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1.
Lab Chip ; 24(4): 869-881, 2024 02 13.
Article in English | MEDLINE | ID: mdl-38252454

ABSTRACT

Cardiovascular toxicity causes adverse drug reactions and may lead to drug removal from the pharmaceutical market. Cancer therapies can induce life-threatening cardiovascular side effects such as arrhythmias, muscle cell death, or vascular dysfunction. New technologies have enabled cardiotoxic compounds to be identified earlier in drug development. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and vascular endothelial cells (ECs) can screen for drug-induced alterations in cardiovascular cell function and survival. However, most existing hiPSC models for cardiovascular drug toxicity utilize two-dimensional, immature cells grown in static culture. Improved in vitro models to mechanistically interrogate cardiotoxicity would utilize more adult-like, mature hiPSC-derived cells in an integrated system whereby toxic drugs and protective agents can flow between hiPSC-ECs that represent systemic vasculature and hiPSC-CMs that represent heart muscle (myocardium). Such models would be useful for testing the multi-lineage cardiotoxicities of chemotherapeutic drugs such as VEGFR2/PDGFR-inhibiting tyrosine kinase inhibitors (VPTKIs). Here, we develop a multi-lineage, fully-integrated, cardiovascular organ-chip that can enhance hiPSC-EC and hiPSC-CM functional and genetic maturity, model endothelial barrier permeability, and demonstrate long-term functional stability. This microfluidic organ-chip harbors hiPSC-CMs and hiPSC-ECs on separate channels that can be subjected to active fluid flow and rhythmic biomechanical stretch. We demonstrate the utility of this cardiovascular organ-chip as a predictive platform for evaluating multi-lineage VPTKI toxicity. This study may lead to the development of new modalities for the evaluation and prevention of cancer therapy-induced cardiotoxicity.


Subject(s)
Induced Pluripotent Stem Cells , Neoplasms , Humans , Cardiotoxicity/etiology , Cardiotoxicity/metabolism , Endothelial Cells , Myocytes, Cardiac , Neoplasms/metabolism
2.
Nat Biotechnol ; 2023 Aug 28.
Article in English | MEDLINE | ID: mdl-37640947
3.
Stem Cell Reports ; 18(8): 1629-1642, 2023 08 08.
Article in English | MEDLINE | ID: mdl-37084724

ABSTRACT

Human induced pluripotent stem cells (iPSCs) are a renewable cell source that can be differentiated into neural progenitor cells (iNPCs) and transduced with glial cell line-derived neurotrophic factor (iNPC-GDNFs). The goal of the current study is to characterize iNPC-GDNFs and test their therapeutic potential and safety. Single-nuclei RNA-seq show iNPC-GDNFs express NPC markers. iNPC-GDNFs delivered into the subretinal space of the Royal College of Surgeons rodent model of retinal degeneration preserve photoreceptors and visual function. Additionally, iNPC-GDNF transplants in the spinal cord of SOD1G93A amyotrophic lateral sclerosis (ALS) rats preserve motor neurons. Finally, iNPC-GDNF transplants in the spinal cord of athymic nude rats survive and produce GDNF for 9 months, with no signs of tumor formation or continual cell proliferation. iNPC-GDNFs survive long-term, are safe, and provide neuroprotection in models of both retinal degeneration and ALS, indicating their potential as a combined cell and gene therapy for various neurodegenerative diseases.


Subject(s)
Amyotrophic Lateral Sclerosis , Induced Pluripotent Stem Cells , Retinal Degeneration , Humans , Rats , Animals , Amyotrophic Lateral Sclerosis/pathology , Induced Pluripotent Stem Cells/pathology , Rodentia , Retinal Degeneration/therapy , Retinal Degeneration/pathology , Glial Cell Line-Derived Neurotrophic Factor/genetics , Astrocytes/pathology , Disease Models, Animal
4.
Arch Orthop Trauma Surg ; 143(7): 4565-4574, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36808564

ABSTRACT

INTRODUCTION: Over the past years, different fixation techniques focused on rotational stability in order to increase stability and stimulate union rates. Additionally, extracorporeal shockwave therapy (ESWT) has gained importance in the treatment of delayed and nonunions. Purpose of this study was to compare the radiological and clinical outcome of two headless compression screws (HCS) and plate fixation in scaphoid nonunions, in combination with intraoperative high energy ESWT. MATERIALS AND METHODS: Thirty-eight patients with scaphoid nonunions were treated by using a nonvascularized bone graft from the iliac crest and stabilization with either two HCS or a volar angular stable scaphoid plate. All patients received one ESWT session with 3000 impulses and energy flux per pulse of 0.41 mJ/mm2 intraoperatively. Clinical assessment included range of motion (ROM), pain according to the Visual Analog Scale (VAS), grip strength, disability of the Arm Shoulder and Hand Score, Patient-Rated Wrist Evaluation Score, Michigan Hand Outcomes Questionnaire and modified Green O'Brien (Mayo) Wrist Score. To confirm union, a CT scan of the wrist was performed. RESULTS: Thirty-two patients returned for clinical and radiological examination. Out of these, 29 (91%) showed bony union. All patients treated with two HCS compared to 16 out of 19 (84%) patients treated by plate showed bony union on the CT scans. The difference was not statistically significant. However, at a mean follow-up interval of 34 months, no significant differences could be found in ROM, pain, grip strength and patient-reported outcome measurements between the two HCS and plate group. Height-to-length ratio and capitolunate angle improved significantly in both groups compared to preoperative. CONCLUSIONS: Scaphoid nonunion stabilization by using two HCS or angular stable volar plate fixation and intraoperative ESWT results in comparable high union rates and good functional outcome. Due to the higher rate for a secondary intervention (plate removal), HCS might be preferable as first choice, whereas the scaphoid plate fixation should be reserved for recalcitrant (substantial bone loss, humpback deformity or failed prior surgical intervention) scaphoid nonunions.


Subject(s)
Extracorporeal Shockwave Therapy , Fractures, Ununited , Scaphoid Bone , Humans , Fractures, Ununited/surgery , Fractures, Ununited/etiology , Fracture Fixation, Internal/methods , Retrospective Studies , Scaphoid Bone/surgery , Bone Screws , Range of Motion, Articular , Treatment Outcome
5.
Neurotoxicol Teratol ; 91: 107077, 2022.
Article in English | MEDLINE | ID: mdl-35189282

ABSTRACT

The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL) and cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both sexes. Few effects related to the treatments were found on DRL or MWM. During cued CRT, Mn (2 and 4 mg/mL) and stress reduced accuracy in males, while stress and Mn (2 mg/mL) increased anticipatory responding and slowed decision time in both sexes. Stress combined with Mn (2 mg/mL) improved cued accuracy and decision time, and Mn attenuated the effect of stress on anticipatory responding in both sexes. Stress slowed female movement time but when combined with Mn (4 mg/mL) the effect of stress was attenuated. During uncued CRT, except for decision time (which replicated effects observed with the cued task), no other effects of Mn or its combination with stress occurred. Females remained negatively affected by stress in most uncued CRT performance measures, while stressed improved male uncued accuracy. Taken together these data do not support increased cognitive impairment produced by Mn when combined with stress. However, the effects of perinatal stress alone, on these cognitive functions may hinder the detection of effects due to chemical exposures and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals.


Subject(s)
Manganese , Prenatal Exposure Delayed Effects , Adolescent , Animals , Attention , Female , Humans , Male , Manganese/toxicity , Maze Learning , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Rats , Reaction Time
6.
iScience ; 24(11): 103238, 2021 Nov 19.
Article in English | MEDLINE | ID: mdl-34746703

ABSTRACT

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 is known to affect the function of microglia, but to what extent this gene drives microglial gene expression has thus far not been examined. Using a transgenic mouse model of AD that expresses human APOE, we identify a unique transcriptional profile associated with APOE4 expression. We also show a sex and APOE interaction, such that both female sex and APOE4 drive expression of this gene profile. We confirm these findings in human cells, using microglia derived from induced pluripotent stem cells (iMGL). Moreover, we find that these interactions are driven in part by genes related to metal processing, and we show that zinc treatment has APOE genotype-dependent effects on iMGL. These data identify a sex- and APOE4-associated microglial transcription profile and highlight the importance of considering interactive risk factors such as sex and environmental exposures.

8.
Adv Exp Med Biol ; 1232: 285-290, 2020.
Article in English | MEDLINE | ID: mdl-31893422

ABSTRACT

In neonatal intensive care units (NICUs), 87.5% of alarms by the monitoring system are false alarms, often caused by the movements of the neonates. Such false alarms are not only stressful for the neonates as well as for their parents and caregivers, but may also lead to longer response times in real critical situations. The aim of this project was to reduce the rates of false alarms by employing machine learning algorithms (MLA), which intelligently analyze data stemming from standard physiological monitoring in combination with cerebral oximetry data (in-house built, OxyPrem). MATERIALS & METHODS: Four popular MLAs were selected to categorize the alarms as false or real: (i) decision tree (DT), (ii) 5-nearest neighbors (5-NN), (iii) naïve Bayes (NB) and (iv) support vector machine (SVM). We acquired and processed monitoring data (median duration (SD): 54.6 (± 6.9) min) of 14 preterm infants (gestational age: 26 6/7 (± 2 5/7) weeks). A hybrid method of filter and wrapper feature selection generated the candidate subset for training these four MLAs. RESULTS: A high specificity of >99% was achieved by all four approaches. DT showed the highest sensitivity (87%). The cerebral oximetry data improved the classification accuracy. DISCUSSION & CONCLUSION: Despite a (as yet) low amount of data for training, the four MLAs achieved an excellent specificity and a promising sensitivity. Presently, the current sensitivity is insufficient since, in the NICU, it is crucial that no real alarms are missed. This will most likely be improved by including more subjects and data in the training of the MLAs, which makes pursuing this approach worthwhile.


Subject(s)
Intensive Care Units, Neonatal , Intensive Care, Neonatal , Machine Learning , Monitoring, Physiologic , Oximetry , Bayes Theorem , Cerebrovascular Circulation , Humans , Infant, Newborn , Infant, Premature , Intensive Care, Neonatal/methods , Monitoring, Physiologic/methods , Oximetry/methods , Oximetry/standards
9.
Commun Biol ; 2: 73, 2019.
Article in English | MEDLINE | ID: mdl-30820468

ABSTRACT

Restoration of cognitive function in old mice by transfer of blood or plasma from young mice has been attributed to reduced C-C motif chemokine ligand 11 (CCL11) and ß2-microglobulin, which are thought to suppress neurogenesis in the aging brain. However, the specific role of the hematopoietic system in this rejuvenation has not been defined and the importance of neurogenesis in old mice is unclear. Here we report that transplantation of young bone marrow to rejuvenate the hematopoietic system preserved cognitive function in old recipient mice, despite irradiation-induced suppression of neurogenesis, and without reducing ß2-microglobulin. Instead, young bone marrow transplantation preserved synaptic connections and reduced microglial activation in the hippocampus. Circulating CCL11 levels were lower in young bone marrow recipients, and CCL11 administration in young mice had the opposite effect, reducing synapses and increasing microglial activation. In conclusion, young blood or bone marrow may represent a future therapeutic strategy for neurodegenerative disease.


Subject(s)
Aging/physiology , Bone Marrow Transplantation/methods , Cognition/physiology , Learning/physiology , Memory/physiology , Rejuvenation/physiology , Age Factors , Animals , Chemokine CCL11/blood , Hippocampus/cytology , Hippocampus/physiology , Male , Mice, Congenic , Mice, Inbred C57BL , Mice, Transgenic , Neurogenesis/physiology , beta 2-Microglobulin/metabolism
10.
Neurobiol Aging ; 73: 145-160, 2019 01.
Article in English | MEDLINE | ID: mdl-30359877

ABSTRACT

Risk for Alzheimer's disease (AD) is affected by multiple factors, including aging, obesity, and low testosterone. We previously showed that obesity and low testosterone independently and interactively exacerbate AD-related outcomes in young adult rodents. The goals of the present study are two-fold: to examine whether the effects of an obesogenic diet differ with increasing age and to determine if testosterone treatment in middle-aged and aged animals mitigates negative effects of the diet. Male brown Norway rats were maintained on control or high-fat diets for 12 weeks beginning in young adulthood, middle age, or advanced age. Separate cohorts of middle-aged and aged animals were treated with testosterone during dietary manipulations. Endpoints included metabolic indices, inflammation, cognitive performance, and neural health outcomes. Aging was associated with poorer outcomes that were generally exacerbated by high-fat diet, especially at middle age. Testosterone treatment was largely without benefit, exerting only subtle effects on a select number of measures. Understanding how the deleterious effects of obesity are affected by advancing age and the ability of protective strategies such as testosterone to reduce these effects may provide significant insight into both the development and prevention of age-related cognitive decline and AD.


Subject(s)
Aging , Alzheimer Disease/etiology , Diet, High-Fat/adverse effects , Obesity/etiology , Testosterone/deficiency , Alzheimer Disease/prevention & control , Animals , Cognition , Inflammation , Male , Rats, Inbred BN , Testosterone/administration & dosage
11.
J Neuroinflammation ; 15(1): 306, 2018 Nov 05.
Article in English | MEDLINE | ID: mdl-30396359

ABSTRACT

BACKGROUND: Obesity exerts negative effects on brain health, including decreased neurogenesis, impaired learning and memory, and increased risk for Alzheimer's disease and related dementias. Because obesity promotes glial activation, chronic neuroinflammation, and neural injury, microglia are implicated in the deleterious effects of obesity. One pathway that is particularly important in mediating the effects of obesity in peripheral tissues is toll-like receptor 4 (TLR4) signaling. The potential contribution of TLR4 pathways in mediating adverse neural outcomes of obesity has not been well addressed. To investigate this possibility, we examined how pharmacological inhibition of TLR4 affects the peripheral and neural outcomes of diet-induced obesity. METHODS: Male C57BL6/J mice were maintained on either a control or high-fat diet for 12 weeks in the presence or absence of the specific TLR4 signaling inhibitor TAK-242. Outcomes examined included metabolic indices, a range of behavioral assessments, microglial activation, systemic and neuroinflammation, and neural health endpoints. RESULTS: Peripherally, TAK-242 treatment was associated with partial inhibition of inflammation in the adipose tissue but exerted no significant effects on body weight, adiposity, and a range of metabolic measures. In the brain, obese mice treated with TAK-242 exhibited a significant reduction in microglial activation, improved levels of neurogenesis, and inhibition of Alzheimer-related amyloidogenic pathways. High-fat diet and TAK-242 were associated with only very modest effects on a range of behavioral measures. CONCLUSIONS: These results demonstrate a significant protective effect of TLR4 inhibition on neural consequences of obesity, findings that further define the role of microglia in obesity-mediated outcomes and identify a strategy for improving brain health in obese individuals.


Subject(s)
Anti-Obesity Agents/therapeutic use , Neurons/pathology , Obesity/drug therapy , Obesity/pathology , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Adiposity/drug effects , Animals , Blood Glucose/drug effects , Body Composition/drug effects , Body Weight/drug effects , Calcium-Binding Proteins/metabolism , Cholesterol/blood , Conditioning, Classical/drug effects , Diet, High-Fat/adverse effects , Disease Models, Animal , Exploratory Behavior/drug effects , Fear/drug effects , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Microfilament Proteins/metabolism , Neurons/drug effects , Neurons/metabolism , Obesity/chemically induced , Triglycerides/blood
12.
eNeuro ; 4(3)2017.
Article in English | MEDLINE | ID: mdl-28612048

ABSTRACT

Alzheimer's disease (AD) risk is modified by both genetic and environmental risk factors, which are believed to interact to cooperatively modify pathogenesis. Although numerous genetic and environmental risk factors for AD have been identified, relatively little is known about potential gene-environment interactions in regulating disease risk. The strongest genetic risk factor for late-onset AD is the ε4 allele of apolipoprotein E (APOE4). An important modifiable risk factor for AD is obesity, which has been shown to increase AD risk in humans and accelerate development of AD-related pathology in rodent models. Potential interactions between APOE4 and obesity are suggested by the literature but have not been thoroughly investigated. In the current study, we evaluated this relationship by studying the effects of diet-induced obesity (DIO) in the EFAD mouse model, which combines familial AD transgenes with human APOE3 or APOE4. Male E3FAD and E4FAD mice were maintained for 12 weeks on either a control diet or a Western diet high in saturated fat and sugars. We observed that metabolic outcomes of DIO were similar in E3FAD and E4FAD mice. Importantly, our data showed a significant interaction between diet and APOE genotype on AD-related outcomes in which Western diet was associated with robust increases in amyloid deposits, ß-amyloid burden, and glial activation in E4FAD but not in E3FAD mice. These findings demonstrate an important gene-environment interaction in an AD mouse model that suggests that AD risk associated with obesity is strongly influenced by APOE genotype.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/pathology , Apolipoprotein E3/genetics , Apolipoprotein E4/genetics , Obesity/physiopathology , Amyloid beta-Peptides/metabolism , Animals , Apolipoprotein E3/metabolism , Apolipoprotein E4/metabolism , Blood Glucose/metabolism , Cholesterol/metabolism , Cytokines/metabolism , Disease Models, Animal , Fatty Acids/adverse effects , Gene Expression Regulation/genetics , Gene-Environment Interaction , Gliosis/chemically induced , Gliosis/genetics , Glucose/adverse effects , Humans , Mice , Mice, Transgenic , Obesity/etiology , RNA, Messenger/metabolism , Risk Factors , Triglycerides/metabolism
13.
Front Neuroendocrinol ; 43: 60-82, 2016 10.
Article in English | MEDLINE | ID: mdl-27651175

ABSTRACT

Alzheimer's disease (AD) is an age-related neurodegenerative disorder for which there are no effective strategies to prevent or slow its progression. Because AD is multifactorial, recent research has focused on understanding interactions among the numerous risk factors and mechanisms underlying the disease. One mechanism through which several risk factors may be acting is inflammation. AD is characterized by chronic inflammation that is observed before clinical onset of dementia. Several genetic and environmental risk factors for AD increase inflammation, including apolipoprotein E4, obesity, and air pollution. Additionally, sex steroid hormones appear to contribute to AD risk, with age-related losses of estrogens in women and androgens in men associated with increased risk. Importantly, sex steroid hormones have anti-inflammatory actions and can interact with several other AD risk factors. This review examines the individual and interactive roles of inflammation and sex steroid hormones in AD, as well as their relationships with the AD risk factors apolipoprotein E4, obesity, and air pollution.


Subject(s)
Alzheimer Disease/immunology , Alzheimer Disease/metabolism , Gonadal Steroid Hormones/immunology , Gonadal Steroid Hormones/metabolism , Inflammation/immunology , Inflammation/metabolism , Animals , Female , Humans , Male
14.
Neurosci Biobehav Rev ; 67: 102-18, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26708713

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, for which a number of genetic, environmental, and lifestyle risk factors have been identified. A significant modifiable risk factor is obesity in mid-life. Interestingly, both obesity and AD exhibit sex differences and are regulated by sex steroid hormones. Accumulating evidence suggests interactions between obesity and sex in regulation of AD risk, although the pathways underlying this relationship are unclear. Inflammation and the E4 allele of apolipoprotein E have been identified as independent risk factors for AD and both interact with obesity and sex steroid hormones. We review the individual and cooperative effects of obesity and sex on development of AD and examine the potential contributions of apolipoprotein E, inflammation, and their interactions to this relationship.


Subject(s)
Alzheimer Disease , Obesity , Apolipoproteins E , Humans , Risk Factors
15.
Neurotoxicol Teratol ; 49: 59-73, 2015.
Article in English | MEDLINE | ID: mdl-25876165

ABSTRACT

Developmental exposure to inhaled ethanol-gasoline fuel blends is a potential public health concern. Here we assessed cognitive functions in adult offspring of pregnant rats that were exposed to vapors of gasoline blended with a range of ethanol concentrations, including gasoline alone (E0) and gasoline with 15% or 85% ethanol (E15 and E85, respectively). Rat dams were exposed for 6.5h daily to the vapors at concentrations of 0, 3000, 6000, or 9000 ppm in inhalation chambers from gestational day (GD) 9 through 20. Cage controls (offspring of non-exposed dams that remained in the animal facility during these exposures) were also assessed in the E0 experiment, but showed no consistent differences from the offspring of air-exposed controls. Offspring were tested as adults with trace fear conditioning, Morris water maze, or appetitive operant responding. With fear conditioning, no significant effects were observed on cue or context learning. In the water maze, there were no differences in place learning or escaping to a visible platform. However, during the reference memory probe (no platform) male rats exposed prenatally to E85 vapor (6000 and 9000 ppm) failed to show a bias for the target quadrant. Across studies, females (treated and some controls) were less consistent in this measure. Males showed no differences during match-to-place learning (platform moved each day) in any experiment and females showed only transient differences in latency and path length in the E0 experiment. Similarly, no differences were observed in delayed match-to-sample operant performance of E0 males or females; thus this test was not used to evaluate effects of E15 or E85 vapors. During choice reaction time assessments (only males were tested) decision and movement times were unimpaired by any prenatal exposure, while anticipatory responses were increased by vapors of E0 (9000 ppm) and E15 (6000 and 9000 ppm), and the latter group also showed reduced accuracy. E85 vapors did not disrupt any choice reaction time measure. Finally, no response inhibition deficit was observed in a differential reinforcement of low rate (DRL) response schedule in males or females in the E15 or E85 experiments. In summary, prenatal exposure to these fuel blends produced few deficits in adult offspring on these cognitive tests. Significant effects found during a water maze probe trial and choice reaction time tests were observed at vapor concentrations of 6000 ppm or higher, a concentration that is 4-6 orders of magnitude higher than those associated with normal automotive fueling operations and garages. Similar effects were not consistently observed in a previous study of inhaled ethanol, and thus these effects cannot be attributed to the concentration of ethanol in the mixture.


Subject(s)
Cognition Disorders/chemically induced , Ethanol/toxicity , Gasoline/toxicity , Prenatal Exposure Delayed Effects/psychology , Administration, Inhalation , Animals , Conditioning, Classical/drug effects , Conditioning, Operant/drug effects , Ethanol/administration & dosage , Fear/drug effects , Female , Male , Maze Learning/drug effects , Pregnancy , Rats , Rats, Long-Evans , Reinforcement Schedule
16.
Neurotoxicol Teratol ; 45: 44-58, 2014.
Article in English | MEDLINE | ID: mdl-25020118

ABSTRACT

Increased use of ethanol blends in gasoline suggests a need to assess the potential public health risks of exposure to these fuels. Ethanol consumed during pregnancy is a teratogen. However, little is known about the potential developmental neurotoxicity of ethanol delivered by inhalation, the most likely route of exposure from gasoline-ethanol fuel blends. We evaluated the potential cognitive consequences of ethanol inhalation by exposing pregnant Long Evans rats to clean air or ethanol vapor from gestational days 9-20, a critical period of neuronal development. Concentrations of inhaled ethanol (5000, 10,000, or 21,000 ppm for 6.5h/day) produced modeled peak blood ethanol concentrations (BECs) in exposed dams of 2.3, 6.8, and 192 mg/dL, respectively. In offspring, no dose-related impairments were observed on spatial learning or working memory in the Morris water maze or in operant delayed match-to-position tests. Two measures showed significant effects in female offspring at all ethanol doses: 1) impaired cue learning after trace fear conditioning, and 2) an absence of bias for the correct quadrant after place training during a reference memory probe in the Morris water maze. In choice reaction time tests, male offspring (females were not tested) from the 5000 and 10,000 ppm groups showed a transient increase in decision times. Also, male offspring from the 21,000 ppm group made more anticipatory responses during a preparatory hold period, suggesting a deficit in response inhibition. The increase in anticipatory responding during the choice reaction time test shows that inhaled ethanol yielding a peak BEC of ~200mg/dL can produce lasting effects in the offspring. The lack of a dose-related decrement in the effects observed in females on cue learning and a reference memory probe may reflect confounding influences in the exposed offspring possibly related to maternal care or altered anxiety levels in females. The surprising lack of more pervasive cognitive deficits, as reported by others at BECs in the 200mg/dL range, may reflect route-dependent differences in the kinetics of ethanol. These data show that response inhibition was impaired in the offspring of pregnant rats that inhaled ethanol at concentrations at least 5 orders of magnitude higher than concentrations observed during normal automotive transport and fueling operations, which rarely exceed 100 ppb.


Subject(s)
Cognition Disorders/chemically induced , Ethanol/toxicity , Prenatal Exposure Delayed Effects , Administration, Inhalation , Animals , Choice Behavior/drug effects , Conditioning, Classical/drug effects , Ethanol/administration & dosage , Female , Male , Maternal Exposure , Pregnancy , Rats , Rats, Long-Evans , Reaction Time/drug effects , Spatial Learning/drug effects
17.
Gesundheitswesen ; 76(3): 172-80, 2014 Mar.
Article in German | MEDLINE | ID: mdl-24566841

ABSTRACT

Personal contextual factors play an essential part in the model of the International Classification of Functioning, Disability and Health (ICF). The WHO has not yet classified personal factors for global use although they impact on the functioning of persons positively or negatively. In 2010, the ICF working group of the German Society of Social Medicine and Prevention (DGSMP) presented a proposal for the classification of personal factors into 72 categories previously arranged in 6 chapters. Now a positioning paper has been added in order to stimulate a discussion about the fourth component of the ICF, to contribute towards a broader and common understanding about the nature of personal factors and to incite a dialogue among all those involved in health care as well as those people with or with-out health problems in order to gain a comprehensive perspective about a person's condition.


Subject(s)
International Classification of Functioning, Disability and Health/classification , International Classification of Functioning, Disability and Health/standards , Patient-Centered Care/standards , Practice Guidelines as Topic , Precision Medicine/standards , Rehabilitation/standards , Social Medicine/standards , Germany , Humans , Internationality
18.
Endocrinology ; 155(4): 1398-406, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24428527

ABSTRACT

The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed "selective androgen receptor modulators" (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues. The efficacy of SARMs in brain is largely unknown. In this study, we investigate the SARM RAD140 in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of endogenous androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases.


Subject(s)
Acetanilides/pharmacology , Kainic Acid/pharmacology , Neurons/metabolism , Animals , Apoptosis , Cell Survival , Cells, Cultured , Female , Hippocampus/metabolism , Hormone Antagonists/pharmacology , Male , Neurodegenerative Diseases/metabolism , Neurons/drug effects , Neuroprotective Agents/pharmacology , Nitriles , Oxadiazoles , Rats , Rats, Sprague-Dawley , Risk , Signal Transduction
20.
Front Behav Neurosci ; 7: 19, 2013.
Article in English | MEDLINE | ID: mdl-23503677

ABSTRACT

Although stress is implicated in the pathophysiology of mood and anxiety disorders, not all individuals who suffer stressful life events develop psychopathology. Differential susceptibility to stress may be influenced by genetically mediated differences in hypothalamic-pituitary-adrenal (HPA) axis activity and moderation of the stress response by the opioid peptide ß-endorphin (ß-E). The present study investigated genetic contributions to coping behavior by examining anxious behavior of transgenic mice with varying capacities to synthesize ß-E [B6.129S2-Pomc (tm1Low) /J; regulated by insertion of a premature stop codon into one or both copies of the proopiomelanocortin (POMC) gene], both under normal conditions and following 3 min of forced swim (FS). Ten minutes after this stress exposure or a control manipulation, acutely food-deprived female and male transgenic mice were subjected to a novelty-suppressed feeding (NSF) test, during which their interaction with an almond slice located in the center of an open field box was measured. There was an interaction between genotype and stress for latency to approach the almond and whether or not the almond was approached, such that mice with low or absent ß-E displayed a stronger aversion to novelty-feeding after stress exposure than did mice with normal levels. These data provide evidence for a moderating effect of ß-E on the behavioral response to stress. Genotypic differences in anxious behavior emerged when mice were stressed prior to behavioral assessment, suggesting that ß-E plays a role in coping behavior. These findings indicate that genetic variability in sensitivity of the ß-E system to stress may contribute, at least in part, to heritable differences in stress reactivity as well as vulnerability to stress-related psychopathology.

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