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1.
J Biomech Eng ; 141(12)2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31596923

RESUMO

The purpose of this study was to investigate the relationship between cervical, thoracic, and lumbar spinal alignments in one automotive occupant seated posture. An image dataset of the spinal column in the automotive seated posture, previously acquired by an upright open magnetic resonance imaging (MRI) system, was re-analyzed in this study. Spinal alignments were presented by the geometrical centers of the vertebral bodies extracted from the image data. Cervical, thoracic, and lumbar spinal alignments were analyzed separately with multidimensional scaling (MDS). Based on distribution maps of cervical, thoracic, and lumbar spinal alignments created by MDS, representative spinal alignment patterns of the cervical, thoracic, and lumbar spines and the relationship between cervical, thoracic, and lumbar spinal alignments were investigated. As a result, this study found a correlation between cervical and thoracic spinal alignments in an automotive occupant seated posture. According to representative spinal alignment patterns illustrated by the distribution map of spinal alignments, subjects who had kyphotic cervical spinal alignment tended to have less kyphotic thoracic spinal alignment, while subjects who had lordotic cervical spinal alignment tended to have more kyphotic thoracic spinal alignment. For lumbar spinal alignments, no prominent relationship was found between cervical and thoracic spinal alignment in the seated condition of this study.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31093330

RESUMO

BACKGROUND: Vancomycin is commonly used to treat Enterococcus faecium (E. faecium) bacteremia. However, there are very few studies on the association between the trough concentration, area under the curve from 0 to 24 h /minimum inhibitory concentration (AUC24/MIC) ratio, and the therapeutic effect of vancomycin on E. faecium bacteremia. This study aimed to investigate the associations between vancomycin pharmacokinetic/pharmacodynamic parameters, patient characteristics, and mortality in patients with E. faecium bacteremia. METHODS: This retrospective study included patients with E. faecium bacteremia who received vancomycin between April 2012 and February 2018 at a single acute care hospital in Japan. Patients who received renal replacement therapy (hemodialysis or continuous hemodiafiltration), had an unmeasured serum vancomycin concentration, with unmeasured laboratory values, or received other antibiotics for treating E. faecium bacteremia were excluded from the study. The bivariate associations between 30-day all-cause mortality and patient characteristics were assessed. RESULTS: Among 87 patients diagnosed with E. faecium bacteremia, 45 were included in the final analysis. Of these, 12 (26.7%) died within 30 days of the diagnosis. The vancomycin trough concentration was higher in the 30-day all-cause mortality patients than in the survival patients (20.5 vs. 14.6 µg/mL; P = 0.022). There was no significant difference in the proportion of patients with a vancomycin AUC24/MIC ≤389 between the groups. The 30-day all-cause mortality patients showed a higher Charlson Comorbidity Index (CCI) and Sequential Organ Failure Assessment score at the first measurement of the vancomycin trough concentration than the survival patients. The same finding was observed among patients with a high CCI score (≥5 points). CONCLUSIONS: Whereas the vancomycin trough concentration and AUC24/MIC ratio were not associated with mortality in patients with E. faecium bacteremia, disease severity was associated with mortality in these patients.

3.
BMC Infect Dis ; 17(1): 622, 2017 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-28915895

RESUMO

BACKGROUND: Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene polymorphisms (*6 and *28) in Japanese individuals infected with human immunodeficiency virus (HIV)-1 to examine the relationship between their plasma trough concentration of DTG and gene polymorphisms. Recently, neuropsychiatric adverse events (NP-AEs) after the use of DTG have become a concern, so the association between UGT1A1 gene polymorphisms and selected NP-AEs was also investigated. METHODS: The study subjects were 107 Japanese patients with HIV-1 infections who were receiving DTG. Five symptoms (dizziness, headache, insomnia, restlessness, and anxiety) were selected as NP-AEs. The subjects were classified by their UGT1A1 gene polymorphisms for the group comparison of DTG trough concentration and the presence or absence of NP-AEs. RESULTS: The subjects consisted of eight (7%) *6 homozygotes, three (3%) *28 homozygotes, four (4%) for *6/*28 compound heterozygotes, 23 (21%) *6 heterozygotes, 18 (17%) *28 heterozygotes, and 51 (48%) patients carrying the normal allele. The plasma DTG trough concentration of the *6 homozygous patients was significantly higher than that of the patients carrying the normal allele (median, 1.43 and 0.82 µg/mL, respectively, p = 0.0054). The *6 and *28 heterozygous patients also showed significantly higher values than those shown by patients with the normal allele. Multivariate analysis revealed that carrying one or two UGT1A1*6 gene polymorphisms, one UGT1A1*28 polymorphism, and age of < 40 years were independent factors associated with high DTG trough concentrations. The median DTG trough concentration was significantly higher in the patients with NP-AEs (1.31 µg/mL) than in those without NP-AEs (1.01 µg/mL). Consistent with these results, subjects carrying UGT1A1*6, UGT1A1*28, or both alleles showed a higher cumulative incidence of having selected NP-AEs than those carrying the normal alleles (p = 0.0454). CONCLUSION: In addition to younger age, carrying UGT1A1*6 and/or UGT1A1*28 was demonstrated to be a factor associated with high DTG trough concentrations. Our results also suggest a relationship between plasma DTG trough concentrations and NP-AEs, and that carrying UGT1A1*6 and/or UGT1A1*28 alleles might be a risk factor for NP-AEs.


Assuntos
Glucuronosiltransferase/genética , Infecções por HIV/genética , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/sangue , Polimorfismo Genético , Adulto , Alelos , Ansiedade/induzido quimicamente , Ansiedade/genética , Povo Asiático/genética , Tontura/induzido quimicamente , Tontura/genética , Feminino , Frequência do Gene , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/sangue , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/genética
4.
Pharmacotherapy ; 37(10): e96-e102, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28699652

RESUMO

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are becoming increasingly common worldwide. Although CPE infections can be fatal, few reports in the literature have described effective and successful treatments for infectious diseases caused by several types of IMP CPE, and, to our knowledge, no reports have described the successful treatment of IMP-6 CPE infections. We describe two patients who developed bacteremia caused by IMP-6 CPE after surgery for cancer who were successfully treated with amikacin plus high-dose prolonged-infusion meropenem. Both patients were treated over a 2-week period using amikacin 15 mg/kg at various intervals based on therapeutic drug monitoring and meropenem 2000 mg infused over 3 hours every 12 hours. The dosages of amikacin and meropenem were determined based on the creatinine clearance of each patient. Both patients were cured of their bacteremia and did not experience any antibiotic-related adverse effects. Based on the outcomes of these patients, it appears that amikacin plus high-dose prolonged-infusion meropenem may be safe and effective for the treatment of bacteremia caused by IMP-6 CPE.


Assuntos
Amicacina/uso terapêutico , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Enterobacteriáceas Resistentes a Carbapenêmicos/enzimologia , Infecções por Enterobacteriaceae/tratamento farmacológico , Tienamicinas/uso terapêutico , Idoso , Amicacina/administração & dosagem , Antibacterianos/administração & dosagem , Bacteriemia/microbiologia , Proteínas de Bactérias/biossíntese , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Quimioterapia Combinada , Infecções por Enterobacteriaceae/microbiologia , Humanos , Masculino , Meropeném , Testes de Sensibilidade Microbiana , Tienamicinas/administração & dosagem , Resultado do Tratamento , beta-Lactamases/biossíntese
5.
Traffic Inj Prev ; 18(2): 199-206, 2017 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-27576139

RESUMO

OBJECTIVE: The aim of this study was to investigate the whole spine alignment in automotive seated postures for both genders and the effects of the spinal alignment patterns on cervical vertebral motion in rear impact using a human finite element (FE) model. METHODS: Image data for 8 female and 7 male subjects in a seated posture acquired by an upright open magnetic resonance imaging (MRI) system were utilized. Spinal alignment was determined from the centers of the vertebrae and average spinal alignment patterns for both genders were estimated by multidimensional scaling (MDS). An occupant FE model of female average size (162 cm, 62 kg; the AF 50 size model) was developed by scaling THUMS AF 05. The average spinal alignment pattern for females was implemented in the model, and model validation was made with respect to female volunteer sled test data from rear end impacts. Thereafter, the average spinal alignment pattern for males and representative spinal alignments for all subjects were implemented in the validated female model, and additional FE simulations of the sled test were conducted to investigate effects of spinal alignment patterns on cervical vertebral motion. RESULTS: The estimated average spinal alignment pattern was slight kyphotic, or almost straight cervical and less-kyphotic thoracic spine for the females and lordotic cervical and more pronounced kyphotic thoracic spine for the males. The AF 50 size model with the female average spinal alignment exhibited spine straightening from upper thoracic vertebra level and showed larger intervertebral angular displacements in the cervical spine than the one with the male average spinal alignment. CONCLUSIONS: The cervical spine alignment is continuous with the thoracic spine, and a trend of the relationship between cervical spine and thoracic spinal alignment was shown in this study. Simulation results suggested that variations in thoracic spinal alignment had a potential impact on cervical spine motion as well as cervical spinal alignment in rear end impact condition.


Assuntos
Acidentes de Trânsito/estatística & dados numéricos , Lesões do Pescoço/fisiopatologia , Postura , Coluna Vertebral/fisiopatologia , Traumatismos em Chicotada/fisiopatologia , Adulto , Fenômenos Biomecânicos , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Lesões do Pescoço/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem , Traumatismos em Chicotada/diagnóstico por imagem , Adulto Jovem
6.
Physiol Behav ; 128: 80-5, 2014 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-24524972

RESUMO

Infections have been shown to alter body odor. Because immune activation accompanies both infection and immunization, we tested the hypothesis that classical immunization might similarly result in the alteration of body odors detectable by trained biosensor mice. Using a Y-maze, we trained biosensor mice to distinguish between urine odors from rabies-vaccinated (RV) and unvaccinated control mice. RV-trained mice generalized this training to mice immunized with the equine West Nile virus (WNV) vaccine compared with urine of corresponding controls. These results suggest that there are similarities between body odors of mice immunized with these two vaccines. This conclusion was reinforced when mice could not be trained to directly discriminate between urine odors of RV- versus WNV-treated mice. Next, we trained biosensor mice to discriminate the urine odors of mice treated with lipopolysaccharide (LPS; a general elicitor of innate immunological responses) from the urine of control mice. These LPS-trained biosensors could distinguish between the odors of LPS-treated mouse urine and RV-treated mouse urine. Finally, biosensor mice trained to distinguish between the odors of RV-treated mouse urine and control mouse urine did not generalize this training to discriminate between the odors of LPS-treated mouse urine and control mouse urine. From these experiments, we conclude that: (1) immunization alters urine odor in similar ways for RV and WNV immunizations; and (2) immune activation with LPS also alters urine odor but in ways different from those of RV and WNV.


Assuntos
Lipopolissacarídeos/farmacologia , Odorantes , Vacina Antirrábica/farmacologia , Animais , Discriminação Psicológica , Feminino , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Olfato , Urina
7.
PLoS One ; 8(10): e75411, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24146753

RESUMO

Changes in body odor are known to be a consequence of many diseases. Much of the published work on disease-related and body odor changes has involved parasites and certain cancers. Much less studied have been viral diseases, possibly due to an absence of good animal model systems. Here we studied possible alteration of fecal odors in animals infected with avian influenza viruses (AIV). In a behavioral study, inbred C57BL/6 mice were trained in a standard Y-maze to discriminate odors emanating from feces collected from mallard ducks (Anas platyrhynchos) infected with low-pathogenic avian influenza virus compared to fecal odors from non-infected controls. Mice could discriminate odors from non-infected compared to infected individual ducks on the basis of fecal odors when feces from post-infection periods were paired with feces from pre-infection periods. Prompted by this indication of odor change, fecal samples were subjected to dynamic headspace and solvent extraction analyses employing gas chromatography/mass spectrometry to identify chemical markers indicative of AIV infection. Chemical analyses indicated that AIV infection was associated with a marked increase of acetoin (3-hydroxy-2-butanone) in feces. These experiments demonstrate that information regarding viral infection exists via volatile metabolites present in feces. Further, they suggest that odor changes following virus infection could play a role in regulating behavior of conspecifics exposed to infected individuals.


Assuntos
Acetoína/farmacologia , Patos/virologia , Fezes/química , Vírus da Influenza A Subtipo H5N2/fisiologia , Influenza Aviária/virologia , Odorantes/análise , Acetoína/isolamento & purificação , Animais , Comportamento Animal/efeitos dos fármacos , Fezes/virologia , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Influenza Aviária/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
8.
Physiol Behav ; 120: 211-9, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23958471

RESUMO

Mice release a variety of chemical signals, particularly through urine, which mediate social interactions and endocrine function. Studies have been conducted to investigate the stability of urinary chemosignals in mice. Neuroendocrine and behavioral responses of mice to urine samples of male and female conspecifics which have aged for different amounts of time have been examined, demonstrating that the quality and intensity of signaling molecules in urine change over time. In this study, we monitored changes in volatile organic compounds (VOCs) released from male and female mouse urine following aging the urine samples. Substantial amounts of some VOCs were lost during the aging process of urine, whereas other VOCs increased. Considerable portions of the VOCs which exhibited the increased release were shown to have previously been dissolved in water and subsequently released as the urine dried. We also demonstrated that some VOCs decreased slightly due to their binding with the major urinary proteins (MUPs) and identified MUP ligands whose headspace concentrations increased as the urine aged. Our results underscore the important role of MUPs and the hydration status in the release of VOCs in urine, which may largely account for the changes in the quality and intensity of urinary signals over time.


Assuntos
Envelhecimento/urina , Proteínas/metabolismo , Compostos Orgânicos Voláteis/urina , Água/química , Animais , Interpretação Estatística de Dados , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Desnaturação Proteica , Proteínas/análise , Caracteres Sexuais
9.
Physiol Behav ; 107(1): 112-20, 2012 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-22728785

RESUMO

Two different structural classes of chemical signals in mouse urine, i.e., volatile organic compounds (VOCs) and the major urinary proteins (MUPs), interact closely because MUPs sequester VOCs. Although qualitative and/or quantitative differences in each chemical class have been reported, previous studies have examined only one of the classes at a time. No study has analyzed these two sets simultaneously, and consequently binding interactions between volatile ligands and proteins in urines of different strains have not been compared. Here, we compared the release of VOCs in male urines of three different inbred strains (C57BL/6J, BALB/b and AKR) before and after denaturation of urinary proteins, mainly MUPs. Both MUP and VOC profiles were distinctive in the intact urine of each strain. Upon denaturation, each of the VOC profiles changed due to the release of ligands previously bound to MUPs. The results indicate that large amounts of numerous ligands are bound to MUPs and that these ligands represent a variety of different structural classes of VOCs. Furthermore, the degree of release in each ligand was different in each strain, indicating that different ligands are differentially bound to proteins in the urines of different strains. Therefore, these data suggest that binding interactions in ligands and MUPs differ between strains, adding yet another layer of complexity to chemical communication in mice.


Assuntos
Variação Genética/genética , Proteínas/genética , Proteínas/metabolismo , Compostos Orgânicos Voláteis/metabolismo , Animais , Cromatografia Gasosa-Espectrometria de Massas/métodos , Focalização Isoelétrica , Ligantes , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Análise de Componente Principal , Ligação Proteica/genética , Compostos Orgânicos Voláteis/urina
10.
Biosci Biotechnol Biochem ; 76(4): 679-84, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22484930

RESUMO

Lung cancer is a leading cause of deaths in cancer. Hence, developing early-stage diagnostic tests that are non-invasive, highly sensitive, and specific is crucial. In this study, we investigated to determine whether biomarkers derived from urinary volatile organic compounds (VOCs) can be used to discriminate between lung cancer patients and normal control patients. The VOCs were extracted from the headspace by solid-phase microextraction and were analyzed by gas chromatography time-of-flight mass spectrometry. Nine putative volatile biomarkers were identified as elevated in the lung cancer group. Receiver operating characteristic curve analysis was also performed, and the markers were found to be highly sensitive and specific. Next we used principal component analysis (PCA) modeling to make comparisons compare within the lung cancer group, and found that 2-pentanone may have utility in differentiating between adenocarcinoma and squamous cell carcinomas.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/urina , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pentanonas/urina , Compostos Orgânicos Voláteis/urina , Adenocarcinoma/patologia , Adenocarcinoma/urina , Adenocarcinoma de Pulmão , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/urina , Cromatografia Gasosa , Diagnóstico Diferencial , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/urina , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Curva ROC , Microextração em Fase Sólida , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
11.
Cancer Cell Int ; 12(1): 7, 2012 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-22364569

RESUMO

BACKGROUNDS: A potential strategy for the diagnosis of lung cancer is to exploit the distinct metabolic signature of this disease by way of biomarkers found in different sample types. In this study, we investigated whether specific volatile organic compounds (VOCs) could be detected in the culture medium of the lung cancer cell line A549 in addition to the urine of mice implanted with A549 cells. RESULTS: Several VOCs were found at significantly increased or decreased concentrations in the headspace of the A549 cell culture medium as compared with the culture medium of two normal lung cell lines. We also analyzed the urine of mice implanted with A549 cells and several VOCs were also found to be significantly increased or decreased relative to urine obtained from control mice. It was also revealed that seven VOCs were found at increased concentrations in both sample types. These compounds were found to be dimethyl succinate, 2-pentanone, phenol, 2-methylpyrazine, 2-hexanone, 2-butanone and acetophenone. CONCLUSIONS: Both sample types produce distinct biomarker profiles, and VOCs have potential to distinguish between true- and false-positive screens for lung cancer.

12.
Gan To Kagaku Ryoho ; 38(9): 1477-82, 2011 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-21918342

RESUMO

BACKGROUND: S-1, an oral fluoropyrimidine, is one of the standard chemotherapeutic agents for the treatment of metastatic gastric cancer(MGC). However, the most effective second-line regimen after failure of treatment with first-line agents such as S-1 is yet to be determined. The aim of this study was to investigate the various second-line chemotherapy regimens in MGC patients. METHODS: We retrospectively studied patients with MGC who received second-line treatment after failure of the first-line S-1 or S-1/cisplatin treatment. The overall survival times with each second-line regimen were determined using the Kaplan-Meier method, and the effect on overall survival was analyzed using Cox regression analysis. RESULTS: The median survival time for all patients was 14. 2 months(95% confidence interval(CI): 12. 88-15. 43 months)with a 1-year survival rate of 60. 4%. Kaplan-Meier analysis revealed that the second-line regimens containing irinotecan significantly improved the median survival time as compared to regimens without irinotecan(median survival time: 16. 5 and 13. 8 months, respectively). Cox regression analysis showed that irinotecan-containing regimens were associated with improved overall survival(hazard ratio: 0. 165; 95% CI: 0. 041-0. 665). CONCLUSION: The use of irinotecan-containing regimens as second-line chemotherapy after failure of first-line S-1 therapy may be beneficial for MGC patients.


Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias/tratamento farmacológico , Equipe de Assistência ao Paciente , Farmacêuticos , Institutos de Câncer , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos
13.
Chem Senses ; 36(5): 443-52, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21398415

RESUMO

Mice secrete substantial amounts of protein, particularly proteins called the major urinary proteins (MUPs), in urine. One function of MUPs is to sequester volatile pheromone ligands, thereby delaying their release and providing a stable long-lasting signal. Previously, only MUPs isolated from male mice have been used to identify ligands. Here, we tested the hypothesis that MUPs derived from females may also sequester volatile organic compounds. We identified butylated hydroxytoluene (BHT), a synthetic antioxidant present in the laboratory rodent diet, as a major ligand bound to urinary proteins derived from C57BL/6J female urine. BHT was also bound to the male-derived proteins, but the binding was less prominent than that in female urine, even though males express approximately 4 times more proteins than females. We confirmed that the majority of BHT in female urine was associated with the high molecular weight fraction (>10 kDa) and the majority of the proteins that sequestered BHT were MUPs as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The sequestration of BHT by MUPs was further confirmed by employing the recombinant MUP8 whose natural analogue has been reported in both sexes. Therefore, our data indicate that MUPs expressed in both sexes can bind, transport, and excrete xenobiotics into urine and raise the possibility that in addition to the known role in chemical communication, MUPs function as a defense mechanism against exogenous toxins.


Assuntos
Hidroxitolueno Butilado/química , Hidroxitolueno Butilado/metabolismo , Ligantes , Proteínas/metabolismo , Animais , Eletroforese em Gel de Poliacrilamida , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos Orgânicos Voláteis/química
14.
Proc Biol Sci ; 277(1693): 2417-25, 2010 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-20356897

RESUMO

Mice can discriminate between chemosignals of individuals based solely on genetic differences confined to the major histocompatibility complex (MHC). Two different sets of compounds have been suggested: volatile compounds and non-volatile peptides. Here, we focus on volatiles and review a number of publications that have identified MHC-regulated compounds in inbred laboratory mice. Surprisingly, there is little agreement among different studies as to the identity of these compounds. One recent approach to specifying MHC-regulated compounds is to study volatile urinary profiles in mouse strains with varying MHC types, genetic backgrounds and different diets. An unexpected finding from these studies is that the concentrations of numerous compounds are influenced by interactions among these variables. As a result, only a few compounds can be identified that are consistently regulated by MHC variation alone. Nevertheless, since trained animals are readily able to discriminate the MHC differences, it is apparent that chemical studies are somehow missing important information underlying mouse recognition of MHC odourtypes. To make progress in this area, we propose a focus on the search for behaviourally relevant odourants rather than a random search for volatiles that are regulated by MHC variation. Furthermore, there is a need to consider a 'combinatorial odour recognition' code whereby patterns of volatile metabolites (the basis for odours) specify MHC odourtypes.


Assuntos
Variação Genética , Complexo Principal de Histocompatibilidade/genética , Odorantes , Feromônios/química , Comunicação Animal , Animais , Dieta , Discriminação Psicológica , Camundongos , Camundongos Endogâmicos , Volatilização
15.
PLoS One ; 5(1): e8819, 2010 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-20111698

RESUMO

A potential strategy for diagnosing lung cancer, the leading cause of cancer-related death, is to identify metabolic signatures (biomarkers) of the disease. Although data supports the hypothesis that volatile compounds can be detected in the breath of lung cancer patients by the sense of smell or through bioanalytical techniques, analysis of breath samples is cumbersome and technically challenging, thus limiting its applicability. The hypothesis explored here is that variations in small molecular weight volatile organic compounds ("odorants") in urine could be used as biomarkers for lung cancer. To demonstrate the presence and chemical structures of volatile biomarkers, we studied mouse olfactory-guided behavior and metabolomics of volatile constituents of urine. Sensor mice could be trained to discriminate between odors of mice with and without experimental tumors demonstrating that volatile odorants are sufficient to identify tumor-bearing mice. Consistent with this result, chemical analyses of urinary volatiles demonstrated that the amounts of several compounds were dramatically different between tumor and control mice. Using principal component analysis and supervised machine-learning, we accurately discriminated between tumor and control groups, a result that was cross validated with novel test groups. Although there were shared differences between experimental and control animals in the two tumor models, we also found chemical differences between these models, demonstrating tumor-based specificity. The success of these studies provides a novel proof-of-principle demonstration of lung tumor diagnosis through urinary volatile odorants. This work should provide an impetus for similar searches for volatile diagnostic biomarkers in the urine of human lung cancer patients.


Assuntos
Biomarcadores Tumorais/urina , Modelos Animais de Doenças , Neoplasias Pulmonares/urina , Odorantes , Animais , Comportamento Animal , Biomarcadores Tumorais/química , Camundongos , Olfato , Volatilização
16.
Physiol Behav ; 96(1): 184-8, 2009 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-18957300

RESUMO

Major histocompatibility complex (MHC) genes influence urinary odors (odortypes) of mice. That volatile odorants are involved is supported by the observation that odortype identity can be detected from a distance. Furthermore, chemical analyses of urines have revealed numerous volatile odorants that differ in relative abundance between mice that differ only in MHC genotypes. In addition, urines from MHC-different mice evoke distinct odor-induced activity maps in the main olfactory bulbs. However, recent studies report that non-volatile MHC class I peptides may directly act as MHC-associated signals and may thereby be seen to call into question the evidence for a volatile MHC signal. To evaluate this question, we designed a procedure to collect peptide-free urinary volatiles and tested these volatiles for their ability to mediate chemosensory discrimination of MHC-congenic mice differing in their MHC genotype. The headspace volatiles from urines of C57BL/6 congenic mice (haplotypes H2(b) and H2(k)) were collected by solid phase microextraction (SPME). These volatiles were then desorbed into a gas chromatograph (GC) and the entire chromatographic eluate was collected into a buffer solution. Our results conclusively demonstrate that mice trained to discriminate between unadulterated urinary signals of the congenic mice generalize the discrimination, without reward or training, to the buffer solution containing the peptide-free urinary volatiles (p<0.001, binomial test). Thus volatile signals, perhaps along with non-volatile ones, are capable of mediating behavioral discriminations of mice of different MHC genotypes.


Assuntos
Complexo Principal de Histocompatibilidade/genética , Odorantes , Percepção Olfatória/genética , Olfato/genética , Animais , Comportamento Animal , Cromatografia Gasosa , Discriminação Psicológica/fisiologia , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Urina/química , Volatilização
17.
PLoS One ; 3(10): e3591, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18974891

RESUMO

Individual mice have a unique odor, or odortype, that facilitates individual recognition. Odortypes, like other phenotypes, can be influenced by genetic and environmental variation. The genetic influence derives in part from genes of the major histocompatibility complex (MHC). A major environmental influence is diet, which could obscure the genetic contribution to odortype. Because odortype stability is a prerequisite for individual recognition under normal behavioral conditions, we investigated whether MHC-determined urinary odortypes of inbred mice can be identified in the face of large diet-induced variation. Mice trained to discriminate urines from panels of mice that differed both in diet and MHC type found the diet odor more salient in generalization trials. Nevertheless, when mice were trained to discriminate mice with only MHC differences (but on the same diet), they recognized the MHC difference when tested with urines from mice on a different diet. This indicates that MHC odor profiles remain despite large dietary variation. Chemical analyses of urinary volatile organic compounds (VOCs) extracted by solid phase microextraction (SPME) and analyzed by gas chromatography/mass spectrometry (GC/MS) are consistent with this inference. Although diet influenced VOC variation more than MHC, with algorithmic training (supervised classification) MHC types could be accurately discriminated across different diets. Thus, although there are clear diet effects on urinary volatile profiles, they do not obscure MHC effects.


Assuntos
Comportamento Alimentar/fisiologia , Perfilação da Expressão Gênica , Percepção Olfatória/genética , Olfato/genética , Ração Animal/análise , Animais , Dieta , Feminino , Complexo Principal de Histocompatibilidade/genética , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Odorantes , Urina/química , Volatilização
19.
Biosci Biotechnol Biochem ; 72(5): 1249-56, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18460805

RESUMO

We had previously found that male mice could be trained to discriminate between the urine odor of aged and young adult (adult) mice. We hypothesized that these odors that characterized the older animals might be inhibited by a mixture of extracts (AAM) of mugwort and mushroom, because previous studies have indicated that these extracts could be used to reduce the intensity of unpleasant body odors. The findings of this chemical study strongly suggest that the AAM function helped to modify the aged mouse urine odor so that it more closely resembled the smell of urine from younger mice. Based on the results of the chemical studies, a set of behavioral experiments were therefore conducted. The results of three sets of generalization trials also strongly supported the results of the chemical studies. Together, these results suggest that ingested AAM decreased the intensity of odors associated with aging in mice.


Assuntos
Agaricales/química , Envelhecimento , Artemisia/química , Misturas Complexas/farmacologia , Odorantes , Extratos Vegetais/farmacologia , Urina/química , Administração Oral , Animais , Ciências do Comportamento , Misturas Complexas/administração & dosagem , Misturas Complexas/química , Ionização de Chama , Cromatografia Gasosa-Espectrometria de Massas , Camundongos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química
20.
Adv Genet ; 59: 129-45, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17888797

RESUMO

Genes in the major histocompatibility complex (MHC), best known for their role in immune recognition and transplantation success, are also involved in modulating mate choice in mice. Early studies with inbred, congenic mouse lines showed that mate choice tended to favor nonself MHC types. A similar phenomenon was demonstrated with semi-wild mice as well. Subsequent studies showed that, rather than nonself choices, it was more accurate to say that mice chose nonparental MHC types for mates since preferences for nonself could be reversed if mice were fostered from birth on parents with nonself MHC types. Other studies have demonstrated that parent-offspring recognition is also regulated by MHC-determined signals suggesting that this system is one of general importance for mouse behavior. Many studies have now demonstrated that volatile mouse body odors are regulated by MHC genes and it is presumably these odor differences that underlie mate choice and familial recognition. Recent studies have shown that many odorants are controlled by the MHC but the mechanism by which MHC genes exert their influence has not been identified. Surprisingly, not only are volatile body odors influenced by MHC genes but so too are nonvolatile signals. Peptides bound to the MHC protein may also function in individual recognition. The extent to which this system is involved in mate choice of other species is unclear although there are some suggestive studies. Indeed, there is tentative evidence that MHC differences, presumably acting via odor changes, may influence human partner selection. Further studies should clarify both the mechanism underlying MHC influence on body odors as well as the generality of their importance in mate selection.


Assuntos
Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Caracteres Sexuais , Comportamento Sexual Animal , Comunicação Animal , Animais , Comportamento de Escolha , Feminino , Antígenos HLA/metabolismo , Humanos , Masculino , Camundongos , Camundongos Congênicos , Modelos Genéticos , Odorantes , Gravidez
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