Search

Background: Cefiderocol is the first antibiotic with effluent flow rate-based dosing recommendations outlined in the product label for patients receiving continuous renal replacement therapy (CRRT). We aimed to investigate the population pharmacokinetics of cefiderocol among patients receiving CRRT and validate these dosing recommendations., Methods: A multicenter, prospective cefiderocol pharmacokinetic study among intensive care unit patients receiving CRRT was conducted (2022-2023). Blood sampling was performed at steady-state and cefiderocol concentrations were assayed by validated liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R software. The free time above the minimum inhibitory concentration ( f T > MIC) and total daily area under the concentration time curve (AUC daily ) were calculated., Results: Fourteen patients with effluent flow rates ranging from 2.1 to 5.1 L/h were enrolled. Cefiderocol concentrations best fitted a 2-compartment model. Mean ± standard deviation (SD) parameter estimates for clearance, central compartment volume, and intercompartment transfer constants (k 12 and k 21 ) were 3.5 ± 1.5 L/hour, 10.7 ± 8.4 L, 3.9 ± 1.8 hours -1 , and 2.2 ± 2.2 hours -1 , respectively. With simulations based on product label dosing recommendations, all patients achieved 100% f T > MIC up to MIC 8 mg/L with an AUC daily (mean ± SD) of 1444 ± 423 mg × hour/L. Cefiderocol was well tolerated among the 14 patients., Conclusions: The current package insert dosing recommendations resulted in pharmacodynamically optimized cefiderocol exposures. Cefiderocol concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUC daily was within the range observed in patients in the phase 3 clinical trials, suggestive of a safe and therapeutic drug profile., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Important tools in preventing the spread of COVID-19 include contract tracing and adherence to isolation guidelines after a positive diagnosis of COVID-19. This is especially relevant among college students who are often away from support systems at home, living in high-density housing, and may not experience serious symptoms from COVID-19 while still contagious. Objective: As text message-based interventions have been found effective in addressing health behaviors among young adults, we conducted formative research to explore how text messaging could support students in adhering to isolation guidelines. Participants: A convenience sample of college students (n = 104) at one university. Methods: An online survey gathered students' perceptions of helpful components to include in a text message-based intervention. Results: Students expressed interest in receiving text messages with support, encouragement, and resources during their time in isolation following a COVID-19 diagnosis. Conclusions: Based on the results, we developed a text message-based intervention designed to provide motivation, support, distraction, and information on resources.

A BiFeO 3 film is grown epitaxially on a PrScO 3 single crystal substrate which imparts ~ 1.45% of biaxial tensile strain to BiFeO 3 resulting from lattice misfit. The biaxial tensile strain effect on BiFeO 3 is investigated in terms of crystal structure, Poisson ratio, and ferroelectric domain structure. Lattice resolution scanning transmission electron microscopy, precession electron diffraction, and X-ray diffraction results clearly show that in-plane interplanar distance of BiFeO 3 is the same as that of PrScO 3 with no sign of misfit dislocations, indicating that the biaxial tensile strain caused by lattice mismatch between BiFeO 3 and PrScO 3 are stored as elastic energy within BiFeO 3 film. Nano-beam electron diffraction patterns compared with structure factor calculation found that the BiFeO 3 maintains rhombohedral symmetry, i.e., space group of R3c. The pattern analysis also revealed two crystallographically distinguishable domains. Their relations with ferroelectric domain structures in terms of size and spontaneous polarization orientations within the domains are further understood using four-dimensional scanning transmission electron microscopy technique., (© 2023. The Author(s).)

Analyzing the orientation of polymeric crystalline lamella at the surface of thin films can be challenging. Even though atomic force microscopy (AFM) is often sufficient for this analysis, there are cases when imaging is not sufficient to confidently determine lamellar orientation. Here, we used sum frequency generation (SFG) spectroscopy to analyze the lamellar orientation at the surface of semi-crystalline isotactic polystyrene (iPS) thin films. The SFG orientation analysis indicated that the iPS chains are oriented perpendicular to the substrate (flat-on lamellar orientation), which was confirmed by AFM. By analyzing the evolution of the SFG spectral features with the progress of crystallization, we demonstrated that the ratios of the SFG intensities of the phenyl ring resonances are a good indication of the surface crystallinity. Furthermore, we explored the challenges associated with SFG measurements of heterogeneous surfaces, which is commonly present in many semi-crystalline polymeric films. To the best of our knowledge, this is the first time that the surface lamellar orientation of semi-crystalline polymeric thin films was determined by SFG. Also, this work pioneers in reporting the surface conformation of semi-crystalline and amorphous iPS thin films by SFG and in linking the SFG intensity ratios to the progress of the crystallization and the surface crystallinity. This study demonstrates the potential applicability of SFG spectroscopy in the conformational analysis of polymeric crystalline structures at interfaces and opens the way to the investigation of more complex polymeric structures and crystalline arrangements, especially for the case of buried interfaces, where AFM imaging is not an option., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Graphene is the strongest known material. However, the challenge of translating that strength from the microscale to the more useful macroscale remains unmet. Preparing solid structures from self-assembled graphene oxide liquid crystals has allowed the creation of paper and fibers with excellent mechanical properties. Conventionally, vacuum filtration, wet spinning, and freeze-drying are used to prepare such structures from graphene oxide liquid crystals. Here, we introduce photocuring as an additional option to create solid structures of self-assembled graphene oxide liquid crystals that allows for thicker samples and other shapes to be realized. The photocured graphene oxide paper prepared here exhibited mechanical properties comparable to those of benchmark samples prepared by vacuum filtration., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Hypophosphatemia in critically ill patients is a common electrolyte disturbance associated with a myriad of adverse effects. Critically ill patients requiring continuous renal replacement therapy (CRRT) are at high risk of hypophosphatemia and often require phosphate supplementation during therapy. The aim of this study was to evaluate the association of phosphate versus non-phosphate containing CRRT solutions with incident hypophosphatemia in critically ill patients requiring CRRT., Materials and Methods: This is a single-center, retrospective, cohort study at a tertiary academic medical center of 1,396 adult patients requiring CRRT during their intensive care unit stay comprising 7,529 (phosphate containing) and 4,821 (non-phosphate containing) cumulative days of CRRT. Multivariable logistic regression was used to model the primary outcome of hypophosphatemia during CRRT according to exposure to phosphate versus non-phosphate containing CRRT solutions., Results: Incident hypophosphatemia during CRRT, serum phosphate <2.5 mg/dL or 0.81 mmol/L, was significantly higher in the non-phosphate versus phosphate containing solution group: 304/489 (62%) versus 175/853 (21%) (p < 0.001). Cumulative phosphate supplementation was also significantly higher in the non-phosphate versus phosphate containing solution group: 79 (IQR: 0-320) versus 0 (0-16) mmol (p < 0.001). Non-phosphate solutions were associated with an 8-fold increase in the incidence of hypophosphatemia (adjusted OR 8.05; 95% CI 5.77, 11.26; p < 0.001)., Discussion/conclusions: The use of phosphate containing CRRT solutions was independently associated with reduced risk of incident hypophosphatemia and decreased phosphate supplementation during CRRT. Interventional studies to confirm these findings are needed., (© 2021 S. Karger AG, Basel.)

Introduction: The combination of vancomycin/piperacillin-tazobactam is associated with increases in serum creatinine compared to other antibiotic combinations in the treatment of infections for hospitalized patients. However, the available literature is limited to the study of incident acute kidney injury (AKI). The combination has not been evaluated in patients with AKI already present and the degree to which the trajectory of AKI is influenced by this combination is unknown., Methods: This was a single center, retrospective cohort study of adult patients with sepsis and AKI present on admission prescribed a combination of vancomycin with either piperacillin-tazobactam or cefepime within the first 3 days of admission. The primary outcome was maximum serum creatinine observed within days 2-7 of the hospital stay. Subsequent kidney outcomes were evaluated at one week and hospital discharge., Results: Of 480 patients with sepsis and AKI who met inclusion criteria, 288 (60%) received vancomycin/piperacillin-tazobactam, and 192 (40%) received vancomycin/cefepime. Patients were well-matched on clinical factors, including severity of illness, stage of AKI, exposure to other nephrotoxins, and durations of antimicrobial therapy. There were no differences in AKI trajectory during the first week as assessed by maximum serum creatinine (2.1 (1.4-3.5) mg/dl vs. 2.1 (1.4-3.0) mg/dl; p=0.459) and AKI progression (24.0% vs. 23.4%; p=0.895). No differences were observed with other kidney related outcomes, including the need for dialysis (14.6% vs. 13.0%; p=0.628) or major adverse kidney events at hospital discharge (48.3% vs. 47.9%; p=0.941)., Conclusions: In patients with sepsis and AKI, the combination of vancomycin/piperacillin-tazobactam compared to vancomycin/cefepime was not associated with higher serum creatinine values or AKI progression in the week following ICU admission., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The dependence between the conformation of polystyrene (PS) and its molecular weight (Mw) in the vicinity of a metal interface was investigated by sum frequency generation (SFG) spectroscopy. Tilt angles θ ≥ 50 ° (the angle between the C 2 axis of the pendant phenyl ring and the surface normal) were observed for all samples because of the interaction between the aromatic rings and the metal surface. Furthermore, it was found that θ decreases with increasing Mw for PS samples ranging from 20 × 10 3 g/mol to 400 × 10 3 g/mol. The intensity of the backbone SFG signal was higher for high Mw PS, compared to low Mw PS, indicating a greater number of backbone interactions with the silver substrate surface for the high Mw sample. These structural differences are driven by different entropic and enthalpic contributions to the free energy of adsorption for different polymer molecular weights. Differences in the polymer free volume and in the relative amount of chain ends with higher mobility may also influence the chain conformation. These results suggest that important interfacial properties of polymeric thin films, such as adhesion and wettability, could be tailored by modifying the polymer Mw to achieve the desired interfacial conformation.

Quantum dots have unique size-dependent properties and promising applications. However, their use in many applications remains hindered by mechanical, thermal, and chemical instability and the lack of viable quantum dot mass-production processes. Embedding quantum dots in matrices such as silica counteracts the instability challenges in some applications while preserving their unique properties and applicability. Here, we synthesize quantum dots of four different metal oxides embedded in a silica matrix in a one-step mass-production process using flame spray pyrolysis., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

In this study, we produce highly porous (up to ∼91%) composite scaffolds of polylactic acid (PLA) containing 2 wt % sol-gel-derived 45S5 Bioglass ® particles via nonsolvent induced phase separation at -23°C with no sacrificial phases involved. Before the incorporation of the bioglass with PLA, the particles are surface modified with a silane coupling agent which effectively diminishes agglomeration between them leading to a better dispersion of bioactive particles throughout the scaffold. Interestingly, the incorporation route (via solvent dichloromethane or nonsolvent hexane) of the surface modified particles in the foaming process has the greatest impact on porosity, crystallinity, and morphology of the scaffolds. The composite scaffolds with a morphology consisting of both mesopores and large macropores, which is potentially beneficial for bone regeneration applications, are examined further. SEM images show that the surface modified bioglass particles take-up a unique configuration within the mesoporous structure of these scaffolds ensuring that the particles are well interlocked but not completely covered by PLA such that they can be in contact with physiological fluids. The results of preliminary in vitro tests confirm that this PLA/bioglass configuration promotes the interaction of the bioactive phase with physiological fluids. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2433-2442, 2017., (© 2016 Wiley Periodicals, Inc.)

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Among the existing sexual assault prevention efforts on college campuses, few use mass communication strategies designed to simultaneously entertain and educate. Although many entertainment-education efforts are guided by social cognitive theory, other theories may be useful in entertainment-education design. Previous research has found that social cognitive theory and social norms theory can successfully influence participants' perceived norms and efficacy related to sexual assault reduction; however, whether such results can be replicated in a naturalistic setting and the extent to which the guiding theoretical foundation may influence outcomes remain unknown. We used a pre- and posttest field experiment with college students in residence halls to assess how different theoretical foundations may influence effects. Over the course of a semester, the participants viewed eight mini-magazines developed using (1) social cognitive theory, (2) social norms theory, (3) a combination of both theoretical frameworks, or (4) a control condition with no sexual assault prevention messaging. Participants in the combined content condition had greater levels of self-efficacy related to sexual assault prevention and more accurate norm perceptions. There were also effects for the mini-magazines developed with only one theoretical framework. Overall, we found that multiple theories can effectively guide entertainment-education message development.

More than four decades after the discovery of 45S5 Bioglass® as the first bioactive material, this composition is still one of the most promising materials in the tissue engineering field. Sol-gel-derived bioactive glasses generally possess improved properties over other bioactive glasses, because of their highly porous microstructure and unique surface chemistry which accelerate hydroxyapatite formation. In the current study, a new combination of precursors with lactic acid as the hydrolysis catalyst have been employed to design an organic, nitrate-free sol-gel procedure for synthesizing of 45S5 Bioglass®. This straightforward route is able to produce fully amorphous submicron particles of this glass with an appropriately high specific surface area on the order of ten times higher than that of the melt-derived glasses. These characteristics are expected to lead to rapid hydroxyapatite formation and consequently more efficient bone bonding., (Copyright © 2014 Elsevier B.V. All rights reserved.)

There are many reasons that a child does not have a functional or legal guardian. The parent may be incarcerated, deceased, debilitated, deported, or have abandoned them. The teen may be a runaway or may have been exited from foster care. School nurses are challenged to find an adult who can legally consent to treatment when an unaccompanied minor needs health care. This article provides strategies for case management of these students. The school needs to be a stable and safe environment where the unaccompanied teen can thrive and succeed.

Content analyses have cataloged the sexual scripts present in magazines largely because of their perceived value to readers and their potential role as sex educators. Although it is generally agreed that magazines have the potential to influence sexual attitudes and behavioral intentions, the effects of this medium are not as frequently researched as are other forms of media. The current study tested whether exposure to magazines was associated with intentions related to sexual consent negotiation. A survey of 313 college students indicated that exposure to men's magazines was significantly associated with lower intentions to seek sexual consent and lower intentions to adhere to decisions about sexual consent. In contrast, exposure to women's magazines was significantly associated with greater intentions to refuse unwanted sexual activity. Overall, the findings of this study further reinforce the critical need for responsible and realistic portrayals of sex in entertainment media, specifically magazines.

Popular crime dramas have tackled sensitive issues such as sexual assault with increasing frequency over the past 20 years. These popular programs increasingly demonstrate the emotional and physical effect of sexual assault on its victims, and in some instances they depict individuals being rewarded for intervening to prevent or stop an assault in progress. It is possible that this content could affect attitudes related to sexual assault prevention. However, no previous research has examined this possibility. In the fall 2008 semester, 508 undergraduates at a large northwestern university completed a questionnaire about media use and bystander intervention in a sexual assault situation. Results from hierarchical regressions lend support for the integrative model of behavioral prediction in that instrumentality, rape myth acceptance, perceived social norms, perceived efficacy related to intervening, and exposure to primetime crime dramas were associated with participants' intentions to intervene in a sexual assault. The results suggest that crime dramas may be a useful venue for prevention messages as exposure to crime dramas uniquely contributed to intentions to intervene in a sexual assault.

A novel space-filling trialkoxysilane derivative was synthesized using a two-step strategy from commercially available starting materials to produce the precursor for the formation of low-density self-assembled monolayers. Self-assembled monolayers of the synthesized compound were prepared on three different substrates (Si/SiO(2), glass and ITO) and were characterized using contact angle, ellipsometry and sum-frequency generation spectroscopy. Removal of the space-filling protecting group, (2-chlorophenyl)diphenyl methanol, yields a carboxy-terminated surface. Correspondingly, the contact angle and film thickness decrease and the SFG spectra clearly indicate an increase in gauche defect concentration characteristic of a low-density disordered monolayer.

A study of the frequency response of AFM microcantilevers in liquid media contained in a commercial fluid cell is presented. Such systems exhibit complicated dynamics which are often not well described by available theories. Their dynamic behavior has a direct effect on the use of the AFM in dynamic mode while imaging in liquid or while extracting the rheological properties of the fluid. We explore the issues related to the design of the cantilever holder/fluid cell and propose an approach for evaluating, minimizing and recognizing the ultimate limitations of commercial cantilever holders. A technique for estimating the frequency response spectrum of the fluid cell itself from experimental data is presented. This spectrum can then be used to evaluate whether or not the fluid cell is suited for the desired purpose.

Alterations in thyroid hormone level or responsivity to thyroid hormone have significant neurologic sequelae throughout the life cycle. During fetal and early neonatal periods, disorders of thyroid hormone may lead to the development of motor and cognitive disorders. During childhood and adult life, thyroid hormone is required for neuronal maintenance as well as normal metabolic function. Those with an underlying disorder of thyroid hormone homeostasis or mitochondrial function may be at greater risk for developing cognitive, motor, or metabolic dysfunction upon exposure to substances which alter thyroid hormone economy. Polychlorinated biphenyls (PCBs) and dioxins have been argued to interfere with thyroid hormone action and thus may affect the developing and mature brain. Animal models provide useful tools for studying the effects of thyroid hormone disorders and the effects of environmental endocrine disruptors. The congenitally hypothyroid, hyt/hyt, mouse exhibits abnormalities in both the cognitive and motor systems. In this mouse and other animal models of thyroid hormone disorders, delayed somatic and reflexive development are noted, as are permanent deficits in hearing and locomotor and adaptive motor behavior. This animal's behavioral abnormalities are predicated on anatomic abnormalities in the nervous system. In turn, these abnormalities are correlated with differences in neuronal structural proteins. In normal mice, the expression of mRNAs coding for these proteins occurs temporally with the onset of autonomous thyroid hormone production. The hyt/hyt mouse has a mutation in the thyroid stimulating hormone receptor (TSHr) gene which renders it incapable of transducing the TSH signal in the thyrocyte to produce thyroid hormone. Some behavioral and possibly some biochemical abnormalities in mice exposed to PCBs are similar to those seen in the hyt/hyt mouse. In addition to direct effects on brain development and neuronal maintenance, thyroid hormone is necessary for maintaining metabolic functioning through its influence on mitochondria. Because the brain is particularly sensitive to inadequate energy generation, disorders of thyroid hormone economy also indirectly impair brain functioning. Alterations in thyroid hormone level result in differing expression of mitochondrial genes. Mutations in these mitochondrial genes lead to well-recognized syndromes of encephalomyopathy, myopathy, and multisystem disorder. Hence, PCBs and dioxins, by possibly altering the thyroid hormone milieu, may alter the functioning of mitochondria in the generation of adenosine triphosphate (ATP). The use of animal models of thyroid hormone deficiency for behavioral, anatomic, histologic, and molecular comparison will help elucidate the mechanisms of action of these putative endocrine-disrupting compounds. The study of thyroid hormone disorders provides a template for relating thyroid hormone mediated effects on the brain to these compounds.

The kdr insecticide resistance trait of the house fly (Musca domestica .L.), which confers reduced neuronal sensitivity to DDT and pyrethroid insecticides, was previously shown to exhibit tight genetic linkage to restriction fragment length polymorphism markers lying within a voltage-sensitive sodium channel gene that is homologous to the para gene of Drosophila melanogaster. In the present study, the 6315 nucleotide coding sequences of this voltage-sensitive sodium channel gene from insecticide-susceptible (NAIDM strain) and kdr (538ge strain) house flies were determined by automated direct DNA sequencing of PCR fragments obtained by amplification on first strand cDNA from adult heads. The deduced 2105-residue amino acid sequence from each strain exhibited overall structure and organization typical of sodium channel alpha subunit genes and was 90.0% identical to that of the D. melanogaster para gene product. We did not detect any splice variants among voltage-sensitive sodium channel cDNAs obtained from adult house fly head preparations. Comparison of the coding sequence of the voltage-sensitive sodium channel gene of the kdr house fly strain to that of the NAIDM strain revealed 12 amino acid differences in the 538ge strain. The significance of these polymorphisms as candidate resistance-conferring mutations is discussed.

The hyt/hyt mouse has an autosomal recessive, fetal onset, characterized by severe hypothyroidism that persists throughout life and is a reliable model of human sporadic congenital hypothyroidism. The hypothyroidism in the hyt/hyt mouse reflects the hyporesponsiveness of the thyroid gland to thyrotropin (TSH). This is attributable to a point mutation of C to T at nucleotide position 1666, resulting in the replacement of a Pro with Leu at position 556 in transmembrane domain IV of the G protein-linked TSH receptor. This mutation leads to a reduction in all cAMP-regulated events, including thyroid hormone synthesis. The diminution in T3/T4 in serum and other organs, including the brain, also leads to alterations in the level and timing of expression of critical brain molecules, i.e. selected tubulin isoforms (M beta 5, M beta 2, and M alpha 1), microtubule associated proteins (MAPs), and myelin basic protein, as well as to changes in important neuronal cytoskeletal events, i.e. microtubule assembly and SCa and SCb axonal transport. In the hyt/hyt mouse, fetal hypothyroidism leads to reductions in M beta 5, M beta 2, and M alpha 1 mRNAs, important tubulin isoforms, and M beta 5 and M beta 2 proteins, which comprise the microtubules. These molecules are localized to layer V pyramidal neurons in the sensorimotor cortex, a site of differentiating neurons, as well as a site for localization of specific thyroid hormone receptors. These molecular abnormalities in specific cells and at specific times of development or maturation may contribute to the observed neuroanatomical abnormalities, i.e. altered neuronal process growth and maintenance, synaptogenesis, and myelination, in hypothyroid brain. Abnormal neuroanatomical development in selected brain regions may be the factor underlying the abnormalities in reflexive, locomotor, and adaptive behavior seen in the hyt/hyt mouse and other hypothyroid animals.

The offspring of matings between hyt/hyt male mice and hyt/+ females were examined for somatic and behavioral differences. The hyt/hyt offspring displayed delayed somatic development for eye opening and ear extension relative to their euthyroid littermates. Behavioral measurement of locomotor activity indicated hyperactivity at 14 days of age and hypoactivity at 21 and 40 days relative to the euthyroid mice. Impaired swimming escape behavior and Morris maze spatial learning were observed in the hyt/hyt animals. Comparative evaluation of +/+ progenitor strain offspring having no hypothyroidism in their genetic background indicated significant differences in somatic and behavioral endpoints between the hyt/hyt and euthyroid (hyt/+, +/+) animals. These results confirm the utility of the hyt/hyt mouse for studies of the impact of congenital hypothyroidism on the functional development of the offspring.

Thyroid hormone significantly affects molecular and neuroanatomical properties of the developing nervous system. Altered connectivity in hypothyroidism may reflect reductions in process growth, alterations in process maintenance, or changes in synaptogenesis or synaptic maintenance. These events are dependent on microtubules, neurofilaments, microfilaments, and associated molecular components. Reductions in delivery of microtubules and neurofilaments to the distal axon by slow component a (SCa) of axonal transport may contribute to the neuroanatomical abnormalities of hypothyroidism (Stein et al., J Neurosci Res 28:121-133, 1991). However, hypothyroidism might also affect the axon and synaptic connections by altering slow component b (SCb), which includes actin microfilaments and proteins that contribute to synaptic function, i.e., clathrin, HSC70 (clathrin uncoating ATPase), spectrin, and calmodulin. To determine the effect of hypothyroidism on SCb proteins, slow axonal transport was analyzed in optic nerves of hyt/hyt hypothyroid mice, which have severe primary hypothyroidism, and euthyroid control mice. Clathrin, spectrin, HSC70, and actin showed significant reductions in transport velocity in hyt/hyt optic nerves relative to euthyroid nerves, but the transport rate for calmodulin was less affected. However, the amount of calmodulin was significantly elevated in hyt/hyt nerve over euthyroid nerves. Hypothyroidism selectively reduces transport of SCb proteins, which are thought to play significant roles in synaptic function and in the growth cone. The effects of hypothyroidism on microtubules and neurofilaments combined with actions on SCb suggest that changes in neuronal function associated with reduced thyroid hormone during development and maturity (i.e., alterations in neuronal connectivity, nerve conduction, and synaptic function) may be mediated in part by effects on slow axonal transport.

The hyt/hyt mouse has a severe and pervasive primary inherited hypothyroidism with significantly depressed serum T4, elevated serum and pituitary TSH, and reduced thyroid gland iodide uptake. Previous ultrastructural and histologic analysis of the hyt/hyt thyroid gland along with these biochemical abnormalities support an inherited defect in TSH responsiveness of the hyt/hyt thyroid gland. In order to evaluate the potential site of the defect in the hyt/hyt mouse, we have studied the hyt/hyt gland and hyt/hyt TSH from a biochemical and molecular standpoint. Based on demonstrated bioactivity of hyt/hyt serum in the McKenzie bioassay, this reduced responsiveness to TSH in the hyt/hyt mouse is not due to reduced bioactivity of hyt/hyt TSH or a major structural abnormality in the hyt/hyt TSH molecule. In comparison to hyt/ + euthyroid littermates and +/+ BALB/cBY progenitor strain mice, the hyt/hyt mouse demonstrates a twofold reduction in thyroid gland basal cAMP and a markedly diminished response of adenylyl cyclase to exogenous TSH. However, hyt/hyt cAMP production is equivalent to the euthyroid mice after stimulation of thyroid glands by forskolin, cholera toxin, PGE1, and isoproterenol. These results support a defect in the TSH-G protein-adenylyl cyclase system in the hyt/hyt thyroid gland. Specifically, these findings suggest that the hyt/hyt mouse has a defect in TSH responsivity due to an inherited defect in the thyroid gland TSH receptor molecule. Since the hyt/hyt gland makes T3 and T4 but at diminished levels, the proposed defect in the TSH receptor would still impart partial function. Both hyt/hyt and euthyroid hyt/ + littermates make TSH receptor mRNAs of 5500 and 2400 base pairs. This suggests that the receptor defect does not represent a major structural abnormality of the gene. The receptor defect could represent a reduction in receptor number, receptor-TSH affinity, or TSH receptor-G protein coupling. The specificity of this effect on adenylyl cyclase-cAMP is shown by the reduction of TSH-cAMP regulated thyroid peroxidase (TPO) and thyroglobulin mRNAs in the hyt/hyt thyroid gland. Given the importance of TPO and thyroglobulin in normal thyroid hormone synthesis, the reductions in TPO and thyroglobulin mRNAs in the hyt/hyt thyroid gland may underlie the significant decrease in thyroid hormone production by the hyt/hyt mouse.

Thyroid hormone deficiency in the developing brain leads to disorders of neuronal process growth. This is evidenced by reduced axonal and dendritic size and complexity (Garza et al.: Developmental Brain Research 43:287-297, 1988; Ruiz-Marcos: Iodine and the Brain. New York: Plenum Press, pp 91-102, 1989). These findings may be related to alterations in the neuronal cytoskeleton in hypothyroidism, such as reduced or abnormal microtubular number and density (Faivre et al.: Developmental Brain Research 8: 21-30, 1983), and altered assembly, stabilization, and composition of microtubule protein in the hypothyroid brain. Neurofilaments also contribute to axonal caliber and process stability. Similar to microtubules, certain properties of neurofilaments are altered in developing hypothyroid axons (Marc and Rabie: International Journal of Developmental Neuroscience 3: 353-358, 1985; Faivre et al.: Developmental Brain Research 8:21-30, 1983) that may affect axonal caliber and process stability. Normal process growth is predicted on formation of appropriate numbers of microtubules and on the normal synthesis and axonal transport of cytoskeletal components [tubulin, microtubule associated proteins (MAPs), and neurofilament proteins]. Hypothyroidism might alter the neuronal cytoskeleton and neuronal growth either by affecting the developmental programs for expression of specific isoforms of cytoskeletal proteins or by changing the delivery of cytoskeletal proteins via slow axonal transport, particularly slow component a (SCa). Previous studies had demonstrated changes in the amount of specific microtubule protein isoforms and mRNAs (Stein et al.: Iodine and the Brain. New York: Plenum Press, pp 59-78, 1989a). To further elucidate the molecular basis for process growth abnormalities in the hypothyroid brain, we investigated slow axonal transport in the mouse to determine the effects of thyroid hormone deficiency on the rate and composition of SCa. Comparisons of SCa in the optic nerve of hyt/hyt hypothyroid mouse and euthyroid hyt/+ littermates and euthyroid progenitor strain, BALB/cBY +/+ mice, indicated that the velocity of SCa was significantly reduced in hyt/hyt optic nerve relative to hyt/+ and +/+. The axonal transport rate for tubulin, which is carried in SCa, was 0.118 mm/day in the hyt/hyt optic nerves. This rate was significantly different for the tubulin rates for the hyt/+ optic nerves (0.127 mm/day) and for the +/+ optic nerves (0.138 mm/day). Neurofilament proteins, as measured by the 140,000 daltons component, NFM, also appeared to be reduced in velocity in the hyt/hyt versus the hyt/+ and +/+ optic nerves.(ABSTRACT TRUNCATED AT 400 WORDS)

The assessment of behavioral development in the progeny of males exposed to known mutagenic chemicals is a potentially sensitive endpoint for detecting transmissible abnormalities. A genetic component is demonstrated as these behavioral abnormalities can also be passed on to the F2 generation. In this review, experimental studies exploring transmission of behavioral deficits from paternal exposure to drugs, chemicals and radiation are addressed. Additionally included is a brief synopsis of recent work performed in our laboratory investigating such abnormalities in offspring from male rats exposed to ionizing radiations. The implications of these behavioral endpoints to humans is also discussed.

The effect of Fenclor 42 (PCB) exposure of female rats (Fischer 344 strain) was studied through assessment of the behavioral development of their F1 progeny. Female rats were exposed to PCB according to the following treatment schedule: (A) (5 days) 2 weeks prior to mating, (B) during gestation (Days 6-15 of pregnancy), (C) during lactation (Days 1-21 after delivery). Behavioral endpoints of motor reflexes, motor coordination, activity (preweaning behaviors), and learning (postweaning behavior) were evaluated for PCB ip dosages of 5-10 mg/kg/day for 5 days (preconception exposure), and PCB oral dosages of 2-4 mg/kg/day for 10 days (in utero exposure) and of 1-2 mg/kg/day for 20 days (during lactation exposure). Dosage-dependent differences in the evaluated behaviors were found in the offspring of the PCB-exposed females when compared to the offspring of corn-oil (vehicle)-exposed females. Significant differences in the development of cliff avoidance reflexive behavior, swimming ability, and open field activity were particularly evident. Furthermore the PCB exposure of female rats during gestation and lactation resulted in impaired acquisition of the active avoidance behavior while preconceptional PCB exposure significantly affected active avoidance performance as reflected in increased number of avoidance responses to reach criterion for extinction. These results show that Fenclor 42 does possess a significant risk to the offspring of exposed females, and further illustrate the sensitivity of progeny behavioral assessment in detecting suspected functional teratogenesis.

The effects of perinatal chlordiazepoxide (CDZ) exposure were studied in 3 to 30 day old F344 rats. Pregnant primaparous rats were treated daily on days 1-21 of pregnancy with CDZ (1 mg/kg) or saline (IP). Lactating females were treated with CDZ or saline in order to expose pups on postnatal days 1-21. Behavioral measures on all litters included: cliff avoidance (postnatal days 4-10), swimming (postnatal days 6-10), open field activity (postnatal days 14 and 21) and active avoidance (beginning postnatal day 30). Neonates perinatally exposed to CDZ were significantly slower in cliff avoidance development as measured by latency to meet criterion. Swimming development was impaired by both prenatal and postnatal CDZ exposure. Open field activity was minimally affected on day 14 but only for males exposed postnatally to CDZ. Postnatal CDZ exposure significantly affected active avoidance performance as reflected in faster response latencies and an increased number of avoidance responses to reach criterion for extinction. Only the postnatally exposed male pups were significantly affected on the avoidance behavior. These results are consistent with the suggestion that CDZ is a potential behavioral teratogen.

Phencyclidine (PCP), a widely abused drug currently, has multiple pharmacological actions, including psychotomimetic [1], anesthetic [2], sympathomimetic [2], anticholinergic [3-7], and dopaminergic [8-10]. Similarly, PCP intoxication in man can present with diverse symptoms: schizophrenia-like delusions and hallucinations; mania; violence, dyskinetic, catatonic, or stereotyped movements; hypertension; and coma [11, 12]. There is general agreement that the treatment of PCP intoxication includes support of vital functions and acidification of the urine [13]. However, there is no known specific antidote for PCP toxicity. Although diazepam [13], haloperidol [14, 15], and chlorpromazine [16] have been reported to improve the agitation and psychotic symptoms caused by PCP, the therapeutic efficacy of these agents has rarely been documented with objective clinical measures. Recently we found that intramuscular physostigmine and haloperidol [17, 18] improved several symptoms of acute PCP intoxication as measured by the Brief Psychiatric Rating Scale (BPRS) [19].

Transmission of the effects of paternal pre-fertilization exposure to a genotoxic drug being manifested in the F1 progeny is well established using the traditional rodent dominant lethal protocol [7]. More recently, the induction of genotoxic effects in the F1 progeny following chronic paternal exposure prior to fertilization has been described in rats using behavioral testing as an endpoint [1]. In our initial study, male F344 adult rats were treated chronically with 10 mg/kg cyclophosphamide (CP) or saline for 5 weeks (5 days of daily treatment and 2 days of rest). The present study describes the behavior of progeny whose fathers were treated with a single intraperitoneal injection of 10 mg/kg CP and mated at different times post-injection. This design showed that post-meiotic germ cells are the most sensitive to the effects of CP as seen by behavioral testing of the F1 progeny.

Fischer 344 male rats were treated with cyclophosphamide (10 milligrams per kilogram of body weight) for 5 weeks and subsequently mated to females previously treated with saline or cyclophosphamide. The F1 progeny of the cyclophosphamide-treated males exhibited behavior deficits when compared to controls. These data could indicate a chemically induced genetic effect manifested by behavioral alterations.

Twenty-four patients with phencyclidine intoxication were treated with either physostigmine (2 mg i.m.) or haloperidol (5 mg i.m.) based on the presence of delusions and/or hallucinations. Several symptoms subsequently improved. Schizophreniform symptoms showed substantial improvement with haloperidol.

The effects of avermectin B1a (AVM) on the gamma-aminobutyric acid (GABA) receptor-chloride ionophore complex of mouse and rat brain were determined using assays of basal and GABA-stimulated 36Cl-uptake by brain vesicles. In the mouse, AVM acted solely as a potent non-competitive inhibitor of GABA-dependent chloride uptake. In the rat, inhibition of GABA-dependent chloride uptake was potent but incomplete, and AVM applied in the chloride uptake medium stimulated chloride uptake in the absence of GABA. The data provide evidence for qualitative differences between the GABA receptor complexes of mouse and rat brain in their responses to AVM.

The hyt/hyt mouse (BALB/cBY-hyt, C.hytRF) provides a useful model for exploring the effect of inherited severe primary hypothyroidism. Studies were undertaken to try to define the basis of the primary hypothyroidism in mice homozygous for the autosomal recessive gene, hyt. These mice had congenital hypothyroidism of fetal onset after 15 days post conception. Through their lifetime, the hyt/hyt mice had reduced serum thyroxine (T4), triiodothyronine (T3), reduced thyroid gland intralumenal colloid on electron microscopy and a 100-fold elevation of TSH-like activity compared to hyt/+ littermates. Thyroglobulin made in hyt/hyt animals was similar in size to normal thyroglobulin which was inconsistent with a major structural thyroglobulin gene defect. The thyroglobulin was iodinated. Marked, erratic dilation of rough endoplasmic reticulum (RER) was noted in hyt/hyt mouse follicular cells. Despite these ultrastructural findings, pulse chase and immunoprecipitation studies with isolated hyt/hyt and normal thyroid glands indicated that normal thyroglobulin processing occurred in the RER and Golgi of the hyt/hyt mice. The hyt/hyt thyroid glands were hypoplastic compared to hyt/+ littermates. Histologically, the hyt/hyt thyroid glands demonstrated an increase in smaller follicular cells, and greater variability in follicular size compared to hyt/+ littermates. Histological and ultrastructural abnormalities in the gland were similar to those seen in certain cases of human congenital hypothyroidism with TSH receptor insensitivity of the thyroid gland. These findings along with the significant TSH elevation, the reduction in colloid and in serum T3 and T4, the efficacy of the hypothalamo-pituitary-thyroid feedback system, and previous observations of reduced iodine uptake and intrathyroidal T4, suggested that primary hypothyroidism in the hyt/hyt mouse might be due to a defect in TSH responsivity of the thyroid gland.

Selected polychlorocycloalkane and pyrethroid insecticides were evaluated as inhibitors of gamma-aminobutyric acid (GABA)-dependent chloride flux into mouse brain vesicles. The inhibitory potencies of the polychlorocycloalkane insecticides, measured as concentrations producing 50% inhibition, spanned a 1200-fold concentration range in the following order of decreasing potency: 12-ketoendrin; isobenzan; endrin; dieldrin; heptachlor epoxide; aldrin; heptachlor; and lindane. For the cyclodienes, inhibition of chloride uptake was closely correlated with both mammalian toxicity and the ability to displace the binding of [35S]t-butylbicyclophosphorothionate (TBPS). However, lindane was much less potent as an inhibitor of GABA-dependent chloride uptake than would be expected from its acute toxicity or potency as an inhibitor of [35S]TBPS binding. Mirex and chlordecone were poor inhibitors of GABA-dependent chloride uptake, indicating that other sites are likely to be involved in their toxic action. The pyrethroid insecticide deltamethrin gave 50% inhibition of GABA-dependent chloride uptake at 25 microM, but the extent of inhibition was not increased at higher concentrations. In addition, the nontoxic enantiomer of deltamethrin produced dose-dependent inhibition in the chloride flux assay with a potency about 10-fold less than deltamethrin. These results demonstrate the utility of this functional assay to identify compounds that act at the GABAA receptor-ionophore complex and implicate this complex as the principal site of neurotoxic action for cyclodiene insecticides. Although lindane and deltamethrin also altered GABAA receptor-ionophore function, their low potencies and the incomplete stereospecificity of deltamethrin inhibition suggest that this complex is not involved in the neurotoxic action of lindane and alpha-cyano-substituted pyrethroids.

The effects of naloxone, metenkephalin, and morphine were tested on phencyclidine(PCP)-induced stereotyped behaviors, ataxia, and hyperactivity in the rat. Naloxone (8 mg/kg) significantly decreased stereotypy, ataxia, and hyperactivity across all PCP doses tested (2.0, 4.0, and 6.0 mg/kg). Metenkephalin (40 micrograms/kg) and morphine (5 and 10 mg/kg) increased ataxia at the 4.0 and 6.0 mg/kg PCP doses. Stereotypy was altered by the opiates in a dose-dependent manner; enhanced by metenkephalin (40 micrograms/kg) at 2.0 mg/kg and inhibited by metenkephalin (40 micrograms/kg) and morphine (10 mg/kg) at 4.0 and 6.0 mg/kg PCP. Locomotor activity was increased by morphine (5 mg/kg) at 2 mg/kg PCP. These results suggest an involvement of central opiate receptor mechanisms in the mediation of PCP-induced behaviors in the rat.

In the present study the effects of perinatal diazepam (DZP) exposure on behavior and benzodiazepine binding site characteristics in offspring were investigated. Pregnant F344 rats were treated during the last trimester of gestation with vehicle or diazepam (3 mg/kg, 5 mg/kg, or 10 mg/kg). Lactating dams were similarly treated on postnatal days 1-7. Both prenatal and postnatal exposure to diazepam resulted in significant effects on the acquisition and extinction of active avoidance behavior measured postweaning. The number of trials to extinction of one-way active avoidance behavior was significantly greater in offspring exposed gestationally to 3 mg/kg and 10 mg/kg diazepam and postnatally to 10 mg/kg diazepam. The mean response latencies for all diazepam treated groups were significantly shorter than those of the vehicle treated rats during the first 15 trials under extinction conditions. In contrast, neither gestational nor postnatal diazepam exposure significantly affected either acquisition or retention of a passive avoidance task. In addition, the binding affinity between the benzodiazepine type I selective ligand, CL218,872, and cortical membranes, as well as the degree to which GABA potentiated 3H-flunitrazepam were significantly altered by perinatal diazepam exposure. No treatment altered the approximate number of benzodiazepine binding sites in either the cortex, hippocampus, or cerebellum. The results of this study further support diazepam as a behavioral teratogen and give new evidence for neurochemical effects following gestational as well as postnatal diazepam exposure.