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Biomedical subjects

F Welsch

Publications and source records attributed to F Welsch.

At least 19 recordsLinked to original sources
PubMed2006

[Nuclear medicine techniques in the diagnosis of orthopaedic diseases].

Nuclear medicine techniques show metabolic processes, allowing the diagnoses of many bone and joint disorders. For most orthopaedic indications three-phase bone scintigraphy is used, showing inflammatory bone and joint diseases, traumatic and post-operative disorders as well as necrotic or malignant changes. In addition to bone scintigraphy, there are radiopharmaceuticals to depict inflammatory processes. Finally, positron emission tomography is a modern imaging technique used mainly for tumor diagnostics, but also for detection of inflammation.

Bone Diseases↗
PubMed2004

Patella kinematics and patello-femoral contact areas in patients with genu varum and mild osteoarthritis.

BACKGROUND: Patients with genu varum of the knee and moderate to severe osteoarthritis often suffer from additional symptoms of the patello-femoral joint. These patients have a poor prognosis following high tibial osteotomy. It is unclear whether varus knees with only mild femoro-tibial osteoarthritis are also associated with alterations of patella biomechanics, and affect the prognosis of intended high tibial osteotomy. METHODS: Fifteen patients with genu varum and mild osteoarthritis and 15 healthy volunteers were assessed in an open MRI-scanner. 3D-GRE sequences of the knee were obtained in 0 degrees, 30 degrees and 90 degrees with and without activity of the extensor muscles. After segmentation of patella, femur, tibia and the adjacent cartilage, a patella-based local coordinate system was established. Femoral and tibial reference points allowed definition of the spatial position of the patella. Contact areas were defined by intersection of opposing cartilage volumes. FINDINGS: No significant differences in patella kinematics and patello-femoral contact areas could be found (P > 0.05) between varus knees with mild osteoarthritis and healthy knees either at different flexion angles or under extending muscle activity. INTERPRETATION: In knees with genu varum and mild medial osteoarthritis we could detect no alterations in patello-femoral kinematics. Since the alterations of patients with genu varum and mild osteoarthritis are restricted to the medial femoro-tibial joint high tibial osteotomy might be successful.

Adult↗
PubMed2002

[Is meniscal repair an adequate procedure to prevent early osteoarthritis in athletes with chronic anterior knee instabilitity?].

We retrospectively evaluated the clinical outcome of arthroscopic assisted meniscal suture repair in athletes on different competitive sports levels with stable joint function and persisting anterior knee instability. Return to former sports levels and early osteoarthrotic changes were especially focussed. Examination included 50 athletes (32 men, 18 women) who underwent meniscal repair in inside-out technique during the period of 1989 to 1998. 23 patients had isolated full-thickness meniscal tears, 27 an associated rupture of the anterior cruciate ligament which was reconstructed in 13 cases with a patellar-tendon autograft. 3 study groups were formed referring to the athletes preoperative sports level evaluated with Tegner's score. Reexamination included Lysholm score, IKDC score and Fairbank's score. With a mean age of 32.1 years (range 13-53 years) and an average follow-up of 6.3 years 72 % of the patients (n = 36) showed a stable joint function on reexamination. With no persisting anterior knee instability 86 % of the professional athletes returned to former full sports activities on competitive levels. Non competitive athletes returned in all cases (100 %) to their former level. Fairbank's score increased by 0.1 observing minimal osteoarthitic signs. However, persisting anterior knee instability showed on reexamination poor results. Only one third of all athletes were able to return to former activity levels. Osteoarthritic changes were observed in all patients. Professional athletes had the most severe osteoarthritic changes with a significant (p = 0.03) increase of 0.8 in Fairbank's score. The results demonstrate that complete recovery on sports activities after meniscal repair is not possible without reconstruction of the anterior cruciate ligament. Isolated meniscal repair shows poor results in persisting anterior knee instability and does not prevent increasing osteoarthritic changes in athletes.

Adolescent↗
PubMed2000

Metabolism and disposition of bisphenol A in female rats.

Bisphenol A (BPA), which is used in the manufacture of polycarbonates, elicits weak estrogenic activity in in vitro and in vivo test systems. The objectives of this study were to compare the patterns of disposition of radioactivity in adult female F-344 and CD rats after oral administration of (14)C BPA (100 mg/kg), to isolate the glucuronide of BPA and to assess its estrogenic activity in vitro, and to evaluate the transfer of radioactivity to pups from lactating dams administered (14)C BPA. Over 6 days, F-344 rats excreted more radioactivity in urine than CD rats. The major metabolite in urine was identified as bisphenol A glucuronide (BPA gluc) by incubation with beta-glucuronidase and (1)H and (13)C NMR spectroscopy. In lactating CD rats administered (14)C BPA (100 mg/kg) by gavage, only a small fraction of the label was found in milk, with 0.95 +/- 0.66, 0.63 +/- 0.13, and 0.26 +/- 0.10 microg equiv/ml (mean +/- SD) from dams collected 1, 8, and 26 h after dosing, respectively. Radioactivity in pup carcasses indicated exposure in the range of microgram equivalents per kilogram; those values ranged from 44.3 +/- 24.4 for pups separated from their lactating dams at 2 h to 78.4 +/- 10.9 at 24 h. BPA gluc was the prominent metabolite in milk and plasma. In test systems for activation of in vitro estrogen receptors alpha and beta, BPA gluc did not show appreciable efficacy at concentrations up to 0.03 mM, indicating that metabolism via glucuronidation is a detoxication reaction.

Air Pollutants, Occupational↗
PubMed2000

Development of a physiologically based pharmacokinetic model of 2-methoxyethanol and 2-methoxyacetic acid disposition in pregnant rats.

An accurate description of developing embryos' exposure to a xenobiotic is a desirable component of mechanism-based risk assessments for humans exposed to potential developmental toxicants during pregnancy. 2-Methoxyethanol (2-ME), a solvent used in the manufacture of semiconductors, is embryotoxic and teratogenic in all species tested including nonhuman primates. 2-Methoxyacetic acid (2-MAA) is the primary metabolite of 2-ME and the proximate embryotoxic agent. The objective of the work described here was to adapt an existing physiologically based pharmacokinetic (PBPK) model for 2-ME and 2-MAA kinetics during midorganogenesis in mice to rats on gestation days (GD) 13 and 15. Blood and tissue data were analyzed using the extrapolated PBPK model that was modified to simulate 2-ME and 2-MAA kinetics in maternal plasma and total embryo tissues in pregnant rats. The original mouse model was simplified by combining the embryos and placenta with the richly perfused tissue compartment. The model includes a description of the growth of the developing embryo and changes in the physiology of the dam during pregnancy. Biotransformation pathways of 2-ME to either ethylene glycol (EG) or to 2-MAA were described as first-order processes based on the data collected from rats by Green et al., (Occup. Hyg. 2, 67-75, 1996). Tissue partition coefficients (PCs) for 2-ME and 2-MAA were determined for a variety of maternal tissues and the embryos. Model simulations closely reflected the biological measurement of 2-ME and 2-MAA concentrations in blood and embryo tissue following gavage or iv administration of 2-ME or 2-MAA. The PBPK model for rats as described here is well suited for extrapolation to pregnant women and for assessment of 2-MAA dosimetry under various conditions of possible human exposure to 2-ME.

Acetates↗
PubMed2000

Primary human bone cultures from older patients do not respond at continuum levels of in vivo strain magnitudes.

Osteoporosis is characterized by excessive loss of bone mass, while exercise is believed to maintain or enhance bone mass. Since exercise marginally affects osteoporosis, we wondered whether bone cells from osteoporotic patients would fail to respond to strain. Primary human bone-like cultures were obtained from females over age 60 with hip arthroplasty procedures performed for either osteoporotic fracture (n = 8) or non-osteoporotic osteoarthrosis (n = 5). Cultures (96,000 cell/cm2) were strained in rectangular optically clear silastic wells. Three periods of uniaxial substratum strain (1000 micro-strain, 1 Hz, 10,000 cycles, sine wave) were provided every 24 h using a four-point bending, computer-controlled device. Results at a frequency of 1 Hz were compared to cultures exposed to 20 Hz with bone cells derived from one osteoarthritic subject. Alterations in protein level expression of bone-related proteins were determined using a semi-quantitative confocal approach along with enzyme (alkaline phosphatase) activity and enzyme mRNA copy number using cRNA RT-PCR. Strain did not alter levels of bone-related protein levels, enzyme activity, or steady state copy number per cell in response to strain in either group. Strained cultures from osteoporotic patients exhibited little variation from unstrained controls, while individual cultures from osteoarthritic patients exhibited increases in one protein or the other. The results suggest that bone cells from older individuals may not be responsive to continuum levels of strain anticipated with vigorous activity.

Aged↗
PubMed2000

Oestrogen receptor alpha and beta in rat prostate and epididymis.

The cellular localization of two oestrogen receptor (ER) subtypes, ER alpha and ER beta, was investigated in neonatal, postnatal, immature and adult male rats to determine whether these receptor subtypes are differentially expressed in prostate and epididymis. A monoclonal antibody against ER alpha and two polyclonal ER beta antibodies were used. Paraffin sections revealed a specific nuclear immunoreaction product in certain cells but not in others. In the epididymis, nuclear ER alpha immunoreactivity (IR) was detected in epithelial cells of efferent ductules and initial segments as well as in connective tissue surrounding the tubules in caput, corpus and cauda. No IR was observed in rete testis. Epithelial cells of the prostate lacked ER alpha IR, but connective tissue cells surrounding prostatic buds in the early neonatal period revealed IR. In prostate, ER beta IR was expressed in epithelial cells of the ventral and dorsolateral lobes, but the IR intensity was higher in the ventral lobe. In neonatal rats, ER beta was expressed in the epididymis but not in the prostate gland. Weak ER beta expression was found in the prostates of 5-day-old rats, and the reaction increased in intensity thereafter. In the epididymis, a similar developmental expression pattern of ER beta was observed. ER beta expression in prostate and epididymis was similar to expression of androgen receptors reported previously for these organs. The results support that both ER alpha and ER beta may be involved in oestrogen modulation of prostate and epididymal functions.

Animals↗
PubMed2000

Analysis of respiratory exchange of methanol in the lung of the monkey using a physiological model.

A physiologically based pharmacokinetic (PBPK) model was developed for the monkey, to account for fractional systemic uptake of inhaled methanol vapors in the lung. Fractional uptake of inhaled [14C]-methanol was estimated using unreported exhaled breath time course measurements of [14C]-methanol from the D.C. Dorman et al. (1994, Toxicol Appl Pharmacol. 128, 229-238) lung-only exposure study. The cumulative amount of [14C]-methanol exhaled was linear with respect to exposure duration (0.5 to 2 h) and concentration (10 to 900 ppm). The model estimated that forty to eighty-one percent of the of inhaled [14C]-methanol delivered to the lung was taken into systemic circulation in female Cynomolgus monkeys exposed for two h to 10-900 ppm of [14C]-methanol. There was no apparent trend between the percent of inhaled [14C]-methanol absorbed systemically and the [14C]-methanol exposure concentration. Model simulations were conducted using a single saturable Michaelis-Menten equation with Vmaxc, the metabolic capacity set to 15.54 mg/kg/h and Km, the affinity constant, to 0.66 mg/l. The [14C]-methanol blood concentrations were variable across [14C]-methanol exposure groups and the PBPK model tended to over-predict systemic clearance of [14C]-methanol. Accounting for fractional uptake of inhaled polar solvents is an important consideration for risk assessment of inhaled polar solvents.

Administration, Inhalation↗
PubMed2000

Pubertal development and reproductive functions of Crl:CD BR Sprague-Dawley rats exposed to bisphenol A during prenatal and postnatal development.

Bisphenol A (BPA) is used on a large scale in the manufacture of polycarbonate plastics. BPA has been shown to bind weakly to both estrogen receptor (ER)alpha and ERbeta, and to transactivate reporter genes in vitro. The purpose of the present study was to determine whether exposure of rats to BPA during pre- and postnatal development affects estrogen-mediated end points related to pubertal development and reproductive functions. BPA was administered to pregnant Crl:CD BR Sprague-Dawley rats by gavage at 0, 3.2, 32, or 320 mg/kg/day from gestation day (GD) 11 through postnatal day (PND) 20. Diethylstilbestrol (DES) at 15 microg/kg/day was used as a reference chemical with known estrogenic effects. Female pubertal development was not affected by indirect BPA exposure of the offspring at any of the dose levels. Treatment with this chemical also did not produce detectable effects on the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA), estrous cyclicity, sexual behavior, or male reproductive organ weights of F(1) offspring. However, DES at 15 microg/kg/day increased the volume of the SDN-POA of female offspring and affected their normal estrous cyclicity following puberty. In this study, pre- and postnatal exposure of rats to BPA at 3.2, 32, or 320 mg/kg/day from GD 11 through PND 20 did not have any apparent adverse effects on female rat pubertal development and reproductive functions.

Animals↗
PubMed1999

Differential expression of estrogen receptor-beta and estrogen receptor-alpha in the rat ovary.

Immunohistochemical localization of two estrogen receptor (ER) subtypes, ER beta and ER alpha, was performed in neonatal, early postnatal, immature, and adult rats to determine whether ER alpha and ER beta are differentially expressed in the ovary. ER beta and ER alpha were visualized using a polyclonal anti-ER beta antibody and a monoclonal ER alpha (ID5) antibody, respectively. Postfixed frozen sections and antigen-retrieved paraffin sections of the ovary revealed nuclear ER beta immunoreactivity (IR) in granulosa cells, which was prevented when peptide-adsorbed antibody was used instead. In immature and adult rat ovaries, ER beta was expressed exclusively in nuclei of granulosa cells of primary, secondary, and mature follicles. Atretic follicle granulosa cells showed only weak or no staining. No specific nuclear ER beta IR was detected in thecal cells, luteal cells, interstitial cells, germinal epithelium, or oocytes. In neonatal rat ovary, no ER beta expression was found. In ovaries of 5- and 10-day-old rats, weak ER beta IR was observed in granulosa cells of primary and secondary follicles, but no staining was detected in the primordial follicles. ER alpha protein exhibited a differential distribution in the ovary with no detectable expression in the granulosa cells but evidence of ER alpha IR in germinal epithelium, interstitial cells, and thecal cells. In the oviduct and uterus, IR for ER alpha, but not ER beta, was found in luminal epithelium, stromal cells, muscle cells, and gland cells. Our present study demonstrates that ER beta and ER alpha proteins are expressed in distinctly different cell types in the ovary. The exclusive presence of ER beta in granulosa cells implies that this specific new subtype of ER beta mediates some effects of estrogen action in the regulation of growth and maturation of ovarian follicles.

Aging↗
PubMed1998

Characterization of cell death induced by 2-methoxyethanol in CD-1 mouse embryos on gestation day 8.

Cell death was analyzed in neurulating mouse embryos after in vivo doses of 2-methoxyethanol (2-ME) that produce anterior neural tube defects. Characterization of 2-ME-induced cell death was performed by evaluating: (1) vital fluorochrome staining in whole embryos applying confocal laser scanning microscopy; (2) characteristics of cell debris in conventional histological sections revealed by light microscopy; and (3) Apoptag in situ immunohistochemical staining for apoptosis using light microscopy. Methods for quantification of cell death identified by these three techniques were explored using computerized image analysis. Physiological cell death in control embryos primarily occurred in the neural crest region during neural fold elevation. Embryos exposed to 2-ME had expanded areas of cell death in the neural crest and also new areas of cell death in medial regions of the anterior neural tube. Both physiological and 2-ME-induced embryonic cell death had morphological, immunohistochemical, and fluorochrome staining characteristics of apoptosis. When fluorescence data from confocal microscopic analysis of vital fluorochrome-stained embryos were analyzed, a dose-dependent increase was found in embryos exposed to 2-ME. Similar results were obtained when cell death was analyzed in either conventional histological sections or sections prepared for immunohistochemical detection of apoptosis. The cell death data obtained in this study correlate with previously observed near-term malformation rates, suggesting that a quantitative relationship exists between 2-ME-induced embryonic cell death and neural tube defects.

Acridine Orange↗
PubMed1997

Development of a physiologically based pharmacokinetic model to describe the disposition of methanol in pregnant rats and mice.

Physiologically based pharmacokinetic (PBPK) models have been developed in recent years to describe the disposition of xenobiotics during gestation. These models can account for the dynamics of physiologic changes associated with pregnancy and represent a significant advantage in quantitatively assessing potential exposure of the conceptus. The PBPK approach was used to develop a model of methanol disposition during gestation in rats and mice. To validate this model, concentrations of methanol in the dam and the conceptus were determined after methanol exposure of rats on Gestational Day (gd) 14 and 20 and of mice on gd 18. At the developmental stages examined, the model provided a good description of methanol disposition in the maternal circulation and the conceptus of both species. Furthermore, the model was capable of providing good fits to methanol concentration-time data from the literature. In pregnant animals, conceptal/maternal AUC and Cmax ratios decreased with increasing dose at both gd 14 and gd 20 in the rat and at gd 18 in the mouse. Additionally, the conceptal/maternal diffusion constant ratio consistently decreased with increasing dose in pregnant rats and mice. These results are consistent with earlier observations that methanol limits its own delivery to the conceptus. Further experimentation is required to continue the process of developing a generalized PBPK model to describe the disposition of xenobiotics in pregnancy, to examine specific mechanisms of nonlinear conceptal methanol disposition, and to expand the model to extrapolate to low-dose human exposures.

Animals↗
PubMed1996

Effects of 2-methoxyethanol on mouse neurulation.

The potent developmental toxicant, 2-methoxyethanol (2-ME), elicits exencephaly in near-term mouse fetuses following a single maternal treatment early on gestation day (gd) 8. Deleterious morphological consequences to the neurulating embryo shortly after exposure have not been reported. The present study was designed to fill this gap and to investigate the impact of 2-ME treatment on cell death patterns in the embryonic neural folds. Dams were injected subcutaneously with saline, 250 or 325 mg 2-ME/kg 2 hr prior to the beginning of gd 8. The effect of 2-ME on gross and microscopic neural development was examined in conceptuses on gd 9, 6 hr (9:6), 10:6, and 18:0. Compared to saline, 2-ME treatment increased the percentage of embryos with open neural tubes (ONTs) at all gestation days. Although few statistically significant differences (P < 0.05) existed among the ONT rates on the 3 observation days, an interesting biological response occurred. Both high and low 2-ME doses appeared to elicit the greatest incidence of neural tube patency on gd 9:6 (affecting approximately 27% of embryos). During the subsequent 24 hr, recovery occurred and many neural folds apparently closed. Consequently, the ONT incidences on gd 10:6 (approximately 11%) were quite similar to the gd 18 exencephaly rates elicited by both chemical treatments (approximately 15%). A dose response was not seen due to a substantial increase in resorption rates following the 325 mg/kg dose. Compared to the other treatment groups, the low 2-ME dose significantly inhibited embryonic growth as indicated by reduced crown-rump and head lengths and increased incidence of developmentally delayed brain maturation. To evaluate chemically induced changes in cell death, neurulating embryos were collected on gd 8:6 and either immersed in the vital dye, Nile blue sulfate (NBS), or processed for histopathology. In 2-ME-exposed embryos, excessive NBS uptake occurred in neural fold neuroepithelium at sites of nonclosure. Using histopathology, the extent of cell death in the cephalic neural folds was dependent on the 2-ME dose, and the neuroepithelium was more severely affected than the mesenchyme. These observations suggest 1) a trend toward repair and catch-up growth later in gestation which may ameliorate the overt early effects of 2-ME, and 2) an association between enhanced cell death and regions of the neural tube particularly vulnerable to nonclosure.

Animals↗
PubMed1996

Developmental phase specificity and dose-response effects of 2-methoxyethanol in rats.

Methoxyethanol (ME) produces embryotoxic effects in rodents, rabbits, and nonhuman primates. Mechanistic evaluations of ME dysmorphogenesis have focused mainly on developmental insults and chemical disposition in the mouse. These assessments in mice were based on developmental phase specificity (DPS) and dose-response relationship (DRR) of ME. DPS and DRR indicated treatments for selectively inducing defects to study ME disposition and expressed dysmorphogenesis. This study was conducted to establish DPS and DRR of ME in the rat. DPS was determined by injecting 500 mg ME/kg (6.6 mmol/kg) into the tail vein on Gestational Day (gd; sperm-positive day = gd 0) 10, 11, 12, 13, 14, or 15 (n = 6 dams/gd; saline controls on gd 12). On gd 20, embryolethality incidence was 100% after gd 10 dosing; at gd 11 through 15, it was 50, 32, 15, 2, and 5% respectively (control, 2%). Incidences of external defects in live fetuses exposed on gd 11-15 were 97, 98, 100, 44, and 0% and those of viscera were 100, 62, 44, 10, and 0%, respectively. The predominant anomalies observed were ectrodacyly and renal agenesis. DRR was determined on gd 13, when live embryos/litter and external malformations (ectro- and syndactyly, micromelia) were maximal. Dams (n = 8/dose group) were injected intravenously with 0, 100, 250, 350, or 500 mg ME/kg. On gd 20, fetal defect rates were 0, 0, 82.5, 83.0, and 100% at these concentrations, respectively. Based on these studies, appropriate ME doses, times of maternal exposure, and critical phases of development in the rat model are available for reproducing selective defects to investigate biochemical and pharmacokinetic determinants underlying their expression.

Animals↗
PubMed1995

Role of formate in methanol-induced exencephaly in CD-1 mice.

Mouse embryos develop exencephaly when dams are exposed by inhalation to high concentrations (> or = 10,000 ppm) of methanol on gestational day 8 (GD8; copulation plug = GD0). The present study examined the role of formate, an oxidative metabolite of methanol, in the development of methanol-induced exencephaly in CD-1 mice and cultured mouse embryos. The pharmacokinetics and developmental toxicity of sodium formate (750 mg/kg by gavage), a 6-hr methanol inhalation (10,000 or 15,000 ppm), or methanol gavage (1.5 g/kg) in pregnant CD-1 mice on GD8 were determined. Gross morphological evaluations for neural tube closure status in embryos or exencephaly in near-term fetuses were performed. Decidual swellings and maternal plasma were analyzed for methanol and formate. The mean (+/- S.E.M.) end-of-exposure plasma methanol concentration was 223 +/- 23 mM following the 6-hr, 15,000 ppm methanol inhalation. There were no changes in blood or decidual swelling formate concentrations under any of the methanol exposure conditions. Peak formate levels in plasma (1.05 +/- 0.2 mM; control 0.5 +/- 0.3 mM) and decidual swelling (2.0 +/- 0.2 mM; control 1.1 +/- 0.2 mM) from pregnant mice (GD8) given sodium formate (750 mg/kg, po) were similar to those observed following a 6-hr methanol inhalation of 15,000 ppm (plasma = 0.75 +/- 0.1 mM; decidual swelling = 2.2 +/- 0.3 mM) but did not result in exencephaly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Development of a physiologically based pharmacokinetic model describing 2-methoxyacetic acid disposition in the pregnant mouse.

Using the potent developmental toxicant 2-methoxyethanol (2-ME) as a prototypical compound, a physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of its primary metabolite and proximate toxicant 2-methoxyacetic acid (2-MAA) in the pregnant CD-1 mouse. Data were collected during early, mid, and late organogenesis, specifically Gestation Days (GD) 8, 11, and 13 (GD 0 = plug-positive date). Pharmacokinetics and tissue partition coefficients for 2-MAA were determined in maternal plasma and conceptus on GD 8 and in maternal plasma, embryo, and extraembryonic/amniotic fluid (EAF) on GD 11 and 13. For simulation of GD 8 data, the conceptus was described as a single compartment, combining the yolk sac placenta, embryo, EAF, and decidua. For GD 11 and 13, the placenta, embryo, and EAF were explicitly described. Several hypotheses were tested for their ability to predict 2-MAA dosimetry. These hypotheses were encoded as alternative models having (a) blood flow-limited delivery of 2-MAA to model compartments, (b) pH trapping of ionized 2-MAA within compartments, (c) active transport of 2-MAA into compartments, and (d) reversible binding of 2-MAA within compartments. While the flow-limited description adequately predicted GD 8 dosimetry, the best simulations of the pharmacokinetic data collected on GD 11 and 13 were obtained with the active transport models. Since the mechanism by which 2-MAA accumulates into the embryo and EAF has not yet been elucidated, these mathematical descriptions are empirical. Further development of this PBPK model for 2-MAA in pregnant mice, in particular its scale-up to humans, will facilitate more realistic human risk assessments for the developmental toxicity of 2-ME and related compounds.

Acetates↗