separated in time and space. The presence of similar alleles in Mus musculus and Mus domesticus suggests that some of them may have been separated for more than 1 million years. This must also be the minimal age of the t chromosomes but, because at least two of the three main branches appear to be related in their origin, the actual age of t chromosomes could be much greater. The observations support the proposal that H-2 genes evolve slowly.

Alleles↗
PubMed1985

Regulation of epidermal proliferation in mouse epidermis by combination of difluoromethyl ornithine (DFMO) and methylglyoxal bis(guanylhydrazone) (MGBG).

Topical methylglyoxal bis(guanylhydrazone) (MGBG) and alpha-difluoromethylornithine (DFMO) individually have been shown to produce partial clinical improvement in psoriasis. In an effort to further enhance therapeutic activity, studies were designed to optimize percutaneous penetraton of DFMO in vitro and to determine the effects of the combination of DFMO and MGBG on DNA synthesis and polyamine levels in hairless mouse skin. MGBG was shown to be more effective than DFMO in inhibiting DNA synthesis in vitro and in vivo. Maximum in vitro percutaneous penetration of DFMO (5%) was obtained in Vehicle N containing 10% Azone (297 micrograms/h/cm2). Topical administration of the combination of 5% DFMO and 0.1% MGBG in this vehicle produced a greater inhibition of DNA synthesis and depletion of polyamine levels than either drug individually. The simultaneous topical administration of DFMO and MGBG, allowing the use of lower concentrations of the more toxic MGBG, may be useful for therapy of psoriasis and other cutaneous disorders associated with abnormalities in polyamine metabolism.

Animals↗
PubMed1985

Helper effects required during in vivo priming for a cytolytic response to the H-Y antigen in nonresponder mice.

Induction of H-Y-specific cytotoxic T lymphocyte (CTL) responses in nonresponder female mice was attempted by i.v. injection of allogeneic male cells, followed by in vitro restimulation of recipient spleen cells with syngeneic male cells. Responses were obtained only in two strain combinations in which the recipients, although phenotypically nonresponders, carried responder alleles at class I major histocompatibility complex (MHC) loci, and the immunizing cells differed from the recipients at class II MHC loci. The two positive strain combinations were B10.A(2R) anti-B10.A(4R), and B10.GD anti-B10.D2(R101). In the first combination, both recipient and donor are nonresponders to H-Y, and the CTL are induced via a bystander effect of another CTL response to a previously undetected minor histocompatibility (H) antigen. This "carrier" antigen can only induce CTL against H-Y and itself when the immunizing cells express class II MHC molecules. Furthermore, the presence of H-Y and the carrier antigen on the same cell is a prerequisite for the generation of H-Y-specific CTL. In the second combination, the recipient is a nonresponder, whereas the donor is a responder. The two strains differ at only E alpha and E beta class II MHC loci. For the induction of CTL, H-Y and the foreign E molecule must be expressed on the same cells. Thus, the B10.D2(R101) cells that express E molecules on their surface probably provide the E-nonexpressor B10.GD recipients with a stimulus for the generation of H-Y-specific T helper cells. The data are consistent with the notion that antigen-specific class II MHC-restricted T helper cells are involved in the initiation of CTL responses to minor H antigens.

Animals↗
PubMed1985

Fentanyl pharmacokinetics and hemodynamic effects in preterm infants during ligation of patent ductus arteriosus.

A bolus of 30 micrograms X kg-1 fentanyl was given to nine preterm infants (gestational age 31.8 +/- 4.7 weeks, weight 1100 +/- 309 g) for induction of anesthesia for ligation of a patent ductus arteriosus. Thirty minutes after the injection, fentanyl plasma concentrations were between 7.7 and 13.6 ng X ml-1. Elimination half-life was 6-32 hr (mean +/- SD, 17.7 +/- 9.3). Systolic blood pressure remained stable throughout surgery. There was a gradual increase in heart rate from 159 +/- 12 min-1 at the time of skin incision to 173 +/- 15 min-1 at the time of skin closure (P less than 0.05). Fentanyl plasma concentrations remained virtually unchanged between 30 min (10.6 +/- 1.9 ng X ml-1) and 120 min (9.6 +/- 1.6 ng X ml-1); whereas at the end of surgery most infants moved and breathed spontaneously. This phenomenon can be explained by redistribution of fentanyl from brain into pharmacodynamically inert tissues.

Anesthesia, Intravenous↗
PubMed1985

Cytotoxic T-cell response to H-Y antigen by B6.C-H-2bm12 and B10.BR mice.

Cytotoxic T-cell response to the male-specific histocompatibility antigen (H-Y) is often used as an experimental model for studying the genetic control of the immune response. This anti-H-Y response is shown to be a complex one, with multicellular interactions involving genes of the H-2 complex, and also some genes unlinked to H-2. For the analysis of the genetic control of the anti-H-Y immune response, different inbred strains have been used and classified accordingly as responders or non-responders. During the authors' studies of the genetic control of the immune response, some of the strains described as non-responders were found to behave as responders, namely strains B6.C-H-2bm12 and B10.BR. This finding has added to the intricacy of current data on the genetic control of immune response to H-Y antigen.

Animals↗
PubMed1985

Recessive T cell response to poly (Glu50Tyr50) possibly caused by self tolerance.

The proliferative T cell response of inbred mouse strains to the random copolymer poly(Glu50Tyr50) (GT) was found to fall into two categories. Some strains responded only marginally (delta cpm values less than 10,000 and stimulation indices less than 3), whereas other strains mounted a substantial response (delta cpm 10,000 to 80,000, SI 3 to 30). The response is controlled by the A alpha and A beta loci of the major histocompatibility complex (MHC), as well as by genes not linked to the MHC. Because the response is selectively inhibited by monoclonal antibodies specific for the A alpha A beta molecule, we assume that its control by A loci is manifested as an A-restriction of the participating T (Ly-1high, Ly-2-) cells. It is of interest that the responsiveness is recessive in F1 hybrids of responder and nonresponder strains that are H-2-identical, but differ at their genetic background. Nonresponsiveness of these F1 mice is caused neither by a defect of antigen presentation, nor the result of immune suppression on priming or at the effector phase of the response. It is most likely the consequence of clonal deletion during the establishment of self-tolerance.

Animals↗
PubMed1985

Hegemony of mediocrity in contemporary sciences, particularly in immunology.

The controversial article which follows, grapples with the "business of doing science." As a criticism of research generally and immunology in particular, it bears directly on lymphology as an investigative discipline. As an indictment of modern scientific research the author cuts a broad swathe and paints a grim if not grimy picture of academia and the research enterprise. If this eminent immunologist's highly critical thesis strikes a responsive chord, then not only is wide dissemination of his message justified, but along with it honest reappraisal and remediation of harmful trends in medical research and scientific communication as currently practiced world-wide (CLW).

Allergy and Immunology↗
PubMed1984

Early right atrial pacing after myocardial infarction. II. Results in 77 patients with predischarge angina pectoris, congestive heart failure, or age older than 70 years.

Seventy-seven consecutive postinfarction patients who had either predischarge angina pectoris or congestive heart failure, or who were older than 70 years of age, underwent right atrial (RA) pacing before hospital discharge. In 60% of these patients, ischemic changes developed during RA pacing; this high yield of positive response indicates advanced coronary arterial disease. During a mean follow-up of 15 months, these patients had a high mortality rate (18%) and a reinfarction rate of 9%. RA pacing separated this a priori high-risk group into lower- and higher-risk subsets. Of the 46 patients with a positive RA pacing response, 6 had reinfarction, while none of the 31 patients with a negative RA pacing response had reinfarction (p = 0.04); 10 of the 14 cardiac deaths were among the patients who had positive RA pacing responses at discharge (p = not significant). Thus, of the 20 major cardiac events, 16 occurred among those with positive RA pacing responses (p less than 0.05). Predischarge clinical symptoms, however, were not good predictors of subsequent major cardiac events. We conclude that RA pacing can be safely performed even in high-risk and elderly patients and a positive response can identify those who have a poorer prognosis. Therefore, for postinfarction patients who, according to the prevailing criteria, are excluded from treadmill testing, we advocate the use of RA pacing.

Adult↗
PubMed1984

Feedback regulation of immune suppression by a suppressor factor.

Mouse hybridomas generated by fusion between a lactate dehydrogenase-B (LDH-B)-specific B10.A(2R) T suppressor (Ts) cell line and the BW5147 thymoma secrete two suppressor factors, TsF-A and TsF-E. The factors carry the same antigen-binding chains but different major histocompatibility complex (MHC) chains (A beta-like and E beta-like, respectively). The TsF-A suppresses the proliferation of A-restricted, LDH-B-specific T helper (Th) cells. In this report we demonstrate that the addition of the TsF-E (isolated on immunosorbent columns with Ek- or Jk-specific antibodies) to the culture of LDH-B-primed B10.A(2R) lymph node cells turns the nonresponder (suppressed) cultures into proliferating ones, and that this change is antigen specific. This enhancing effect occurs in the early phase of the cell culture; the factor has no effect when added 2 days after the initiation of the culture. Because pretreatment of the Ly-2+ but not of the Ly-1+2- cells with TsF-E induces responsiveness, it is very likely that the targets of the factor are the Ts cells or their precursors that belong to the Ly-2+ subset. An incubation period of about 4 h is necessary for the TsF-E to exert its action. The enhancing effect of the TsF-E is abrogated by monoclonal antibodies specific for Ek and Jk antigenic determinants. However, only some of the antibodies that retain the TsF-E on the immunosorbent column neutralize the factor in a functional test. Antibody blocking studies also indicate that the MHC determinants involved in the interaction between the antigen-presenting and the Ts cell during Ts cell activation, and in the TsF-E Ts cell interaction are either very similar or identical. We interpret the data as indicating that the Ts cells or their precursors recognize the TsF-E with the same receptors as they use for the recognition of LDH-B together with the Ek on the antigen-presenting cells. The recognition of the TsF-E inactivates the Ts cell so that proliferation of Th cells then occurs unhindered. Thus, the production of the TsF-E may provide a feedback mechanism that regulates the activation of the Ts cells and, consequently, the degree of suppression in the response to LDH-B.

Animals↗
PubMed1984

Structure of the murine Ia-associated invariant (Ii) chain as deduced from a cDNA clone.

The invariant (Ii) chain is a membrane-spanning glycoprotein found intracellularly associated with class II major histocompatibility complex (MHC) molecules. Using hybrid-selected translation and the Ii-specific monoclonal antibody In-1, we have isolated a cDNA clone (pIi-5) coding for most of the Ii chain. Sequence analysis of this clone reveals an open reading frame encoding 169 amino acid residues. The protein is rich in methionine and contains two potential N-glycosylation sites. No stretch of uncharged amino acid residues, characteristic for a membrane-spanning segment, is found close to the COOH-terminal end. There is one, however, close to the NH2-terminal end. As it is know that approximately 20 amino acid residues of Ii chain are exposed on the cytoplasmic side, we conclude that the Ii chain spans the membrane exposing the NH2 terminus on the cytoplasmic side and the COOH terminus on the luminal side.

Amino Acid Sequence↗
PubMed1984

Eo: a history of a mutation.

Eighteen mouse t haplotype-carrying strains were found not to express cell-surface E molecules controlled by class II genes of the H-2 complex (= Eo strains). Northern and Southern blot analysis of these and other, non-t strains that also fail to express the E molecule, has revealed two kinds of defect. Three strains (CRO437, tw2, and presumably to) were found to transcribe the E alpha gene, but they were not able to convert the message into a functional protein. All other Eo strains fail to transcribe the E alpha gene because of a deletion encompassing the promoter region, the RNA initiation site, and the first exon. The length of the deletion is approximately 650 +/- 50 bp. These two defects closely resemble those found previously in standard inbred strains carrying the H-2f, H-2q (failure of E mRNA to be expressed functionally), H-2b, and H-2s (deletion of a part of the E alpha gene) haplotypes. In particular, the location and length of the E alpha deletion appear to be the same in the strains carrying this mutation. The E alpha deletion is in linkage disequilibrium with certain alleles at other H-2 loci in some of the strains. These observations, combined with the growing evidence that H-2 haplotypes associated with t chromosomes derive from a single ancestral haplotype, suggest that the E alpha deletion is an old mutation and that it has been disseminated in mouse populations by the t chromosomes.

Animals↗
PubMed1984

Evolutionary relationships between the t and H-2 haplotypes in the house mouse.

Thirty-three mouse strains carrying t haplotypes were typed with a large battery of monoclonal and polyclonal antibodies specific for class I and class II antigens controlled by the H-2 complex. Among these t haplotypes were representatives of the six complementation groups defined previously and of eight new groups defined by us recently. The typing resulted in the identification of the H-2 haplotypes of these strains and of their alleles at K, D, A, and E loci. Nineteen of the 33 strains proved to carry a mutation that prevents the expression of the E molecule on the cell surface. All H-2 haplotypes of the t strains are related in terms of sharing certain antigenic determinants, most of which have not, as yet, been found in inbred strains or in wild mice that do not carry t haplotypes. According to the degree of serological relatedness, the haplotypes can be arranged into a pedigree presumably reflecting the evolutionary history of the t chromosomes. The ancestral t chromosome from which the 33 chromosomes derive was presumably present in the mouse population before the divergence of the Mus musculus and Mus domesticus species. The E0 mutation, too, is apparently ancient because it occurs in different branches of the evolutionary tree.

Animals↗
PubMed1984

Major histocompatibility complex of the mole-rat. I. Serological and biochemical analysis.

The mole-rat, Spalax ehrenbergi, is a complex subterranean rodent species whose habitat is restricted largely to the Middle East and North Africa. We typed over 50 mole-rats with mouse monoclonal and polyclonal antibodies specific for class I and class II major histocompatibility complex (Mhc) molecules. Some of these antibodies were produced against mouse Mhc molecules, others against Mhc molecules of other species. About 25% of the antibodies reacted with mole-rat lymphocytes in the cytotoxic test. Some of the serologically positive antibodies precipitated from a glycoprotein pool of mole-rat spleen cell molecules that corresponded in size with class I and class II molecules of other species. We conclude, therefore, that mole-rats, like other mammals, possess the Mhc which consists of class I and class II loci. We call this Mhc Spalax major histocompatibility (Smh) complex. The occurrence of a large number of different serotypes among the tested animals suggests that Smh loci are polymorphic. This Mhc polymorphism of the mole-rat contrasts with the monomorphism or oligomorphism of the Syrian hamster, a rodent with a similar ecology. Thus far no qualitative correlation could be found between Smh polymorphism and chromosome variation described in this superspecies.

Animals↗
PubMed1984

Congenital muscular dystrophy, brain malformation and ocular problems (muscle, eye and brain disease) in two German families.

We report on two brothers and an unrelated girl with congenital muscular dystrophy (CMD), brain malformation and ocular changes (strabismus, myopia, glaucoma, cataracts, retinal dystrophy). Correlations with the inherited autosomal recessive syndromes of CMD, including the Fukuyama-type CMD with CNS malformation, and the Muscle, Eye and Brain Disease published by Santavuori are discussed.

Brain Diseases↗
PubMed1984

Sequestration of fentanyl by the cardiopulmonary bypass (CPBP).

Immediately following the connection of pediatric patients to cardiopulmonary bypass we have consistently observed a steep decrease in fentanyl plasma concentration (74 +/- 8.7%) (mean +/- SD), much greater than would have been expected from hemodilution alone (50.6% +/- 12.0%) (p less than 0.0001). Priming of the pump with 20 ng/ml of fentanyl before connection to the patients did not prevent this phenomenon. In order to study the possibility that fentanyl is sequestered by the bypass, levels of the primed drug in the bypass were assessed before connecting the pump to the children and a steep fall from 20 ng/ml to zero was shown before initiation of bypass. Pharmacokinetic assessment of fentanyl in a closed pump circuit showed that levels of 120 ng/ml fall to 2 ng/ml within 3 min and remain stable at the lower concentration for at least 30 min. Further studies have identified the membrane oxygenator as the major site of fentanyl sequestration. Concentrations across the membrane fall from 120 ng/ml to 10 ng/ml. The attached siliconized tubing is associated with a minor binding effect sufficient to reduce concentrations from 110 to 84 ng/ml. The pvc tubing, aluminium heat exchanger and plastic reservoir had no binding effect on fentanyl. The possibility that a decrease in fentanyl protein binding caused the fall in serum concentration was checked in 5 patients undergoing open heart surgery. After initiation of the cardiopulmonary bypass, there was a significant decrease in albumin serum concentrations from 32.0 +/- 2.3 mM to 15.0 +/- 1.6 mM (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Aminoglycoside-related nephrotoxicity in the premature newborn.

The nephrotoxicity of gentamicin and amikacin was compared during presumed sepsis in 107 premature neonates. To examine the possibility that nephrotoxicity was directly associated with the clinical conditions of "sepsis," a control group of 26 chloramphenicol-treated newborns was also studied. Two markers of proximal renal tubular injury, N-acetyl-beta-glucosaminidase (NAG) and beta 2-microglobulin, were measured in 6-hr aliquots of urine. Because urine creatinine excretion increased with postconception age, markers were expressed in terms of excretion rate rather than per milligram of creatinine. The NAG excretion rate was significantly higher in gentamicin-treated patients (138 +/- 10 U/min, mean +/- SE) than in amikacin-treated patients (85 +/- 7 U/min) but did not differ between patients treated with amikacin and those treated with chloramphenicol (81 +/- 11 U/min). Excretion of beta 2-microglobulin did not differ among the three patient groups. We conclude that amikacin may be less nephrotoxic than gentamicin in the premature newborn.

Acetylglucosaminidase↗