Janus Kinase Inhibitors and Risk of Venous Thromboembolism: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess the risk of venous thromboembolism (VTE) in patients treated with Janus kinase (JAK) inhibitors in clinical trials. PATIENTS AND METHODS: We performed a literature search of Ovid MEDLINE and ePub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily; Ovid EMBASE; Ovid Cochrane Central Register of Controlled Trials; Ovid Cochrane Database of Systematic Reviews; and Scopus, from inception to December 4, 2019, for randomized, placebo-controlled trials with JAK inhibitors as an intervention and reported adverse events. Odds ratio with 95% CI was calculated to estimate the VTE risk using a random effects model. Two independent reviewers screened and extracted data. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to assess certainty in estimated VTE risk. RESULTS: We included 29 trials (13,910 patients). No statistically significant association was found between use of JAK inhibitors and risk of VTE (odds ratio, 0.91; 95% CI, 0.57 to 1.47; P=.70; I2=0; low certainty because of serious imprecision). Results using Bayesian analysis were consistent with those of the primary analysis. Results of stratified and meta-regression analyses suggested no interaction by dose of drug, indication for treatment, or length of follow-up. CONCLUSION: We found insufficient evidence to support an increased risk of JAK inhibitor-associated VTE based on currently available data.

Strategies for assessing the implications of malformed frogs for environmental health.

The recent increase in the incidence of deformities among natural frog populations has raised concern about the state of the environment and the possible impact of unidentified causative agents on the health of wildlife and human populations. An open workshop on Strategies for Assessing the Implications of Malformed Frogs for Environmental Health was convened on 4-5 December 1997 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. The purpose of the workshop was to share information among a multidisciplinary group with scientific interest and responsibility for human and environmental health at the federal and state level. Discussions highlighted possible causes and recent findings directly related to frog deformities and provided insight into problems and strategies applicable to continuing investigation in several areas. Possible causes of the deformities were evaluated in terms of diagnostics performed on field amphibians, biologic mechanisms that can lead to the types of malformations observed, and parallel laboratory and field studies. Hydrogeochemistry must be more integrated into environmental toxicology because of the pivotal role of the aquatic environment and the importance of fates and transport relative to any potential exposure. There is no indication of whether there may be a human health factor associated with the deformities. However, the possibility that causal agents may be waterborne indicates a need to identify the relevant factors and establish the relationship between environmental and human health in terms of hazard assessment.

The return of thalidomide: can birth defects be prevented?

Thalidomide, the drug that caused a worldwide epidemic of serious birth defects in the late 1950s and early 1960s, was recently approved by the US Food and Drug Administration (FDA) for use in treating the skin disease erythema nodosum leprosum, a complication of leprosy. The drug has also shown promise in the treatment of other serious diseases. If thalidomide is eventually approved for use in the US and other countries for treatment of diseases more prevalent than erythema nodosum leprosum, or if use of the drug for non-approved indications becomes widespread, hundreds of thousands of women with childbearing ability could be treated. If this should happen, can we prevent another epidemic of birth defects? In an effort to prevent fetal exposures to thalidomide, the FDA mandated a comprehensive programme to regulate prescription, dispensing and use of the drug. The programme is designed to require registration of all participating prescribers, pharmacies and patients. It also requires use of effective methods of contraception and periodic pregnancy testing of all patients with childbearing ability during treatment. Prescribers are directed to counsel both female and male patients on the risks, benefits and proper use of the drug, as well as on the proper use of contraceptives during treatment. The patient is required to sign an informed consent form before beginning treatment. Prescription and dispensing of thalidomide will be tightly controlled. Athalidomide registry will monitor prescription. dispensing and use of the drug, and will investigate all reported fetal exposures. This mandatory, but untested, programme promises to be effective at preventing fetal exposures to thalidomide, provided that patients, prescribers and pharmacists comply with all of its provisions. However, even if the programme proves to be successful in the US, there is concern that thalidomide may eventually be widely used in countries that may not require such stringent controls. In Brazil, where thalidomide is commercially available for treatment of leprosy patients, 33 cases of thalidomide embryopathy have already been reported in the literature. Even in countries that may tightly regulate the distribution and use of thalidomide, some patients may obtain the drug through black market sources. Should these events occur, many cases of thalidomide-induced birth defects could appear. Therefore, there is a need to develop nonteratogenic analogues of thalidomide that can provide effective treatment for erythema nodosum leprosum and other serious conditions without increasing the potential for another epidemic of thalidomide-related birth defects.

Absence of embryotoxic effects from low-level (nonthermal) exposure of rats to 100 MHz radiofrequency radiation.

Pregnant Sprague-Dawley rats were exposed to radio-frequency radiation at a frequency of 100 MHz and a power density of 25 mW/cm2 for 6 h 40 min daily on gestation days 6--11. The total exposure time was 40 h. The exposure resulted in a specific absorption rate of 0.4 W/kg. This value corresponds to the maximum permissible level for specific absorption rate in the 1982 American National Standards Institute (ANSI) standard for radiofrequency/microwave exposure. The exposure produced no increase in maternal colonic temperature. Irradiated rats did not differ from sham-irradiated rats with respect to the number of implantations per litter, percentage of implantations dead or resorbed, percentage of fetuses malformed. fetal weight, fetal crown-rump length, or fetal sex ratio. The irradiated fetuses had fewer minor skeletal variations than the controls. These results suggest that radiofrequency/microwave radiation is not teratogenic or embryotoxic for rats at the maximum permissible exposure level of the 1982 ANSI standard.

Kinetic investigations of the quaternary enhancement effect and alpha/beta differences in binding the last oxygen to hemoglobin tetramers and dimers.

Analysis of O2 binding equilibria by two independent groups has suggested that the affinity for binding the fourth O2 to Hb tetramers is very high, about 800-1200 cal/mol higher than that of dimers (Chu, A. H., Turner, B. W., and Ackers, G. K. (1984) Biochemistry 23, 604-167; Di Cera, E., Robert, C. H., and Gill, S. J. (1987) Biochemistry 26, 4003-4008). Recently, Gibson and Edelstein challenged the reality of the quaternary enhancement effect, based on kinetic data (Gibson, Q. H., and Edelstein, S. J. (1987) J. Biol. Chem. 262, 516-519). However, these studies failed to directly address the key issue of the relative affinities of dimers and alpha 2 beta 2(O2)3. Furthermore, the extent to which alpha/beta differences influence these results remains an open question. Using partial laser photolysis and O2/CO replacement techniques we have, for the first time, resolved the rates of O2 association and dissociation to both alpha and beta chains within "R state" tetramers and dimers. We find that the beta chains are faster than alpha for both O2 binding (approximately 2-fold) and release (approximately 3-fold). The kinetically determined O2 affinities derived from these data are essentially identical for dimers and alpha 2 beta 2(O2)3. That is, the data do not show significant quaternary enhancement and suggest that the equilibrium data have both overestimated the affinity of alpha 2 beta 2(O2)3 and underestimated the affinity of dimers. The significance of and possible origins for the discrepancy between equilibrium and kinetic data are discussed.

Prevalence of spina bifida at birth--United States, 1983-1990: a comparison of two surveillance systems.

PROBLEM/CONDITION: Spina bifida is a birth defect of the spinal column that is a substantial contributor to serious developmental disabilities in the United States. The risk for spina bifida and other neural tube defects (NTDs) can be reduced if women consume 0.4 mg of folic acid before and during the first trimester of pregnancy. Public health programs are being developed to prevent many NTDs by increasing the consumption of folic acid by women of childbearing age. To assess the national impact of these programs on the prevalence of NTDs at birth, multistate surveillance is needed to monitor secular trends in birth-prevalence rates. This report summarizes a collaborative effort by CDC and state birth defect surveillance programs in 16 states to a) obtain multistate, population-based data concerning the birth prevalence and descriptive epidemiology of spina bifida and b) determine the usefulness of combining state surveillance data to monitor national trends in the birth prevalence of NTDs. REPORTING PERIOD: This report presents data from birth defects surveillance systems in 16 states for the period 1983-1990 (specific periods covered varied by state). These findings are compared with CDC's Birth Defects Monitoring Program (BDMP) for the same period. DESCRIPTION OF SYSTEMS: Population-based data about live-born and stillborn infants who have spina bifida were analyzed from 16 state programs. These 16 programs differed in size and racial/ethnic composition of the populations, surveillance methods, and completeness of case ascertainment. Hospital-based data about live-born and stillborn infants who have spina bifida also were analyzed from BDMP, a passive case ascertainment surveillance system that obtains data from participating hospitals in 50 states. RESULTS AND INTERPRETATION: From 1983 through 1990, the birth-prevalence rate for spina bifida for the 16 states was 4.6 cases per 10,000 births; the BDMP rate was nearly identical (4.4 cases). State-specific rates varied substantially, ranging from 3.0 (Washington) to 7.8 (Arkansas). Both state-based and BDMP rates varied among racial/ethnic groups; in both systems, the rates were highest for Hispanics and lowest for Asians/Pacific Islanders. In both the state-based surveillance systems and BDMP, the annual rate of spina bifida for the total population declined during the period 1983-1990. Much of this decline can be attributed to increased prenatal diagnosis in the 1980s. However, because of decline in the rates of spina bifida and other NTDs in the United States began before the widespread availability of prenatal diagnostic services, an environmental component may have contributed substantially to the etiologies of these defects. The birth-prevalence rate of spina bifida was slightly higher among females than males. The ratio of female-to-male prevalence rates was 1.2 for both the state-based surveillance systems and BDMP. This ratio varied considerably among racial/ethnic groups and among states. The similarities of rates and trends in the birth prevalence of spina bifida between the state-based surveillance data and the BDMP data indicate that both types of surveillance systems can provide reliable information concerning national trends in the birth prevalence of spina bifida. ACTIONS TAKEN: CDC and state birth defects surveillance programs will use results from this analysis to monitor national trends in the birth prevalence of spina bifida in the United States. Aggregated state-based surveillance data about spina bifida, anencephaly, and other NTDs will facilitate the monitoring of changes in NTDs after implementation of programs to increase folic acid consumption by women of childbearing age.

Laterality patterns in infants with external birth defects.

The lateral distribution of external birth defects has not been reported in a comprehensive way, and patterns in this distribution have not been examined. This study presents the lateral distribution of 6,390 unilateral defects from among 102 defect categories in data collected by the Metropolitan Atlanta Congenital Defects Program. Among all defects, 49% (95% CI 48-51%) were right-sided. Among males and females, 51% (95% CI 50-53%) and 47% (95% CI 46-49%) of the defects, respectively, were right-sided. Of the 102 defect types, 57 had an excess of defects on the right side of the body; 39 had an excess of defects on the left side; and 6 were equally distributed. The excess on the right side was statistically significant for inguinal hernia, incarcerated inguinal hernia, microtia, preauricular sinus, talipes calcaneovalgus, and lambdoidal craniosynostosis. For the left side, the excess was statistically significant for preauricular tags, cleft lip, fused lip and cleft gum, cleft lip with cleft palate, congenital hip dysplasia, unstable hip, absent forearm or hand, anomaly of the knee, and skin tags. The percentage of right-sided defects among case subjects with unilateral defects was correlated with the percentage of males among all case subjects (r = 0.24, P < 0.05). Among male case subjects with unilateral defects, the correlation coefficient was 0.31 (P < 0. 01), and among females with unilateral defects, it was 0.11 (P > 0. 10). Differences in the lateral distribution of specific birth defects may be due to subtle differences in morphogenesis on the left and right sides of the embryo brought about by establishment of left-right asymmetry prior to organogenesis. The fact that more defect categories were right-sided than left-sided may be related to the observation that mitochondrial maturation in rat embryos is delayed on the right side. The right side, therefore, may be more susceptible than the left to defects caused by prenatal hypoxia. The significant correlation between the percentage right-sided and percentage male may then also be related to the observation that male sex hormones lower the mitochondrial respiration rate in rats and increase rat sensitivity to chemical hypoxia. Investigators should consider reporting the laterality of specific defects in both laboratory and epidemiological studies of birth defects. Right- and left-sided defects should perhaps be considered separately in etiologic studies of birth defects. Teratology 60:265-271, 1999. Published 1999 Wiley-Liss, Inc.

Sex differences in the prevalence of human birth defects: a population-based study.

BACKGROUND: Sex differences in the prevalence of several human birth defects have often been reported in the literature, but the extent of sex differences for most birth defects is unknown. To determine the full extent of sex differences in birth defects in a population, we examined population-based data from the Metropolitan Atlanta Congenital Defects Program (MACDP). METHODS: MACDP records were analyzed for 1968 through 1995. We determined the sex-specific prevalence of all major birth defects, using the total number of live births by sex during these years as the denominator. For each specific defect, we calculated a relative risk with regard to sex on the basis of the ratio of prevalence among males to prevalence among females. Male-female relative risks were also determined for total major birth defects and for several broad categories of defects. RESULTS: The overall prevalence of major defects at birth was 3.9% among males and 2.8% among females. All but two of the major categories of birth defects (nervous system defects and endocrine system defects) had a higher prevalence among males. Defects of the sex organs were eight and one-half times more prevalent among males and accounted for about half of the increased risk of birth defects among males relative to females. Urinary tract defects were 62% more prevalent among males, and gastrointestinal tract defects were 55% more prevalent among males. Among specific defect types, twofold or greater differences in prevalence by sex were common. CONCLUSIONS: Our data indicate that sex differences in the prevalence of specific human birth defects are common, and male infants are at greater risk for birth defects than female infants. Several mechanisms have been proposed to account for these differences.

Quaternary interactions in hemoglobin beta subunit tetramers. Kinetics of ligand binding and self-assembly.

We have investigated the rates of monomer in equilibrium with tetramer self-association of oxygenated beta SH subunits of human hemoglobin A as well as the influence of self-association on the binding kinetics for O2 and CO. A 4 beta in equilibrium with 2 beta 2 in equilibrium with beta 4 assembly pathway can be used to describe the association equilibria and kinetics. We have determined all four elementary rate constants for this assembly pathway at 15 degrees C in 0.1 M Tris-HCl, 0.1 M NaCl, 1 mM Na2EDTA, pH 7.4. These data imply that a significant amount (approximately 17%) of beta 2 can be present. Laser photolysis kinetic studies of O2 binding indicate that the O2 association rate constant is unaffected by the degree of self-association. In contrast, photolysis of beta CO solutions shows an overall rate of CO binding that increases at higher protein concentrations. These data are consistent with a concentration-dependent equilibrium between two protein species with CO association rates differing by a factor of 2.5, but they do not appear to be compatible with a direct assignment of different CO binding rates to the different assembly states. Rather, we believe the data imply that CO binding to beta oligomers is heterogeneous, with both a fast binding and a slow binding form being present in single association states. The fast binding form predominates (approximately equal to 87%) in beta 4, while the beta monomer has very little or none of the fast binding form. We propose that the slow binding component within beta 4 may be those subunits with rotationally disordered hemes (La Mar, G. N., Yamamoto, Y., Jue, T., Smith, K. M., and Pandey, R. K. (1985) Biochemistry 24, 3826-3831). The implications of these findings for the use of isolated subunits as models for the subunits within "R state" hemoglobin tetramers are discussed.

Interactions between cycloheximide and T-locus alleles during mouse embryogenesis.

Female CD-1 mice were mated with CD-1 X T/ + F1 males that were heterozygous for the brachyury (T') semidominant lethal gene or were +/+. Fetuses from CD-1 X +/+ matings were normal when observed on gestation Day 17 (plug day = Day 0). Those from the CD-1 X T/+ cross exhibited the expected 1:1 ratio of short:normal tail lengths, but 10% of these fetuses were tailless, apparently due to factors in the CD-1 genotype that increased the expressivity of the T-gene with regard to reduction of tail length. Additional CD-1 females were mated with CD-1 X tw18/+ F1 males. Fetuses from the CD-1 X tw18/+ matings were normal. CD-1 females carrying CD-1 X +/+, CD-1 X T/+, or CD-1 X tw18/+ litters were injected ip on gestation Day 9 with 30 mg/kg cycloheximide or were untreated. Cycloheximide was teratogenic for litters from all three crosses. Polydactyly, oligodactyly, and a variety of skeletal abnormalities were observed. Gross malformations and total skeletal malformations were increased in treated CD-1 X T/ + or tw18/+ litters in comparison with CD-1 X +/+ litters, as were nonvertebral skeletal defects in CD-1 X tw18/+ litters. Prenatal mortality was also greater in treated mutant-containing litters than in +/+ litters, and fetal weights were similarly decreased in treated CD-1 X tw18/+ litters. The incidence of taillessness was also higher in treated (26%) than in control (10%) CD-1 X T/+ litters. Thus both the T and tw18 alleles appear to have enhanced the teratogenicity of cycloheximide, and the inhibitor may have increased the expressivity of T.

Quaternary structure dynamics and carbon monoxide binding kinetics of hemoglobin valency hybrids.

The kinetics of CO binding and changes in quaternary structure for symmetric valency hybrids of human hemoglobin have been extensively studied by laser photolysis techniques. Both alpha+beta and alpha beta+ hybrids were studied with five different ferric ligands, over a broad range of CO concentrations and photolysis levels. After full CO photolysis, the hybrid tetramers switch extensively and rapidly (< 200 microseconds) to the T quaternary structure. Both R --> T and T --> R transition rates for valency hybrid tetramers with 0 and 1 bound CO have been obtained, as well as the CO association rates for alpha and beta subunits in the R and T states. The results reveal submillisecond R reversible T interconversion, and, for the first time, the changes in quaternary rates and equilibria due to binding a single CO per tetramer have been resolved. The data also show significant alpha-beta differences in quaternary dynamics and equilibria. The allosteric constants do not vary with the spin states of the ferric subunits as predicted by the Perutz stereochemical model. For the alpha beta+CN hybrid the kinetics are heterogeneous and imply partial conversion to a T-like state with very low (seconds) R reversible T interconversion.

Teratogenic effects of 27.12 MHz radiofrequency radiation in rats.

High-intensity 27.12 MHz radiofrequency (RF) radiation was determined to be teratogenic in rats during most of the gestation period. Eight groups of pregnant rats were exposed to a magnetic field strength of 55 amps/meter and an electric field strength of 300 volts/meter on gestation days 1, 3, 5, 7, 9, 11, 13, or 15. Exposures ceased once the dam's colonic temperature reached 43.0 degrees C (about 20-40 minutes' duration). Eight matching control groups were sham-irradiated for 30 minutes at 0 amps/meter and 0 volts/meter. An additional group of pregnant rats received no treatment. With one exception, no significant differences occurred between sham-irradiated and untreated control groups. RF exposure, however, caused a significant incidence of fetal malformations throughout the postimplantation period (days 7 through 15). It also caused a low but significant incidence of preimplantation malformations. Fetal weight and crown-rump length were reduced in all postimplantation exposure groups but were not affected by preimplantation exposure. The incidence of dead or resorbed fetuses was significantly increased in rats irradiated on days 7 or 9. The effects observed appeared to be caused by RF-induced hyperthermia in the treated dams. Since a number of industrial, scientific, and medical devices operating at or near 27.12 MHz can cause hyperthermia in humans, women of childbearing age should avoid exposure to RF-radiation levels that exceed current US occupational standards.

Magnetic field measurements near RF induction heaters.

We discuss initial magnetic field strength measurements made around radiofrequency (RF) induction heaters. These measurements were made with a monitor developed for the National Institute for Occupational Safety and Health (NIOSH) by the National Bureau of Standards (NBS). The monitor has a dynamic range of .01 to 10,000 A2/m2, a frequency range of 300 kHz to 100 MHz, an isotropic response (+/- .3 dB) with three mutally orthogonal loop antennas that have the ability to measure and display each of three orthogonal magnetic field components, a high probe burnout protection level of 20,000 A2/m2, and an accuracy of +/- 1.0 dB at 13 calibration frequencies. The portable survey monitor was used to measure the magnetic field strengths in the vicinity of 16 RF induction heaters. Typically these induction heaters are operated continuously for several hours. The maximum field strengths (without duty factor correction) ranged from 15 to 4,500 A2/m2 and were measured 5 to 51 cm from the loop applicators of the induction heaters. At locations commonly occupied by workers (ie, approximately 30 to 76 cm from heaters), the fields ranged from .01 to 300 A2/m2 (without duty factor correction).

Dose-response relationship between body temperature and birth defects in radiofrequency-irradiated rats.

Five groups of pregnant Sprague-Dawley rats were irradiated for 10-40 min on gestation day 9 in a 27.12-MHz radiofrequency field at a magnetic field strength of 55 A/m and an electric field strength of 300 V/m. The specific absorption rate was 10.8 +/- 0.3 W/kg. Exposures were terminated after the rat's colonic temperature reached 41.0 degrees C, 41.5 degrees C, 42.0 degrees C, 42.5 degrees C, or 43.0 degrees C. A control group was sham irradiated at 0 A/m and 0 V/m on gestation day 9, whereas a second control group was untreated. The incidence of both birth defects and prenatal death was directly related to maternal body temperature once a temperature threshold was exceeded. The temperature threshold for both types of effects was approximately 41.5 degrees C. A few pregnant rats died after exposure to 43.0 degrees C, and higher temperatures were nearly always lethal.

Increased risk for developmental disabilities in children who have major birth defects: a population-based study.

OBJECTIVE: We sought to quantify the strength of associations between each of four specific developmental disabilities (DDs) and specific types of major birth defects. METHODS: We linked data from 2 independent surveillance systems, the Metropolitan Atlanta Congenital Defects Program and the Metropolitan Atlanta Developmental Disabilities Surveillance Program. Children with major birth defects (n = 9142; born 1981-1991 in metro Atlanta) and 3- to 10-year-old children who were born between 1981 and 1991 in metro Atlanta and identified between 1991 and 1994 as having mental retardation, cerebral palsy, hearing impairment, or vision impairment (n = 3685) were studied. Prevalence ratio (PR), which is the prevalence of a DD in children with 1 or more major birth defects divided by the prevalence of the same DD in children without major birth defects, was measured. RESULTS: Among the 9142 children who were born with a major birth defect, 657 (7.2%) had a serious DD compared with 0.9% in children with no major birth defect, yielding a PR of 8.3 (95% confidence interval: 7.6-9.0). In general, the more severe the DD, the higher was the PR. Birth defects that originated in the nervous system and chromosomal defects resulted in the highest PRs for a subsequent DD. For all other categories of birth defects, PRs were lowest when all major birth defects present were confined to a single category (ie, isolated defects). PRs for any DD increased monotonically with the number of coded birth defects per child or the number of different birth defect categories per child, regardless of the severity of the defect or whether defects of the nervous system, chromosomal defects, or "other syndromes" were counted. CONCLUSIONS: These data highlight the possible early prenatal origins of some DDs and suggest that both the number of coded birth defects present and the number of anatomic systems involved are strongly related to functional outcomes.

Teratogenicity of 27.12-MHz radiation in rats is related to duration of hyperthermic exposure.

Five groups of pregnant Sprague-Dawley rats were either sham exposed or were irradiated in a 27.12-MHz radiofrequency (RF) field at 55 A/m and 300 V/m on gestation day 9. The absorbed power (approximately 11 W/kg) caused a relatively rapid increase in the rat's colonic temperature. Rats in group I were sham irradiated for 2.5 h at 0 A/m, 0 V/m. In group II RF irradiation was terminated after the rat's colonic temperature reached 41.0 degrees C. In group III the 41.0- degrees C temperature was maintained an additional 2 h by manually varying the incident field strength. In group IV irradiation was terminated after the rat's colonic temperature reached 42.0 degrees C. In group V the 42.0- degrees C temperature was maintained an additional 15 min by varying the field strength. At both temperatures the teratogenic and embryotoxic effects of the RF-induced hyperthermia increased as the exposure duration increased, but the increase was especially noticeable at 42.0 degrees C. The results indicate that the teratogenic and embryotoxic effects of RF-induced hyperthermia are related to both the temperature of the dam during exposure and the length of time the dam's temperature remains elevated.

Conformation of glutathione adduct and oxidized forms of platelet-derived growth factor.

The conformational properties of several platelet-derived growth factors (PDGFs) were characterized by circular dichroism (CD), Fourier transform infrared spectroscopy (FTIR), gel filtration and sedimentation equilibrium. Three different forms of disulfide linked dimer, PDGF-AA, PDGF-AB, and PDGF-BB, showed similar far UV CD spectra with evidence for slight beta-structure, but little evidence of other regular secondary structures. These spectra were, however, different from the far UV CD spectra of the glutathione adducts of PDGF-A and B, suggesting that the latter two proteins adopt different conformations in the absence of intra- or inter-molecular disulfide bonds. FTIR studies confirmed this by showing that the glutathione adducts of the PDGF-B protein have a significantly lower amount of regular secondary structures than PDGF-BB. Additionally, the increased bandwidths of the amide I components of the FTIR spectrum of the glutathione adduct indicates a more flexible structure relative to the dimeric form. Sedimentation equilibrium analysis showed that PDGF-BB is primarily a dimer and that the glutathione form is primarily a monomer. Thus, it was concluded that the glutathione derivative has little affinity to form non-covalent dimers in neutral solution.

Marked increase in the teratogenicity of the combined administration of the industrial solvent 2-methoxyethanol and radiofrequency radiation in rats.

Limited published animal research reports synergistic teratogenic effects following combined hyperthermia (induced by elevated ambient temperature) and administration of chemical teratogens. Radiofrequency (RF) radiation is widely used in occupational environments. Since RF radiation also elevates the body temperature of, and is teratogenic to, exposed animals, concurrent RF radiation and chemical agent administration may enhance teratogenicity. The present exploratory study, consisting of preliminary dose-finding studies and the primary study, was designed to investigate whether concurrent exposure of rats to RF radiation and the industrial solvent 2-methoxyethanol (2ME) can enhance the developmental toxicity of either agent acting alone. Preliminary dose-finding studies using small numbers of rats investigated the ability of various RF radiation conditions and doses of 2ME to produce external malformations (primarily of the paws) when administered on gestation day 13. Based on these preliminary studies, RF radiation exposure [sufficient to elevate rectal temperature to 42.0 degrees C (4 degrees C above normal for rats) for 30 min] and 2ME administration (150 mg/kg) were selected for the primary study. In the primary study, groups of 18 to 27 pregnant rats were administered RF radiation exposure and distilled water gavage, 2ME gavage and sham RF exposure, RF radiation exposure and 2ME gavage concurrently, or sham RF exposure and distilled water gavage. Pregnant rats were sacrificed on gestation day 20, and the offspring were examined for external malformations. Combined exposures enhanced the adverse effects produced by either experimental agent alone (no malformations were detected in the double sham group). Mean fetal malformations/litter increased from 14% after 2ME and sham RF (15/26 litters affected, with an average of 2 fetuses/litter malformed) and 30% after RF radiation and water gavage (10/18 litters affected, with an average of 4 fetuses/litter malformed), to 76% after the combined treatment (18/18 litters affected, with an average of 12 fetuses/litter malformed). In addition to a significant increase in the frequency of malformations, the severity of malformations also was enhanced by the combination treatment (on a relative severity ranking scale, the 2ME severity score was less than 1, the RF score was 3, and the combination score was 6). This study provided evidence of synergism between RF radiation and 2ME administration, but additional research will be required to characterize the extent of synergism between these two agents. Potential interactive effects between chemical and physical agents need to be investigated to determine the extent to which such interactions should impact occupational exposure standards.