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J L Collins

Publications and source records attributed to J L Collins.

At least 37 records · Page 2Linked to original sources
PubMed1999

Estimates of mouse oviductal fluid tonicity based on osmotic responses of embryos.

Zygotes and early cleavage-stage embryos are very sensitive to increased osmolality in vitro, although the tonicity of their in vivo environment, oviductal fluid, is unknown. A preference for low osmolality in vitro might imply similar conditions in vivo or be specific to culture. Previous electron probe x-ray microanalysis measurements of total ion content predicted oviductal fluid osmolalities of 310-360 mOs/kg, higher than osmolalities tolerated by mouse zygotes in vitro. However, such indirect estimates may not reflect the tonicity experienced by embryos. We have now used embryos themselves as osmosensors to determine the tonicity of mouse oviductal fluid. In one method, we measured the mean volume of zygotes in undiluted oviductal fluid and compared this to the mean volumes measured for zygotes in media spanning a range of osmolalities. The osmolality corresponding to the measured mean volume in oviductal fluid was taken to be isotonic. In another, independent method, the sizes of zygotes and two-cell embryos were measured as a function of time beginning immediately after removal from oviducts. The osmolality in which the embryos neither swelled nor shrank was taken to be isotonic. Both methods yielded approximately the same range for the tonicity of oviductal fluid: around 290-300 mOs/kg.

Animals↗
PubMed1999

School violence, substance use, and availability of illegal drugs on school property among US high school students.

To determine if school violence is associated with substance use and availability of illegal drugs at school, this study examined data from the 1995 Youth Risk Behavior Survey, a nationally representative sample of 10,904 high school students. Adjusted odds ratios were calculated to describe the associations of tobacco, alcohol, and marijuana use (on and off school property), and availability of illegal drugs at school with five indicators of school violence--weapon-carrying, physical fighting, having property stolen or damaged, being threatened or injured, and being absent from school because of feeling unsafe. School violence indicators increased with the number of substances used and the location of use (on school property vs. off school property). School violence was associated with availability of illegal drugs at school, even among students who did not use substances. These findings suggest a need for coordinated violence and substance use prevention programs for youth in school and community settings.

Adolescent↗
PubMed1998

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents.

We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified as a structurally novel PPARgamma agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chemically labile enaminone moiety in compound 2, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid (9). Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARgamma, affording a series of potent and selective PPARgamma agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(methylpyridin-2-ylamino+ ++)ethoxy ]phenyl¿propionic acid (18), 3-¿4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (20). Compounds 18 and 20 show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addition, these analogues are readily prepared in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARgamma agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.

Administration, Oral↗
PubMed1998

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety.

We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (2) (PPARgamma pKi = 8.94, PPARgamma pEC50 = 9.47) as a potent and selective PPARgamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARgamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-pyridin-4-yloxazol+ ++- 4-yl)ethoxy]phenyl¿propionic acid (16) (PPARgamma pKi = 8.85, PPARgamma pEC50 = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-¿2-[5-methyl-2-(4-methylpiperazin+ ++- 1-yl)thiazol-4-yl]ethoxy¿phenyl)propionic acid (24) (PPARgamma pKi = 8.66, PPARgamma pEC50 = 8.89) provided two potent and selective PPARgamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARgamma ligands (PPARgamma pKi's 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARgamma binding, functional activity, selectivity, and aqueous solubility.

Adipocytes↗
PubMed1998

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent.

3-¿4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-¿4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl¿ ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.

Administration, Oral↗
PubMed1998

Heterotopic neurogenesis in a rat with cortical heterotopia.

Early cellular development was studied in the neocortex of the tish rat. This neurological mutant is seizure-prone and displays cortical heterotopia similar to those observed in certain epileptic patients. The present study demonstrates that a single cortical preplate is formed in a typical superficial position of the developing tish neocortex. In contrast, two cortical plates are formed: one in a normotopic position and a second in a heterotopic position in the intermediate zone. As the normotopic cortical plate is formed, it characteristically separates the subplate cells from the superficial Cajal-Retzius cells. In contrast, the heterotopic cortical plate is not intercalated between the preplate cells because of its deeper position in the developing cortex. Cellular proliferation occurs in two zones of the developing tish cortex. One proliferative zone is located in a typical position in the ventricular/subventricular zone. A second proliferative zone is located in a heterotopic position in the superficial intermediate zone, i.e., between the two cortical plates. This misplaced proliferative zone may contribute cells to both the normotopic and heterotopic cortical plates. Taken together, these findings indicate that misplaced cortical plate cells, but not preplate cells, comprise the heterotopia of the tish cortex. Heterotopic neurogenesis is an early developmental event that is initiated before the migration of most cortical plate cells. It is concluded that misplaced cellular proliferation, in addition to disturbed neuronal migration, can play a key role in the formation of large cortical heterotopia.

Animals↗
PubMed1998

Characteristics of health education among secondary schools--School Health Education Profiles, 1996.

PROBLEM/CONDITION: School health education (e.g., classroom training) is an essential component of school health programs; such education promotes the health of youth and improves overall public health. REPORTING PERIOD: February-May 1996. DESCRIPTION OF SYSTEM: The School Health Education Profiles monitor characteristics of health education in middle or junior high schools and senior high schools. The Profiles are school-based surveys conducted by state and local education agencies. This report summarizes results from 35 state surveys and 13 local surveys conducted among representative samples of school principals and lead health education teachers. The lead health education teacher is the person who coordinates health education policies and programs within a middle or junior high school and senior high school. RESULTS: During the study period, almost all schools in states and cities required health education in grades 6-12; of these, a median of 87.6% of states and 75.8% of cities taught a separate health education course. The median percentage of schools that tried to increase student knowledge on certain topics (i.e., prevention of tobacco use, alcohol and other drug use, pregnancy, human immunodeficiency virus [HIV] infection, other sexually transmitted diseases, violence, or suicide; dietary behaviors and nutrition; and physical activity and fitness) was > 72% for each of these topics. The median percentage of schools that tried to improve certain student skills (i.e., communication, decision making, goal setting, resisting social pressures, nonviolent conflict resolution, stress management, and analysis of media messages) was > 69% for each of these skills. The median percentage of schools that had a health education teacher coordinate health education was 33.0% across states and 26.8% across cities. Almost all schools taught HIV education as part of a required health education course (state median: 94.3%; local median: 98.1%), and more than half (state median: 69.5%; local median: 82.5%) had a written policy on HIV infection among students and school staff. A median of 41.0% of schools across states and a median of 25.8% of schools across cities had a lead health education teacher with professional preparation in health and physical education, and < 25% of schools across states or cities had a lead health education teacher with professional preparation in health education only. Across states, the median percentage of schools, whose lead health education teacher had received in-service training on certain health education topics, ranged from 15.6% for suicide prevention to 51.4% for HIV prevention; across cities, the median percentage ranged from 26.2% for suicide prevention to 76.1% for HIV prevention. A median of 19.7% of schools across states and 18.1% of schools across cities had a school health advisory council. Of the schools that received parental feedback (state median: 59.1%; local median: 54.2%), > 78% reported receiving positive feedback. INTERPRETATION: More than 75% of schools have a required course in health education to help provide students with the knowledge and skills they need to adopt healthy lifestyles. ACTIONS TAKEN: The School Health Education Profiles data are being used by state and local education officials to improve school health education and HIV education.

Adolescent↗
PubMed1998

Youth risk behavior surveillance--United States, 1997.

PROBLEM/CONDITION: Priority health-risk behaviors, which contribute to the leading causes of mortality and morbidity among youth and adults, often are established during youth, extend into adulthood, and are interrelated. REPORTING PERIOD: February-May 1997. DESCRIPTION OF THE SYSTEM: The Youth Risk Behavior Surveillance System (YRBSS) monitors six categories of priority health-risk behaviors among youth and young adults--behaviors that contribute to unintentional and intentional injuries; tobacco use; alcohol and other drug use; sexual behaviors that contribute to unintended pregnancy and sexually transmitted diseases (STDs) (including human immunodeficiency virus [HIV] infection); unhealthy dietary behaviors; and physical inactivity. The YRBSS includes a national school-based survey conducted by CDC as well as state, territorial, and local school-based surveys conducted by education and health agencies. This report summarizes results from the national survey, 33 state surveys, 3 territorial surveys, and 17 local surveys conducted among high school students from February through May 1997. RESULTS AND INTERPRETATION: In the United States, 73% of all deaths among youth and young adults 10-24 years of age result from only four causes: motor vehicle crashes, other unintentional injuries, homicide, and suicide. Results from the national 1997 YRBSS demonstrate that many high school students engage in behaviors that increase their likelihood of death from these four causes--19.3% had rarely or never worn a seat belt; during the 30 days preceding the survey, 36.6% had ridden with a driver who had been drinking alcohol; 18.3% had carried a weapon during the 30 days preceding the survey; 50.8% had drunk alcohol during the 30 days preceding the survey; 26.2% had used marijuana during the 30 days preceding the survey; and 7.7% had attempted suicide during the 12 months preceding the survey. Substantial morbidity among school-age youth, young adults, and their children also result from unintended pregnancies and STDs, including HIV infection. YRBSS results indicate that in 1997, 48.4% of high school students had ever had sexual intercourse; 43.2% of sexually active students had not used a condom at last sexual intercourse; and 2.1% had ever injected an illegal drug. Of all deaths and substantial morbidity among adults > or = 25 years of age, 67% result from two causes--cardiovascular disease and cancer. Most of the risk behaviors associated with these causes of death are initiated during adolescence. In 1997, 36.4% of high school students had smoked cigarettes during the 30 days preceding the survey; 70.7% had not eaten five or more servings of fruits and vegetables during the day preceding the survey; and 72.6% had not attended physical education class daily. ACTIONS TAKEN: These YRBSS data are already being used by health and education officials to improve national, state, and local policies and programs to reduce risks associated with the leading causes of morbidity and mortality. YRBSS data also are being used to measure progress toward achieving 21 national health objectives and 1 of the 8 National Education Goals.

Accidents↗
PubMed1998

N-Phenylamidines as selective inhibitors of human neuronal nitric oxide synthase: structure-activity studies and demonstration of in vivo activity.

Selective inhibition of the neuronal isoform of nitric oxide synthase (NOS) compared to the endothelial and inducible isoforms may be required for treatment of neurological disorders caused by excessive production of nitric oxide. Recently, we described N-(3-(aminomethyl)benzyl)acetamidine (13) as a slow, tight-binding inhibitor, highly selective for human inducible nitric oxide synthase (iNOS). Removal of a single methylene bridge between the amidine nitrogen and phenyl ring to give N-(3-(aminomethyl)phenyl)acetamidine (14) dramatically altered the selectivity to give a neuronal selective nitric oxide synthase (nNOS) inhibitor. Part of this large shift in selectivity was due to 14 being a rapidly reversible inhibitor of iNOS in contrast to the essentially irreversible inhibition of iNOS observed with 13. Structure-activity studies revealed that a basic amine functionality tethered to an aromatic ring and a sterically compact amidine are key pharmacophores for this class of NOS inhibitors. Maximal nNOS inhibition potency was achieved with N-(3-(aminomethyl)phenyl)-2-furanylamidine (77) (Ki-nNOS = 0.006 microM; Ki-eNOS = 0.35 microM; Ki-iNOS = 0.16 microM). Finally, alpha-fluoro-N-(3-(aminomethyl)phenyl)acetamidine (74) (Ki-nNOS = 0. 011 microM; Ki-eNOS = 1.1 microM; Ki-iNOS = 0.48 microM) had excellent brain penetration and inhibited nNOS in a rat brain slice assay as well as in the rat brain (cerebellum) in vivo. Thus, N-phenylamidines should be useful in validating the role of nNOS in neurological disorders.

Amidines↗
PubMed1998

Comparison of TNFalpha and TNFbeta cytolytic mechanisms in human ovarian and cervical carcinoma cell lines.

OBJECTIVES: The aim of this study was to determine the potential and mechanism of tumor necrosis factor beta (TNFbeta) mediated cytolysis in human ovarian and cervical carcinoma cells. METHODS: The cytolytic potential of tumor necrosis factor alpha (TNFalpha) and TNFbeta was determined using the TNF reference cell line L929 and human ovarian (SK-OV-3, CaOV-3) and cervical (SiHa, HT-3) carcinoma cell lines. We have previously reported the effects of the lipoxygenase enzyme inhibitor, nordihydroguaiaretic acid, the oxygen radical scavenger glutathione, and fragmented DNA-specific staining with diamidino-2-phenylindole and ApopTag on TNFalpha-mediated cytolysis in these cells. The effects of these agents on TNFbeta-mediated cytolysis were determined. RESULTS: All of the cell lines express a protein-synthesis-dependent TNFalpha and TNFbeta resistance mechanisms. When protein synthesis is inhibited the cytolytic activity of TNFbeta was fivefold greater than that of TNFalpha in L929 cells. In contrast, the cytolytic activity of TNFalpha was fivefold greater than that of TNFbeta in the human cells. Like the TNFalpha cytolytic mechanism, the TNFbeta cytolytic mechanism is dependent on lipoxygenase enzymes, but not oxygen radicals, and results in apoptosis. CONCLUSIONS: To date there is little information about the cytolytic potential of TNFbeta in human cells. The fact that the cytolytic mechanism of TNFbeta appears very similar to that of TNFalpha could be important to our understanding of the potential of these closely related cytokines in anticancer therapies. Although the cytolytic potential of TNFbeta is greater than that of TNFalpha in mouse cells, this is not true in human cells and could limit the efficacy of TNFbeta in anticancer therapies.

Animals↗
PubMed1998

Weapon-carrying, physical fighting, and fight-related injury among U.S. adolescents.

INTRODUCTION: Access to firearms and other weapons has been cited as an important factor contributing to the rise in violence-related injury among adolescents in the United States. METHODS: Data from the Youth Risk Behavior Survey supplement to the 1992 National Health Interview Survey were analyzed to examine relationships among weapon-carrying, physical fighting, and fight-related injury among U.S. adolescents aged 12-21 years (N = 10,269). Adjusted odds ratios (OR) were used to describe the association of weapon-carrying during the past 30 days with physical fighting and fight-related injury during the past 12 months. RESULTS: Weapon-carrying (15%) and physical fighting (39%) were common among adolescents. One out of 30 (3.3%) adolescents reported receiving medical care for fight-related injuries. Controlling for demographic characteristics, youth who carried weapons were more likely than those who did not to have been in a physical fight (OR = 3.3). The association between weapon-carrying and physical fighting was stronger among females (OR = 5.0) than among males (OR = 2.9), but did not vary significantly by age, race/ethnicity, or place of residence (urban, suburban, rural). Controlling for frequency of physical fighting and demographics, adolescents who carried a handgun (OR = 2.6) or other weapon (OR = 1.6) were more likely than those who did not carry a weapon to have had medical care for fight-related injuries. CONCLUSIONS: Among adolescents, weapon-carrying is associated with increased involvement in physical fighting and a greater likelihood of injury among those who do fight. Efforts to reduce fight-related injuries among youth should stress avoidance of weapon-carrying.

Adolescent↗
PubMed1998

Co-occurrence of health-risk behaviors among adolescents in the United States.

PURPOSE: Although it is common for adolescents to experiment with several health-risk behaviors before reaching adulthood, little is known about the co-occurrence of these behaviors. The purposes of this study were to determine the co-occurrence of specific health-risk behaviors among a nationally representative sample of adolescents, and to examine whether the distribution of multiple risk behaviors varies by age, sex, and school enrollment status. METHODS: This study analyzed survey data from a United States national probability sample (n = 10,645) of youth aged 12-21 years. Survey items measuring current seat belt use, weapon carrying, tobacco, alcohol, and other drug use, and sexual behavior were included in the analysis. RESULTS: The majority of adolescents aged 12-17 years did not engage in multiple health-risk behaviors. However, the prevalence of multiple risk behaviors increased dramatically with age. While only 1 in 12 adolescents aged 12-13 years engaged in two or more of these behaviors, one-third of those aged 14-17 years and half of the college-aged youth (18-21 years) did so. Male respondents and out-of-school youth aged 14-17 years were more likely to engage in multiple health-risk behaviors than were other respondents. CONCLUSIONS: These results suggest that the likelihood that adolescents engage in multiple health-risk behaviors is related to age and that many adolescents engage in these behaviors serially rather than at the same time.

Adolescent↗
PubMed1998

Osmolarity-dependent glycine accumulation indicates a role for glycine as an organic osmolyte in early preimplantation mouse embryos.

Mouse zygotes and early cleavage-stage embryos are sensitive to increased osmolarity. However, development can occur at higher osmolarities if any of a number of organic compounds are present. One of the most effective of these is glycine. We have found that the amount of glycine accumulated by embryos during in vitro culture from the zygote to two-cell stage depends on the osmolarity of the medium, with significantly more glycine accumulated at 310 or 340 mOsM than at 250 mOsM. The accumulated glycine is largely retained in a freely diffusible form, as it can be released via a swelling-activated pathway in two-cell embryos. Increased glycine accumulation does not seem to depend on an increase in its rate of transport. The transport rate is not higher in two-cell embryos that have been cultured from zygotes in hypertonic vs. normal medium, and hypertonicity only slightly stimulates transport in zygotes. Our results indicate that glycine functions as an organic osmolyte in early mouse embryos.

Animals↗
PubMed1998

Youth Risk Behavior Surveillance--United States, 1997. State and Local YRBSS Coordinators.

Priority health-risk behaviors, which contribute to the leading causes of mortality and morbidity among youth and adults, often are established during youth, extend into adulthood, and are interrelated. The Youth Risk Behavior Surveillance System (YRBSS) monitors six categories of priority health-risk behaviors among youth and young adults--behaviors that contribute to unintentional and intentional injuries; tobacco use; alcohol and other drug use; sexual behaviors that contribute to unintended pregnancy and sexually transmitted diseases (STDs) (including human immunodeficiency virus [HIV] infection); unhealthy dietary behaviors; and physical inactivity. The YRBSS includes a national school-based survey conducted by the Centers for Disease Control and Prevention as well as state, territorial, and local school-based surveys conducted by education and health agencies. This report summarizes results from the national survey, 33 state surveys, 3 territorial surveys, and 17 local surveys conducted among high school students from February through May 1997. In the United States, 73% of all deaths among youth and young adults 10-24 years of age result from only four causes: motor vehicle crashes, other unintentional injuries, homicide, and suicide. Results from the national 1997 YRBSS demonstrate that many high school students engage in behaviors that increase their likelihood of death from these four causes--19.3% had rarely or never worn a seat belt; during the 30 days preceding the survey, 36.6% had ridden with a driver who had been drinking alcohol; 18.3% had carried a weapon during the 30 days preceding the survey; 50.8% had drunk alcohol during the 30 days preceding the survey; 26.2% had used marijuana during the 30 days preceding the survey; and 7.7% had attempted suicide during the 12 months preceding the survey. Substantial morbidity among school-age youth, young adults, and their children also result from unintended pregnancies and STDs, including HIV infection. YRBSS results indicate that in 1997, 48.4% of high school students had ever had sexual intercourse; 43.2% of sexually active students had not used a condom at last sexual intercourse; and 2.1% had ever injected an illegal drug. Of all deaths and substantial morbidity among adults greater than or equal to 25 years of age, 67% result from two causes--cardiovascular disease and cancer. Most of the risk behaviors associated with these causes of death are initiated during adolescence. In 1997, 36.4% of high school students had smoked cigarettes during the 30 days preceding the survey; 70.7% had not eaten five or more servings of fruits and vegetables during the day preceding the survey; and 72.6% had not attended physical education class daily. These YRBSS data are already being used by health and education officials to improve national, state, and local policies and programs to reduce risks associated with the leading causes of morbidity and mortality. YRBSS data also are being used to measure progress toward achieving 21 national health objectives and one of the eight National Education Goals.

Accidents↗
PubMed1998

Anticancer activity of glaucarubinone analogues.

A series of glaucarubinone analogues, obtained from natural sources as well as synthesized by us, were studied both in vitro and in vivo. The focus of the in vitro assessment was to define solid tumor-selective compounds by quantitating differential cytotoxic activity between murine and human solid tumor cells and either murine leukemia or normal cells. Subsequent in vivo studies were aimed at determining the therapeutic efficacy of these analogues against the murine models. Structure-activity analysis consequent to both the in vitro and in vivo studies demonstrated that few changes could be made in the parent glaucarubinone structure (outside of the C-15 position) without abrogating either cytotoxicity or potency. However, significant changes could be made at the C-15 position which modified, either enhanced or diminished, in vitro differential cytotoxicity, potency, human solid tumor selectively, and differential cytotoxicity to a MDR-expressing murine mammary tumor.

Animals↗
PubMed1997

A genetic animal model of human neocortical heterotopia associated with seizures.

Malformations of the human neocortex are commonly associated with developmental delays, mental retardation, and epilepsy. This study describes a novel neurologically mutant rat exhibiting a forebrain anomaly resembling the human neuronal migration disorder of double cortex. This mutant displays a telencephalic internal structural heterotopia (tish) that is inherited in an autosomal recessive manner. The bilateral heterotopia is prominent below the frontal and parietal neocortices but is rarely observed in temporal neocortex. Neurons in the heterotopia exhibit neocortical-like morphologies and send typical projections to subcortical sites; however, characteristic lamination and radial orientation are disturbed in the heterotopia. The period of neurogenesis during which cells in the heterotopia are generated is the same as in the normotopic neocortex; however, the cells in the heterotopia exhibit a "rim-to-core" neurogenetic pattern rather than the characteristic "inside-out" pattern observed in normotopic neocortex. Similar to the human syndrome of double cortex, some of the animals with the tish phenotype exhibit spontaneous recurrent electrographic and behavioral seizures. The tish rat is a unique neurological mutant that shares several features with a human cortical malformation associated with epilepsy. On the basis of its regional connectivity, histological composition, and period of neurogenesis, the heterotopic region in the tish rat is neocortical in nature. This neurological mutant represents a novel model system for investigating mechanisms of aberrant neocortical development and is likely to provide insights into the cellular and molecular events contributing to seizure development in dysplastic neocortex.

Animals↗
PubMed1997

Age of initiating selected health-risk behaviors among high school students in the United States.

PURPOSE: To estimate and compare the age of initiation of alcohol use, cigarette smoking, sexual intercourse, and marijuana use among female and male students in U.S. high schools. METHODS: Using data from the 1991 and 1993 national school-based Youth Risk Behavior Surveys, life-table analysis was used to create hypothetical cohorts to estimate age of initiation of selected health-risk behaviors. The sample size was 12,272 in 1991 and 16,296 in 1993, with an overall response rate of 68% in 1991 and 70% in 1993. RESULTS: Male students initiate each of these behaviors earlier than female students, but the pace of initiation for females accelerates so that by age 15 years the cumulative proportion of male and female students who have initiated these behaviors is similar. For both female and male students, the youngest cohort appears to initiate use of alcohol and sexual intercourse at earlier ages than older cohorts. Similarly, the younger cohorts of female students appear to initiate smoking cigarettes and using marijuana at earlier ages than older cohorts. CONCLUSIONS: Many high school students are initiating alcohol use, cigarette smoking, sexual intercourse, and marijuana use at early ages. These data suggest a need for intensive intervention programs by middle/junior high school to motivate and prepare students to avoid these behaviors. Clinicians should begin screening and counseling for risk behaviors in early adolescence.

Adolescent↗