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Biomedical subjects

T Brand

Publications and source records attributed to T Brand.

At least 37 records · Page 2Linked to original sources
PubMed1997

Physical load as risk factor for musculoskeletal complaints among tank terminal workers.

In a cross-sectional study, the relationship between physical load and musculoskeletal complaints was examined among operators (n = 77), office workers (n = 52), and miscellaneous workers (n = 15) in a tank terminal company. Information about history of musculoskeletal complaints, individual characteristics, and working conditions in past and present was obtained by a standardized interview. Assessment of physical load was performed by direct observation of awkward postures and forceful exertions during normal activities. Workers filled out a diary regarding the executed tasks during one shift. Physical load was also modeled by linking the average physical load of workers performing a particular task with the task distribution of each worker. The modeling approach was beneficial to estimate infrequent characteristics of physical load, whereas the observations were better for assessing frequent exposure to awkward trunk postures. After adjustment for age and other confounders the observed work time with trunk flexion and rotation was associated with the occurrence of back pain. The modeled work time with arms raised above shoulder showed a relationship with elbow pain, and the modeled work time with forceful exertions over 100 N showed relationships with elbow pain and wrist pain. The described relationships demonstrate that the assessment strategy chosen in a particular study strongly influences random measurement error of physical load, and that inappropriate strategies may mask true associations between physical load and musculoskeletal complaints. Modeling strategies offer the opportunity to assess physical load in dynamic work environments.

Administrative Personnel↗
PubMed1996

FKBP-12 recognition is dispensable for signal generation by type I transforming growth factor-beta receptors.

The FK506-binding protein, FKBP12, is a putative target of type I receptors for transforming growth factor-beta (TbetaR-I). As the FK506 motif that competes with TbetaR-I for FKBP12 resembles an invariant Leu-Pro dipeptide in TbetaR-I, we replaced Leu193 and Pro194 with Ala, along with mutations across the Gly/Ser box. L193A, P194A, and L193A/P194A do not alter TbetaR-I function; T204D partially activates, independent of ligand; L193A/P194A/T204D was an even more potent constitutive mutation. Association with FKBP12 in a yeast two-hybrid assay was disrupted by P194A, L193A/P194A, and L193A/P194A/T204D, but not L193A or T204D alone. Thus, FKBP12 recognition is dispensable for TGFbeta signaling.

Amino Acid Isomerases↗
PubMed1996

Chick NKx-2.3 represents a novel family member of vertebrate homologues to the Drosophila homeobox gene tinman: differential expression of cNKx-2.3 and cNKx-2.5 during heart and gut development.

NKx homeodomain proteins are members of a growing family of vertebrate transcription factors with strong homology to the NK genes in Drosophila. Here, we describe the cloning of cNKx-2.3 and cNKx-2.5 cDNAs and their expression during chick development. Both genes are expressed in the developing heart with distinct but overlapping spatio-temporal patterns. While cNKx-2.5 is activated in early precardiac mesoderm and continues to be uniformly expressed throughout the mature heart, expression of NKx-2.3 starts later in differentiated myocardial cells with regional differences compared to NKx-2.5. Additionally, both genes are expressed in adjacent domains of the developing mid- and hindgut mesoderm as well as in branchial arches. The highly conserved structure of cNKx-2.5 and its similar expression to mouse and Xenopus NKx-2.5 genes and to the Drosophila gene tinman argue that it constitutes the chick homologue of these genes. Different temporal and spatial activity of cNKx-2.3 in heart and gut as well as in a regionally restricted expression domain in the neural tube suggest that cNKx-2.3 is a member of the NK-2 gene family which may be involved in specifying mesodermally and ectodermally derived cell types in the embryo.

Animals↗
PubMed1995

Increased number of vasopressin neurons in the suprachiasmatic nucleus (SCN) of 'bisexual' adult male rats following perinatal treatment with the aromatase blocker ATD.

In an earlier article an enlarged subpopulation of vasopressin containing neurons was found in the suprachiasmatic nucleus (SCN) of homosexual men as compared to heterosexuals. The present study investigates the possibility that the number of vasopressin neurons in the SCN and sexual partner preference behavior in male rats are both influenced by sex hormones during brain development. For this purpose, we studied groups of adult male rats that had been treated either prenatally or pre- and postnatally with the aromatase inhibitor ATD (1,4,6-androstatriene-3,17-dione) which blocks the aromatization of testosterone to estradiol. Rats treated with ATD in both pre- and postnatal periods showed 'bisexual' partner preference behavior and appeared to have 59% more vasopressin-expressing neurons in the SCN than the controls. The prenatally treated rats did not differ from the controls. This observation supports the hypothesis that the increased number of vasopressin neurons found earlier in the SCN of adult homosexual men might reflect differences that took place in the interaction between sex hormones and the brain early in development.

Androstatrienes↗
PubMed1995

Inactive type II and type I receptors for TGF beta are dominant inhibitors of TGF beta-dependent transcription.

Although transforming growth factor-beta (TGF beta) is implicated in differentiation and disease, proof of in vivo function requires specific inhibitors of the TGF beta cascade. TGF beta binds a family of type I and type II receptors (T beta RI, T beta RII), containing a cytoplasmic serine/threonine kinase domain. We previously reported that kinase-deficient T beta RII (delta kT beta RII) blocks TGF beta-dependent transcription in cardiac myocytes. It is controversial whether both receptors are needed in all cells for gene regulation by TGF beta or whether they mediate distinct subsets of TGF beta-dependent events. To resolve this uncertainty, TGF beta-dependent transcription was investigated in cardiac myocytes versus mink lung epithelial cells. 1) delta kT beta RII inhibits induction of a TGF beta-responsive reporter gene, in both cell backgrounds. 2) Charged-to-alanine mutations of key residues of the T beta RII kinase, including consensus ATP binding and amino acid recognition motifs, are competent for binding but not transcriptional activation. Each inactive receptor inhibits TGF beta-dependent transcription in both cell types. 3) Kinase-deficient T beta RI (delta kT beta RI) likewise impairs TGF beta-dependent transcription, less completely than delta kT beta RII; kinase-deficient activin type I receptor has no effect. 4) TGF beta-binding proteins in cardiac cells and Mv1Lu cells are comparable by affinity labeling and immunoprecipitation; however, Mv1Lu cells express up to 3-fold higher levels of T beta RII and T beta RI. Thus, the model inferred from TGF beta-resistant cell lines (that T beta RII and T beta RI are necessary in tandem for the TGF beta-signaling complex to regulate transcription) is valid for cardiac myocytes, the cell type most prominently affected in TGF beta-deficient animals.

Animals↗
PubMed1995

[Cardiac gene expression after brief coronary occlusion].

In the pig short coronary occlusions induce molecular damage on the protein level in the myocardium, which elicit repair mechanisms by increased transcription and translation, including the activation of potential transcription factors (protooncogenes), genes involved in repair processes (heat shock genes) or calcium-binding genes. Additionally, some growth factors like insulin-like growth factor II show increased transcription in accordance with their function as trophic factors for reversibly injured myocardium. Changes in mRNA levels mostly are due to increased transcription rates and rarely due to prolonged half-life of the mRNA. However, at present our data do not allow us to conclude which genes are causative for myocardial stunning and/or ischemic preconditioning.

Animals↗
PubMed1994

Control of cardiac gene transcription by fibroblast growth factors.

Skeletal alpha-actin (SkA) is representative of the cardiac genes that are expressed at high levels in embryonic myocardium, downregulated after birth, and reactivated by tropic signals including basic fibroblast growth factor (FGF-2) and type beta transforming growth factors (TGF beta). To investigate the molecular basis for cardiac-restricted and growth factor-induced SkA transcription, we have undertaken a mutational analysis of the SkA promoter in neonatal ventricular myocytes, with emphasis on the role of three nominal serum response elements. Serum response factor (SRF) and the bifunctional factor YY1 are the predominant cardiac proteins contacting the proximal SRE (SRE1). Mutations of SRE1 that prevent recognition by SRF and YY1. or SRF alone, virtually abolish SkA transcription; mutation of distal SREs was ineffective. A mutation which selectively abrogates YY1 binding increases expression, substantiating the predicted role of YY1 as an inhibitor of SRF effects. SkA transcription requires combinational action of SRE1 with consensus sites for Sp1 and the SV40 enhancer binding protein, TEF-1. As an isolated motif, SRE1 can confer responsiveness to both FGF-2 and TGF beta to a heterologous promoter. Whether TEF-1 binding sites likewise can function as FGF response elements is unknown. Molecular dissection of mechanisms that govern the differentiated cardiac phenotype has largely been undertaken to date in neonatal ventricular myocytes, as the adult ventricular myocyte has been refractory to conventional procedures for gene transfer. To circumvent expected limitations of other methods, we have used replication-deficient adenovirus to achieve efficient gene transfer to adult cardiac cells in culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1994

Altered expression of titin and contractile proteins in failing human myocardium.

Our own previous ultrastructural studies in human hearts with dilated cardiomyopathy and heart failure showed sarcomeric and cytoskeletal disarrangement. On the basis of these findings we tested the hypothesis that in cardiomyopathic failing hearts not only the sarcomere structure but also the organization and the amount of numerous contractile proteins are disturbed. Titin was included in this study because it is the elastic "third" filament of the sarcomere and also plays an important role as template for myosin and actin filaments in sarcomerogenesis. Human cardiac tissue obtained at the time of transplantation surgery was investigated using immunohistochemistry with monoclonal antibodies against titin, myosin, actin, tropomyosin, and troponin T. Additionally, isolated myocytes from rat or pig heart were used for the standardization of the localization pattern. In normal tissue, myosin and the thin filament complex showed a regular cross striation that was wider in myosin staining than for actin, troponin T, and tropomyosin corresponding with the different width of the A and I bands in the sarcomere. Titin localization in normal human and animal myocardium showed a regular cross striation pattern. In diseased cardiac tissue titin fluorescence intensity was reduced and frequently disorganization or almost complete loss of titin from many myocytes were present. Severe abnormalities of contractile proteins consisting of disarrangement or lack of filaments were also observed. Double staining procedures showed that in the same myocyte defects of the contractile apparatus were accompanied by a simultaneous reduction of titin indicating that the "third" sarcomeric filament system is involved in heart failure. Abnormalities of titin expression may be especially important because titin significantly influences sarcomeric elastic behaviour and is necessary as template for the organization of newly synthesized myosin and actin filaments. The loss of titin may contribute to the altered compliance in failing hearts. It is concluded that disorganization and loss of titin, myosin, and the thin filament complex are severe in the failing human heart because of dilated cardiomyopathy and that these changes may represent several of the most important components of the structural correlate of reduced cardiac function.

Adult↗
PubMed1994

SDN-POA volume, sexual behavior, and partner preference of male rats affected by perinatal treatment with ATD.

The present study investigated 1) the importance of the aromatization process during the perinatal period for the development of the sexually dimorphic nucleus in the preoptic area of the hypothalamus (SDN-POA) of male rats, and 2) the relationship between SDN-POA volume and parameters of masculinization in male rats that were treated perinatally with the aromatase-inhibitor ATD. Males were treated with ATD either prenatally or pre- and neonatally, or with the vehicle. Masculine sexual behavior and partner preference were investigated in adulthood. Thereafter, animals were sacrificed and SDN-POA volume was measured. The SDN-POA volume was reduced in both the prenatally and the pre- and neonatally treated group, with a larger reduction in the latter than in the former group. Combined pre- and neonatal ATD treatment resulted in reduced frequency of mounts, intromissions, and ejaculations, as well as a reduced preference for a female over a male. The SDN-POA size was significantly and positively correlated with frequency of masculine sexual behavior, as well as preference for a female over a male.

Androstatrienes↗
PubMed1993

A dominant-negative receptor for type beta transforming growth factors created by deletion of the kinase domain.

To prove the postulated role of type beta transforming growth factors (TGF beta) in cardiac development and other events, specific inhibitors of TGF beta signal transduction are needed. We truncated the type II TGF beta receptor cDNA (delta kT beta RII), to delete the predicted serine/threonine kinase cytoplasmic domain. delta kT beta RII was co-transfected into neonatal cardiac myocytes, together with reporter constructs for two cardiac-restricted genes that are regulated antithetically by TGF beta. delta kT beta RII impaired activation of the skeletal alpha-actin promoter by TGF beta 1, -2, and -3 and, conversely, impaired TGF beta inhibition of alpha-myosin heavy chain transcription. Thus, a kinase-defective T beta RII blocks signaling by all three mammalian TGF beta isoforms, and can disrupt both positive and negative control of transcription by TGF beta.

Animals↗
PubMed1993

Expression of nuclear proto-oncogenes in isoproterenol-induced cardiac hypertrophy.

Rat hearts infused with the beta-adrenergic agonist isoproterenol were examined for the expression of several nuclear proto-oncogenes (c-fos, fosB, c-jun, junB, and junD) and the immediate early gene Egr-1. During the first 24 h after the start of infusion, a strong but transient expression of c-fos was observed. Expression of c-jun and junD were not elevated whereas junB was. By using specific antagonists to the alpha- (prazosin) and beta-adrenergic receptor (propranolol), a beta-adrenoceptor-specific blockade of the isoproterenol-mediated nuclear response was demonstrated. In situ hybridization localized c-fos expression to cardiac myocytes. Labelling was distributed focally in the left and right ventricles, and was strong and homogeneous in the atria. In contrast to beta-adrenergic stimulation, alpha-adrenoceptor stimulation with phenylephrine and norepinephrine caused the induction of c-jun and Egr-1 in addition to the proto-oncogenes induced by isoproterenol. Thus distinct programs of early response gene expression were expressed in response to alpha- versus beta-adrenergic stimulation.

Adrenergic alpha-Agonists↗
PubMed1993

Hormonal regulation of adult partner preference behavior in neonatally ATD-treated male rats.

Male rats, neonatally treated with ATD (1,4,6-androstatriene-3,17-dione), which blocks the aromatization of testosterone into estradiol (E2), were tested for adult partner preference behavior (PPB; estrous female vs. active male). Castration caused a decrease in preference for the female partner in all males, with ATD males showing lower preference for the female partner than controls. Long-term castrated males did not show preference for either partner. Precastration levels of PPB in control males occurred after treatment with E2 or dihydrotestosterone (DHT) plus E2. DHT alone had no effect on PPB. With E2 alone, the ATD males clearly preferred the male partner. When DHT was added, these ATD males showed no preference for either partner or a low preference for the female partner. In conclusion, adult PPB in male rats is activated by endogenous testosterone or by both its metabolites (DHT and E2) or by E2 alone. ATD males showed a much lower preference for the female. There was a differential effect of DHT and E2: DHT had no effect, but E2 clearly caused ATD males to prefer the male partner and control males to prefer the female partner.

Androstatrienes↗
PubMed1993

Transforming growth factor-beta in cardiac ontogeny and adaptation.

The transforming growth factor-beta (TGF-beta) superfamily comprises a set of regulatory peptides with multiple effects on cell growth and differentiation. The elaborate regulation of TGF-beta s during embryonic development of the heart, the upregulation of TGF-beta after hemodynamic stress, and the impact of TGF-beta on cardiac gene expression together imply a prominent functional role for this family of growth factors in cardiac organogenesis and hypertrophy. Basal and TGF-beta-induced expression of skeletal alpha-actin, one of several genes specifically associated with developing or hypertrophied myocardium, each are contingent on transcriptional activation by serum response factor. A truncated form of the type II TGF-beta receptor, created by deletion of the cytoplasmic kinase domain, acts as a dominant suppressor of TGF-beta signal transduction in cultured cardiac muscle cells and may provide a suitable means to establish the functions of TGF-beta in vivo.

Adaptation, Physiological↗
PubMed1993

The pallid mouse. A model of genetic alpha 1-antitrypsin deficiency.

BACKGROUND: The current hypothesis of pulmonary emphysema is based on an alteration of the protease-antiprotease balance within the lower respiratory tract. This hypothesis derives largely from studies in emphysema patients with genetic deficiency in serum alpha 1-antitrypsin. In animals, naturally occurring deficiency in serum elastase inhibitory capacity associated with early development of emphysema has been reported in the tight-skin mouse. We describe here a mouse model of genetic deficiency of alpha 1-antitrypsin in which emphysema occurs late in life. EXPERIMENTAL DESIGN: A genetic deficiency in serum alpha 1-antitrypsin was investigated in pallid mice, a strain with spontaneous occurring emphysema. Additionally, the possible pathogenetic role of an elastase-anti-elastase imbalance in pallid mice was investigated using molecular biologic, biochemical, histologic, ultrastructural, and immunoelectron microscopic methods. RESULTS: Pallid mice have markedly low levels of serum alpha 1-antitrypsin associated with a severe deficiency in serum elastase inhibitory capacity. However, they have normal alpha 1-antitrypsin mRNA levels in the liver. At ultrastructural examination, disruption of alveolar septa is first seen at 8 months of age. At histologic examination, some patchy areas of air-space enlargement with destruction of alveolar septa are seen from 12 months of age onward. These histologic changes are paralleled by a decrease in lung elastin content. The development of the pulmonary lesions is preceded by an alveolar elastolytic burden detected by an immunogold technique. CONCLUSIONS: All these data suggest that the lung changes in pallid mice are the result of an elastolytic process due to a severe inborn deficiency of serum alpha 1-antitrypsin. This animal model reproduces important features of the human condition and may provide new insights into the pathogenesis of emphysema.

Animals↗