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Biomedical subjects

F Beck

Publications and source records attributed to F Beck.

At least 19 recordsLinked to original sources
PubMed2001

Biosynthesis of proteoglycan in bone and cartilage of parathyroid hormone-related protein knockout mice.

Proteoglycans are suggested to regulate cell adhesion, differentiation and mineralization of hard tissues. In vitro studies have shown that many humoral and local factors regulate proteoglycan synthesis. Among them, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) have potent stimulating effects on proteoglycan synthesis. However, the exact role of PTHrP on the biosynthesis and metabolism of proteoglycans during skeletal development is not clear. To clarify this point, we examined bony and cartilaginous explants of newborn mice with disrupted PTHrP alleles. Ribs of homozygous PTHrP-knockout mice and wildtype littermates were dissected into bony and cartilaginous regions and metabolically labeled with [35S]sulfate in culture. Radiolabeled proteoglycans were analyzed by column chromatography. The elution profiles of [35S]-labeled proteoglycan from cartilaginous explants did not differ between homozygous PTHrP-knockout mice and wild-type littermates. However, the amount of labeled proteoglycan in homozygous PTHrP-knockout mice was only 4%-5% that of wild-type littermates. In contrast with cartilaginous explants, the amount of labeled proteoglycans in bony explants did not differ between the two genotypes. Interestingly, besides the common major peak (Kd = 0.10-0.16) observed in the bony explants of both genotypes, a minor peak (Kd = 0.42) was specifically present in homozygous PTHrP-knockout mice. This minor peak was earlier than that of free glycosaminoglycan (GAG) chains, suggesting that the core protein, but not GAG chain, was cleaved in the bony explants of homozygous PTHrP. These findings demonstrate a crucial nonredundant role of PTHrP in the regulation of proteoglycan synthesis and metabolism during skeletal development.

Animals↗
PubMed2000

Homeobox genes and gut development.

The gut of vertebrates exhibits a common anteroposterior regional differentiation. The role of homeobox genes in establishing this pattern is inferred by their sites of expression. It is suggested that the primary source of positional information is in the endoderm, which subsequently establishes a 'dialogue' with the surrounding visceral layer of the lateral plate mesoderm. This results in the anatomical and physiological specialization of the adult gut.

Animals↗
PubMed2000

Mandibular deformities in parathyroid hormone-related protein (PTHrP) deficient mice: possible involvement of masseter muscle.

Previous studies using parathyroid hormone-related protein (PTHrP) null mutant mice have indicated severe abnormalities in the endochondral ossification, suggesting that PTHrP affects chondrocyte differentiation. In this study, we found in newborn PTHrP-deficient mice some deformities in the mandible that is formed via intramembranous ossification. The mandibular ramus was bent downwards and a prominent bone crest to which the deep layer of masseter muscle was tendinously attached was observed in the mandibular body. Transmission electron microscopic studies showed that active bone formation was progressing along the tendon fibers of the masseter muscle. The examination of 3-D reconstruction models indicated that the mandibular ramus was bent at the site of muscle attachment, which was shifted in the direction of the muscle fibers. Muscle fiber type analysis using myosin ATPase staining showed that the masseter muscle in the newborn PTHrP-deficient mice contained numerous type 2B fibers, demonstrating premature maturation of this muscle. Based on these findings, we speculated that premature maturation of the masseter muscle leads, probably due to increased tensile forces, to accelerated bone crest formation and subsequent bending of the mandibular ramus. These results further suggest that PTHrP is involved in the regulation of muscle development in normal animals.

Animals↗
PubMed2000

Collagen studies in late pregnant relaxin null mice.

The relaxin knockout (rlx -/-) mouse was used to assess the effect, during pregnancy, of relaxin with regard to water, collagen content, growth, and morphology of the nipple (N), vagina (V), uterus, cervix (C), pubic symphysis (PS), and mammary gland (MG). The results presented here indicate that during pregnancy, relaxin increases the growth of the N, C, V, and PS. Large increases in water content in the PS (20%) occurred in pregnant (Day 18.5) wild-type (rlx +/+) mice but not in rlx -/- animals. This indicates that in the PS, relaxin might increase the concentration of a water-retaining extracellular matrix component (hyaluronate). In the pregnant rlx +/+ mouse, collagen content decreased significantly in the N and V but not in other tissues. There were no significant changes in the rlx -/- mouse. This contrasts with findings in the rat, in which relaxin has been found to cause decreases in collagen concentrations in the V, C, and PS. Histological analysis showed that the collagen stain was more condensed in the tissues (V, C, PS, N, and MG) of rlx -/- mice than in those of rlx +/+ mice. This phenomenon indicates that the failure of collagen degradation and lack of growth in the N underlie the inability of the rlx -/- mice to feed their young, as reported previously. Vaginal and cervical luminal epithelia, which proliferated markedly in the rlx +/+ pregnant mice, remained relatively atrophic in the rlx -/- mice. As proliferation and differentiation of uterine and vaginal epithelia are thought to be induced by a paracrine stromal factor that acts upon estrogen stimulation, our results indicate that relaxin may be this paracrine factor.

Animals↗
PubMed2000

[Magnetic resonance angiography of stents].

PURPOSE: To understand the behavior of stents during contrast-enhanced magnetic resonance angiography (MRA). MATERIALS AND METHODS: Seven different types of stents are explored in vitro with spin echo (SE) T2 sequence and MRA sequences using classification of the intra-prothesis signal. Six patients with 11 different proximal stents are studied by Gadolinium enhanced MRA with the same classification. RESULTS: Stent material is not the only determinant of behavior. In this way, one stainless steel stent produced less intra-luminal hyposignal than a nitinol device. Nevertheless, only a nitinol stent did not alter the intra-prothesis signal and allowed an appreciation of patency, despite a decrease of diameter and presence of edge artifacts. CONCLUSION: Even if stent compatibility is well known with MRI, even with Gadolinium, cannot be used alone to depict stenosis or diameter reduction. Even patency based on the presence of a constant signal, cannot be confirmed routinely with confidence: indeed, only a single stent does not modify intra-arterial signal.

Aged↗
PubMed1999

Differential responses to parathyroid hormone-related protein (PTHrP) deficiency in the various craniofacial cartilages.

PTHrP null mutant mice exhibit skeletal abnormalities both in the craniofacial region and limbs. In the growth plate cartilage of the null mutant, a diminished number of proliferating chondrocytes and accelerated chondrocytic differentiation are observed. In order to examine the effect of PTHrP deficiency on the craniofacial morphology and highlight the differential feature of the composing cartilages, we examined the various cartilages in the craniofacial region of neonatal PTHrP deficient mice. The major part of the cartilaginous anterior cranial base appeared to be normal in the homozygous PTHrP deficient mice. However, acceleration of chondrocytic differentiation and endochondral bone formation was observed in the posterior part of the anterior cranial base and in the cranial base synchondroses. Ectopic bone formation was observed in the soft tissue-running mid-portion of the Meckel's cartilage, where the cartilage degenerates and converts to ligament in the course of normal development. The zonal structure of the mandibular condylar cartilage was scarcely affected, but the whole condyle was reduced in size. These results suggest the effect of PTHrP deficiency varies widely between the craniofacial cartilages, according to the differential features of each cartilage.

Animals↗
PubMed1999

Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice.

The homeobox gene Cdx2, a homologue of the Drosophila gene caudal, has been implicated in the control of cell differentiation in the intestinal epithelium. Recently, we showed that mice in which one allele of the Cdx2 gene had been inactivated by homologous recombination developed multiple intestinal polyp-like lesions that did not express Cdx2 and that contained areas of squamous metaplasia in the form of keratinizing stratified squamous epithelium, similar to that occurring in the mouse esophagus and forestomach. We have now examined colonic lesions from 98 Cdx2+/- mice and report that the lesions are composed of heterotopic stomach and small intestinal mucosa. We conclude that Cdx2 directs endodermal differentiation toward a caudal phenotype and that haploinsufficient levels of expression in the developing distal intestine lead to homeotic transformation to a more rostral endodermal phenotype, such as forestomach epithelium that does not express Cdx2 during normal development. Intercalary growth (epimorphic regeneration), which previously has never been described in mammals, then occurs, resulting in the ordered "filling in" of tissue types at the discontinuity between the gastric and colonic epithelia. This intercalary growth in a restricted space results in the formation of the polypoid lesions observed.

Animals↗
PubMed1999

Expression of aldose reductase, sorbitol dehydrogenase and Na+/myo-inositol and Na+/Cl-/betaine transporter mRNAs in individual cells of the kidney during changes in the diuretic state.

The effect of changes in medullary extracellular tonicity on mRNA expression for aldose reductase (AR), sorbitol dehydrogenase (SDH), Na+/Cl-/betaine (BGT) and Na+/myo-inositol (SMIT) cotransporter in different kidney zones was studied using Northern blot analysis and non-radioactive in situ hybridization in four groups of rats: controls, acute diuresis (the loop diuretic furosemide was administered), chronic diuresis (5 days of diuresis), and antidiuresis [5 days of diuresis followed by 24 h deamino-Cys1, d-Arg8 vasopressin (dDAVP)]. Acute administration of the loop diuretic furosemide significantly reduced AR, SMIT and BGT gene expression in the inner and outer medulla compared with controls. Administration of dDAVP to chronically diuretic rats raised the expression of these three mRNAs in the inner but not the outer medulla compared with the chronically diuretic rats. None of these alterations in medullary tonicity significantly changed SDH expression. The in situ hybridization studies showed AR, BGT and SMIT mRNAs to be expressed in both epithelial and non-epithelial cells of the outer and inner medulla. The various cell types (epithelial, endothelial and interstitial cells) differed in their expression pattern and intensity of AR, SDH, BGT and SMIT mRNA, but the inner medullary cells responded uniformly to a decrease in extracellular tonicity with a reduction, and to an increase with enhancement of their AR, BGT and SMIT expression.

Aldehyde Reductase↗
PubMed1999

Mice without a functional relaxin gene are unable to deliver milk to their pups.

We have used gene targeting to generate relaxin (rlx)-deficient mice. The majority (15 of 17) of homozygous (rlx-/-) mice are fertile and produce normal litters. However their mammary development is deficient; pups are unable to suckle and die within 24 h of birth unless cross-fostered to a wild-type (rlx+/+) foster mother. The nipples of rlx-/- animals do not enlarge significantly during pregnancy, and their histology retains the appearance of the virgin state. Breast parenchyma is somewhat underdeveloped at term even though milk is produced. Mammary ducts become grossly dilated in these animals. Heterozygous (rlx+/-) mice lactate normally. The interpubic ligament does not relax during pregnancy in rlx-/- mice. Plasma osmolality during late gestation was significantly higher (P < 0.001) in rlx-/- mice than in wild-type controls.

Alleles↗
PubMed1999

Parathyroid hormone-related protein regulates proliferation of condylar hypertrophic chondrocytes.

The condylar cartilage, an important growth site in the mandible, shows characteristic modes of growth and differentiation, e.g., it shows delayed appearance in development relative to the limb bud cartilage, originates from the periosteum rather than from undifferentiated mesenchymal cells, and shows rapid differentiation into hypertrophic chondrocytes as opposed to the epiphyseal growth plate cartilage, which has resting and proliferative zones. Recently, attention has been focused on the role of parathyroid hormone-related protein (PTHrP) in modulating the proliferation and differentiation of chondrocytes. To investigate further the characteristic modes of growth and differentiation of this cartilage, we used mice with a disrupted PTHrP allele. Immunolocalization of type X collagen, the extracellular matrix specifically expressed by hypertrophic chondrocytes, was greatly reduced in the condylar cartilage of homozygous PTHrP-knockout mice compared with wild-type mice. In contrast, immunolocalization of type X collagen of the tibial cartilage did not differ. In wild-type mice, proliferative chondrocytes were mainly located in both the flattened cell layer and hypertrophic cell layer of the condylar cartilage, but were limited to the proliferative zone of the tibial cartilage. The number of proliferative chondrocytes was greatly reduced in both cartilages of homozygous PTHrP-knockout mice. Moreover, apoptotic chondrocytes were scarcely observed in the condylar hypertrophic cell layer, whereas a number of apoptotic chondrocytes were found in the tibial hypertrophic zone. Expression of the type I PTH/PTHrP receptor was localized in the flattened cell layer and hypertrophic cell layer of the condylar cartilage, but was absent from the tibial hypertrophic chondrocytes. It is therefore concluded that, unlike tibial hypertrophic chondrocytes, condylar hypertrophic chondrocytes have proliferative activity in the late embryonic stage, and PTHrP plays a pivotal role in regulating the proliferative capacity and differentiation of these cells.

Animals↗
PubMed1998

[Periodontitis--a ubiquitous illness].

In recent years, periodontitis has been receiving increasing attention, since it not only impairs the general state of health (loss of the teeth), but also appears to have a relationship with cardiovascular and cerebrovascular illnesses (thrombocyte aggregation, insult). Periodontitis is a very frequent, chronic recurrent, unspecific bacterial inflammation of the periodontium that arises in accumulated plaques on the teeth at the gingiva. It leads to an irreversible destruction of soft tissue followed by loss of bony substance. Three types of periodontitis can be distinguished: 1. adult periodontitis (AP), 2. rapidly progressive periodontitis (RPP) and juvenile periodontitis (JP). Periodontitis appears to have a genetic component. Additional risk factors include juvenile diabetes mellitus and smoking. The diagnosis, prevention and treatment are discussed. The basis for prevention and treatment is individual hygiene and professional dental care.

Adolescent↗
PubMed1998

Thermodynamics and energetics of the tonoplast membrane operating as a hysteresis switch in an oscillatory model of Crassulacean acid metabolism.

The observed endogenous circadian rhythm in plants performing Crassulacean acid metabolism is effected by malate transport at the tonoplast membrane. Experimental and theoretical work asks for a hysteresis switch, regulating this transport via the ordering state of the membrane. We apply a schematic molecular model to calculate the thermally averaged order parameter of the membrane lipid structure in its dependence on external parameters temperature and area per molecule. The model shows a first order structural phase transition in a biologically relevant temperature range. Osmotic consequences of malate accumulation can trigger a transition between the two phases by changing the surface area of the cell vacuole. Estimation of the energy needed to expand the vacuole under turgor pressure because of osmotic changes while acidifying shows that energy needed as latent heat for the calculated change between phases can easily be afforded by the cell. Thus, malate content and the coexisting two phases of lipid order, showing hysteretic behavior, can serve as a feedback system in an oscillatory model of Crassulacean acid metabolism, establishing the circadian clock needed for endogenous rhythmicity.

Circadian Rhythm↗
PubMed1998

CDX2, a human homologue of Drosophila caudal, is mutated in both alleles in a replication error positive colorectal cancer.

The Cdx2 gene is one of three murine homologues of the Drosophila homeobox gene caudal. Mice heterozygous for a null mutation in Cdx2 exhibit a variable phenotype including tail abnormalities, stunted growth and a homeotic shift of vertebrae. Most strikingly, however, 90% of heterozygous mice were reported to develop multiple intestinal adenomatous polyps, most notably in the proximal colon (Chawengsaksophak et al., 1997). These observations led us to propose that mutation of CDX2 may be involved in the genesis of some human colorectal tumours. A survey of DNA from 85 colorectal tumours revealed that one with extensive microsatellite instability (RER+ phenotype) has mutations in both alleles of CDX2. Both mutations occur in coding regions which contain repetitive elements and are consistent with those found in RER + tumours.

Adenocarcinoma↗
PubMed1998

Pretreatment with hypertonic NaCl protects MDCK cells against high urea concentrations.

In antidiuresis, the cells of the renal medulla are exposed to high extracellular concentrations of NaCl and urea. Since urea equilibrates with the intracellular compartment and is known to perturb intracellular macromolecules, high urea concentrations may well disturb the structure and function of cell proteins. Two types of organic substances are believed to counteract the adverse effects of high intracellular urea concentrations: specific organic osmolytes of the trimethylamine family [betaine and glycerophosphorylcholine (GPC)], which accumulate in renal medullary cells during prolonged periods of antidiuresis and cytoprotective heat shock proteins (HSPs), the tissue content of two of which (HSPs 27 and 72) is much higher in the inner medulla than in the iso-osmotic renal cortex. To evaluate the contribution of trimethylamines and HSPs to cytoprotection in the presence of high urea concentrations, the effect of HSP induction and osmolyte accumulation prior to exposure to high urea concentrations was examined in Madin-Darby canine kidney (MDCK) cells. Accumulation of organic osmolytes and synthesis of HSP27 and HSP72 was initiated by hypertonic stress (increasing the osmolality of the medium from 290 to 600 mosmol/kg H2O by NaCl addition). Control, non-conditioned cells remained in the isotonic medium for the same period. Upon subsequent exposure to an additional 600 mM urea in the medium for 24 h, 90% of the osmotically conditioned cells but only 15% of non-conditioned cells survived. The HSP72 and trimethylamine contents of the NaCl-conditioned MDCK cells, but not HSP27 content, correlated positively with cell survival. To separate the effects of organic osmolytes and HSP72, chronically NaCl-adapted MDCK cells were returned to isotonic medium for 1 or 2 days, so depleting them of trimethylamine osmolytes. HSP72, with its longer half life, remained elevated. Subsequent exposure of these cells to 600 mM urea in the medium resulted in about 80% survival. These results suggest that in MDCK cells and probably in the renal medulla, HSP72 and perhaps additional protective factors contribute substantially to the resistance against high urea concentrations.

Animals↗
PubMed1998

Effects of long-term changes in medullary osmolality on heat shock proteins HSp25, HSP60, HSP72 and HSP73 in the rat kidney.

The influence of diuresis and antidiuresis on the expression of heat shock proteins (HSP) 25, 60, 72 and 73 in the renal cortex and outer and inner medulla of Wistar rats was analysed. Medullary osmolality was reduced by long-term diuresis (3% sucrose in the drinking water for 3 weeks) and subsequently enhanced by transition to a concentrating state by giving normal drinking water again in combination with deamino-D-arginine vasopressin (dDAVP) for 5 days. Western blot analyses revealed that neither HSP73 nor HSP60 was influenced by any treatment. The HSP72 level in the medulla was markedly reduced (50%) when osmolality was lowered and increased when tonicity was high. RNAse protection assays showed that the effects on HSP72 are parallelled in general by changes in HSP72 mRNA. While levels of HSP25 were not influenced, isoelectric focusing revealed that the degree of phosphorylation of outer and inner medullary HSP25 increased following both treatments. It thus seems that HSP73 and HSP60 are not directly involved in the long-term adaptation to varying medullary osmolalities. The correlation between changes in osmolality and amounts of the major stress-inducible HSP72 in the medulla implies that medullary hypertonicity is stressful for kidney cells. Furthermore, adaptation to pronounced changes in the osmolality of the environment most likely involves phosphorylation of HSP25.

Animals↗
PubMed1998

Comparison of transesophageal Doppler methods with angiography for evaluation of the severity of mitral regurgitation.

Doppler evaluation of mitral regurgitation remains difficult; thus, a head-to-head comparison of the diagnostic accuracy of Doppler methods was undertaken. Fifty patients with native mitral regurgitation underwent multiplane transesophageal echocardiography within 5 days of catheterization. Angiographic grade of mitral regurgitation and, in 20 patients with grade II-IV regurgitation, invasively determined regurgitant stroke volume were compared with color Doppler area, regurgitant jet diameter, ratio of systolic to diastolic peak pulmonary venous flow velocities, and (based on the proximal convergence zone) maximal regurgitant flow rate and regurgitant orifice area. Rank correlation coefficients of angiographic grade with Doppler parameters were 0.61 for color jet area, -0.61 for pulmonary venous flow velocity ratio, 0.69 for color jet diameter, 0.79 for maximal regurgitant flow rate, and 0.78 for regurgitant orifice area (all P < .01). Convergence zone-based parameters also correlated best (r=0.73) with invasively determined regurgitant stroke volume. Receiver operating characteristic curve analysis confirmed higher diagnostic accuracy for proximal jet width and proximal convergence zone parameters than for color jet area or pulmonary venous flow velocity ratio. Proximal convergence zone parameters and proximal color jet diameter best distinguished severe from mild forms of mitral regurgitation.

Cardiac Catheterization↗
PubMed1998

Developmental biology at the Howard Florey Institute.

1. A brief account of the history of developmental biology at the Howard Florey Institute, as well as in a wider general context, is presented and some of the results of developmental studies performed at the Institute over the past 7 years are discussed. 2. In the foetal rat, parathyroid hormone rather than parathyroid hormone-related protein is produced by the parathyroid anlage. This contrasts with results reported by others for the sheep. 3. The control of imprinting of H19 and insulin-like growth factor-II has been studied in the mouse using gene knockout of the coding region of the H19 gene. Bi-allelic expression of H19 in some liver and gut cells was observed. 4. Gene knockout of the homeobox gene Cdx2 produced dramatic effects. Homozygous embryos did not implant in the uterus. Heterozygotes exhibited homeosis involving the gut and skeleton. Animals developed intestinal tumours within a few weeks of birth.

Academies and Institutes↗