The unusual osteochondroma: A case of snapping scapula syndrome and review of the literature.

Snapping scapula syndrome is a rare condition characterized by crepitus of the scapula on motion of the ipsilateral upper extremity. It may be quite painful and disabling. The majority of cases are due to bursal and muscular disorders. Snapping scapula syndrome secondary to an underlying osteochondroma is an even more infrequent phenomenon. The case presented highlights the unusual post pubertal growth of an osteochondroma of the scapula that progressed to develop a snapping scapular syndrome. Review of the literature revealed less than fifty reported cases of this phenomenon secondary to an underlying osteochondroma.

Assessment of ixekizumab, an interleukin-17A monoclonal antibody, for potential effects on reproduction and development, including immune system function, in cynomolgus monkeys.

The reproductive and developmental toxicity of ixekizumab, a selective inhibitor of interleukin-17A (IL-17A), was assessed in the following studies in cynomolgus monkeys: fertility (3-month dosing), embryo-fetal development (EFD; dosing from gestation day (GD) 20 through 139), and pre-postnatal development (PPND; dosing from GD 20 through parturition). Because IL-17A has functional roles in innate and humoral immunity, immune system modulation was evaluated in the EFD and PPND studies; immunological evaluations in infants comprised peripheral blood immunophenotyping, Natural Killer cell cytolytic activity, and T-cell-dependent antibody (IgG and IgM) primary and secondary responses to antigen challenge. Ixekizumab exposure was sustained during the dosing periods in most adult monkeys. Fetal exposure at Cesarean section (GD 140-142; EFD study) was 18-25% of maternal exposure and ixekizumab was present in infants for up to 29 weeks postpartum. There were no adverse effects attributed to ixekizumab in any study. Importantly, immune system development and maturation were unaffected.

The effects of collagen synthesis inhibitory drugs on somitogenesis and myogenin expression in cultured chick and mouse embryos.

The role of fibrillar collagen on myogenic differentiation has previously been studied in tissue culture cell lines but has not been studied in situ. We treated cultured chick and mouse embryos with collagen synthesis inhibitors to determine the role of fibrillar collagen on somitogenesis and on myogenic differentiation in vivo. Stage 12 chick embryos and 8.7 dpc mouse embryos were cultured in control medium or a range of concentrations of the collagen synthesis inhibitors ethyl-3,4-dihydroxybenzoate (EDHB) or cis-hydroxy-proline (CHP). Chick embryos were cultured for 24 h and mouse embryos were cultured for 30 h. Both collagen synthesis inhibitors produced a range of somite abnormalities including formation of fewer and irregular somites in both chick and mouse at high drug concentrations, as well as formation of double somites in EDHB-treated chick embryos. Examination of EDHB-treated mouse embryos by scanning electron microscopy demonstrated a dosage-dependent loss of fibrillar collagen and associated extracellular matrix. Expression of myogenin in EDHB-treated mouse embryos, examined by whole-mount in situ hybridization, was suppressed at higher dosage levels. This study suggests that inhibition of fibrillar collagen production and/or loss of fibrillar collagen in the developing avian and mammalian embryo results in abnormal somite formation and perturbed myogenic differentiation.

The selective estrogen receptor modulator, raloxifene: reproductive assessments following preimplantation exposure in mated female rats.

Raloxifene is a nonsteroidal, selective estrogen receptor modulator being developed for postmenopausal osteoporosis. As part of an integrated reproductive toxicity assessment, two studies were conducted in which raloxifene was administered orally to CD rats during Gestation Days (GD) 0 through 5. In each study, animals received daily raloxifene doses of 0, 0.1, 1, or 10 mg/kg. In Study 1, GD 20 evaluations of maternal reproductive parameters identified dose-related increases in pre- and postimplantation loss, reductions in the numbers of corpora lutea and live conceptuses, and reduced fetal weight. The low fetal weights were consistent with an extent of morphologic development that corresponded to developmental ages up to 8 d younger than GD 20. Study 2 characterized the potential impact of this disrupted and apparently delayed implantation on gestation length, parturition, and progeny viability. Dams were allowed to deliver and rear their offspring through Postpartum Day 21. Gestation lengths were extended up to 1 week, and litter sizes were reduced in a dose-dependent manner. Nevertheless, parturition occurred normally and pup morphology, survival, and physical and behavioral development were unaffected.

Pharmacokinetics of 2-methoxyethanol and 2-methoxyacetic acid in the pregnant mouse: a physiologically based mathematical model.

A physiologically based pharmacokinetic (PBPK) model was created to describe the disposition of 2-methoxyethanol (2-ME) and its teratogenic metabolite, 2-methoxyacetic acid (2-MAA), in the pregnant CD-1 mouse. The model's foundation is a mathematical description of the physiological changes that occur during gestation (O'Flaherty et al., Toxicol. Appl. Pharmacol. 112, 245-256, 1992). The PBPK model was developed and validated with data collected on Gestation Day (GD) 11. Absorption, distribution, and oxidation of 2-ME to 2-MAA and ethylene glycol (EG) were simulated. Flow-limited disposition of 2-ME in maternal tissues was described using in vitro-determined tissue partition coefficients (PCs). The maximum velocity (Vmax) of 2-ME oxidation to 2-MAA was calculated from literature-based in vitro data. Vmax for EG formation, and Michaelis constants for 2-MAA and EG pathways, were estimated from optimized simulations of plasma 2-ME and metabolite levels obtained after intravenous injection of 5-600 mg 2-ME.kg-1.2-MAA disposition and elimination in the dam were described by a nonphysiological one-compartment model, which was linked to the 2-ME model, based on the volume of distribution (0.510 liters.kg-1) and overall elimination rate constant (0.124 hr-1) calculated from iv 2-MAA plasma concentration-time courses. Transfer of 2-MAA between the placenta and conceptus was described as a diffusion-limited process to more accurately simulate the higher concentrations of 2-MAA determined in embryonic compartments compared with maternal plasma levels. Subsequent 2-MAA disposition within the embryo proper and surrounding fluid of the GD 11 conceptus was adequately described using embryo/blood (0.94) and extraembryonic fluid/blood (1.33) PCs. Extension of the PBPK model to oral and subcutaneous 2-ME administrations required optimization of first-order absorption rates; model simulations agreed closely with measured 2-ME/2-MAA levels. With refinements and further validation, the PBPK model of 2-ME/2-MAA disposition should prove helpful for extrapolation throughout gestation and between species.

Characterization of urinary metabolites from [1,2,methoxy-13C]-2-methoxyethanol in mice using 13C nuclear magnetic resonance spectroscopy.

2-Methoxyethanol (2-ME) is an industrial solvent that induces developmental and testicular toxicity in laboratory animals. Oxidation of 2-ME to 2-methoxyacetic acid (2-MAA) is required for the generation of these adverse effects. The urinary metabolites of 2-ME were investigated to characterize the fate of 2-ME and 2-MAA. 13C NMR spectroscopy was used to detect and assign metabolites in the urine of pregnant CD-1 mice following administration of 250 mg/kg of [1,2,methoxy-13C]-2-ME. Two-dimensional NMR methods were used to correlate signals from the labeled carbons in each 2-ME metabolite and to determine the number of hydrogens attached to each carbon. Structures were assigned from the NMR data together with calculated values of shift for biochemically feasible metabolites and by comparison to standards. Pathways involved in forming metabolites assigned in this study include transformation of 2-ME via ethylene glycol, conjugation with glucuronide or sulfate, and oxidation to 2-MAA. Additional metabolites were assigned that can be formed from further conversion of 2-MAA to glycine and glucuronide conjugates, as well as metabolites derived from the incorporation of 2-methoxyacetyl CoA derivatives into intermediary metabolism. Elucidation of the further metabolism of 2-MAA may be important for understanding the mechanisms by which 2-ME induces adverse effects.

2-Methoxyacetic acid dosimetry-teratogenicity relationships in CD-1 mice exposed to 2-methoxyethanol.

The teratogen 2-methoxyethanol (2-ME), an industrial solvent, was administered to pregnant CD-1 mice either as a single subcutaneous (sc) bolus dose (100-250 mg/kg) or via constant-rate infusion from sc implanted osmotic minipumps (34.7 or 69.4 mg/kg/hr for up to 12 hr) on gestation Day 11, when embryonic paw development is maximally sensitive to perturbation by this agent. The sc entry route most closely reflects likely human exposures via dermal penetration, while bolus and constant-rate infusion administrations were contrasted to mimic potential occupational exposure scenarios. The pharmacokinetic profiles of 2-methoxyacetic acid (2-MAA), the proximate toxic metabolite of 2-ME, were quantitated, generating peak concentration (Cmax) and total 2-MAA exposure values (24-hr area under the concentration-time curve; AUC) in the maternal plasma, extraembryonic fluid, and embryo. The total 2-ME dose (mg/kg) required to achieve similar 2-MAA levels (Cmax or AUC) in these compartments was 2- to 3-fold higher by constant-rate infusion than by bolus injection; therefore, no simple association existed between 2-MAA levels and the total 2-ME dose, when the dose rate was not considered. Similarly, there was no good correlation between the combined total 2-ME doses and the fetal malformation rate, although clear dose-response patterns for paw malformations were observed in litters and fetuses for each individual dosing regimen. However, the combined 2-MAA pharmacokinetic data from each of the dosing regimens demonstrated that during the phase of maximum susceptibility of paw morphogenesis to disruption by 2-MAA (from gd 11 to gd 11.5), a strong linear correlation existed between fetal malformation incidence and 2-MAA AUC levels in either maternal plasma or embryonic compartments (linear correlation coefficient, r2 0.91-0.92). The correlation with Cmax was less favorable (r2 0.74-0.81) over the dose range studied. In a further experiment designed to investigate the importance of AUC vs Cmax regarding 2-ME teratogenicity, infusion of 2-ME (34.7 mg/kg/hr for 8 hr) beginning 2.5 hr after bolus loading (175 mg/kg) provided an increased 24-hr 2-MAA AUC without increased Cmax. This resulted in greater than 70% of the fetuses having various digit malformations (micro-, syn-, ectro-, and polydactyly), compared to only 32-35% of fetuses with mostly stunted digits when either dose was applied singularly. These data support total 2-MAA exposure (AUC levels), rather than peak 2-MAA concentrations, as the principle determinant of teratogenesis following exposure to 2-ME.(ABSTRACT TRUNCATED AT 400 WORDS)

A critical review of the toxicology of glutaraldehyde.

Glutaraldehyde, a low molecular weight aldehyde, has been investigated for toxicity in humans and animals. Examination of this dialdehyde was indicated from previous studies with other aldehydes in which carcinogenicity of formaldehyde and toxicity of acetaldehyde and malonaldehyde have been disclosed. Information gaps concerning the actions of glutaraldehyde have been identified in this review and recommendations are suggested for additional short- and long-term studies. In particular, information regarding irritation of the respiratory tract, potential neurotoxicity, and developmental effects would assist in a complete hazard evaluation of glutaraldehyde. Further study related to disposition, metabolism, and reactions of glutaraldehyde may elucidate the mechanism of action.

2-Methoxyethanol metabolism in pregnant CD-1 mice and embryos.

Upon oxidation to 2-methoxyacetic acid (2-MAA), 2-methoxyethanol (2-ME) causes malformations in all animal species that have been examined. Commonly, 2-MAA is thought to be the proximate toxicant. However, our previous studies with [1,2-14C]2-ME and the present data obtained with [1-14C]2-MAA, [2-14C]2-ME and [methoxy-14C]2-ME revealed that metabolism beyond 2-MAA occurs. Regardless of the 14C position, dams exhaled approximately 5% of the radioactivity administered as a single teratogenic oral dose (3.3 mmol/kg on Gestation Day [gd] 11) as 14CO2. With all isotopic variants urine contained 70-80% of the dose within 24 hr after administration and 13-18% in the next 24 hr. Three labeled products were resolved using HPLC: an unidentified Peak A (12-18% of dose), 2-MAA (approximately 50%), and the glycine conjugate of 2-MAA (approximately 25%). Short-term (4 hr) whole embryo culture on gd 11 with 3 mM 2-MAA and a tracer dose of [1-14C]2-MAA, [2-14C]2-MAA, or [methoxy-14C]2-MAA showed that 14CO2 evolved from the former two substrates, while there was none detectable from the latter. The data indicate that dams metabolized [methoxy-14]2-MAA to 14CO2, while embryos apparently did not. The production of labeled CO2 from [2-14C]2-ME suggests that 2-methoxyacetyl approximately CoA (the precursor for amino acid conjugation with glycine) entered into the tricarboxylic acid (TCA) cycle. This interpretation is supported by the inhibition of 14CO2 evolution elicited by fluoroacetate (0.1 or 1.0 mM) and sodium acetate (5 mM). It is not yet clear whether entry of 2-methoxyacetyl approximately CoA as a "false substrate" in the TCA cycle is of significance for the embryotoxic effects of 2-ME/2MAA.

Protection against 2-methoxyethanol-induced teratogenesis by serine enantiomers: studies of potential alteration of 2-methoxyethanol pharmacokinetics.

Several simple physiological compounds attenuate the teratogenic effects of 2-methoxyethanol (2-ME) when coadministered with 2-ME to mice. The mechanism of this protective action, however, has not been elucidated. Alteration of the kinetics of 2-ME and its oxidation product 2-methoxyacetic acid (2-MAA), the putative ultimate toxicant, was considered. D-Serine, the most efficacious attenuator, and L-serine (both 16.5 mmol/kg po) were examined for their abilities to mitigate 2-ME teratogenicity and to alter the disposition of an oral or sc bolus dose of 2-ME (3.3 mmol/kg containing 6 microCi 2-[methoxy-14C]ethanol) given to CD-1 mice on Gestation Day 11. L-Serine reduced the incidence of malformed fetuses from greater than or equal to 72% to 26-28%, while only 18 and 9% of fetuses were affected after coadministration of D-serine with sc and po 2-ME, respectively. Changes in the metabolism of orally administered 2-[14C]ME were specific to each enantiomer. D-Serine reduced the amount of 2-methoxy-N-acetylglycine eliminated in the urine to 70-75% of values observed with 2-ME alone, and concurrently increased the amount of urinary 2-MAA. L-Serine induced an initially higher rate of 14CO2 exhalation. Both enantiomers delayed gastrointestinal absorption of 2-ME, and significantly reduced 2-MAA levels in maternal plasma during the first hour after dosing. This resulted in a nonsignificant decrease (10-17%) in total embryonic exposure to 2-MAA. However, when 2-ME was injected sc, maternal plasma 2-ME/2-MAA pharmacokinetics were not affected by serine. In addition, dosing with 2.3 and 1.3 mmol 2-ME/kg sc alone showed that the embryo 2-MAA exposure levels which cause malformations in less than or equal to 35% fetuses were considerably lower than those measured following serine plus 3.3 mmol 2-ME/kg (po or sc). These data infer that serine does not protect against 2-ME-induced teratogenicity by altering 2-ME pharmacokinetics and reducing 2-MAA levels in the embryo.

Adaptation of postimplantation embryos to culture: membrane lipid synthesis and response to valproate.

The environment of the conceptus in culture is quite different from that in utero. It is likely that the embryo adapts to this environment in various ways, but little is known of adaptation, nor of its significance to mechanistic studies using embryo culture. To illustrate this area, we summarize data from two comparative studies: of membrane lipid synthesis by conceptuses in culture and in utero, and of the morphologic response of conceptuses to valproate in these two environments. The synthesis of the major membrane lipids, cholesterol and phospholipids, is significantly affected by culture. De novo synthesis of cholesterol progressively increases during culture, compared to equivalent stages in utero. In contrast, phospholipid synthesis decreases in culture. Cultured conceptuses were morphologically similar to those in utero, suggesting that apparent structural normality does not guarantee biochemical activity equivalent to that in vivo. Conceptuses exposed to valproate in vivo showed a wide range of severity of defects. Those abnormalities that apparently permit survival to term seem relatively subtle, while more severe defects (as usually reported in culture studies) appear to be lethal. Subtle defects, very similar to those induced in vivo, can be reproduced in culture, but only with short-term, not continuous, exposure. We have previously proposed that valproate may interfere with embryonic lipid synthesis. Thus, despite lipid synthetic pathways adapting to the culture environment, the response to valproate in vitro, can mimic that in utero, with appropriate exposure conditions.