Amino acid/spermine conjugates: polyamine amides as potent spermidine uptake inhibitors.

In this paper we describe the synthesis and characterization of a series of simple spermine/amino acid conjugates, some of which potently inhibit the uptake of spermidine into MDA-MB-231 breast cancer cells. The presence of an amide in the functionalized polyamine appeared to add to the affinity for the polyamine transporter. The extensive biological characterization of an especially potent analogue from this series, the Lys-Spm conjugate (31), showed this molecule will be an extremely useful tool for use in polyamine research. It was shown that the use of 31 in combination with DFMO led to a cytostatic growth inhibition of a variety of cancer cells, even when used in the presence of an extracellular source of transportable spermidine. It was furthermore shown that this combination effectively reduced the cellular levels of putrescine and spermidine while not affecting the levels of spermine. These facts together with the nontoxic nature of 31 make it a novel lead for further anticancer development.

Ocular penetration of N-formimidoyl thienamycin (MK-787) and potentiation by dipeptidase inhibitor (MK-791).

N-formimidoyl thienamycin (MK-787) is a new beta-lactam with potent activity against both aerobic and anaerobic gram-positive and gram-negative bacteria. Its spectrum and activity suggest it may be useful in treatment of complicated intraocular infections. Its ocular penetration was studied in New Zealand white rabbits immediately before and after the third dose of 40 mg/kg administered intravenously at q6h intervals. Plasma, aqueous humor, and vitreous humor were obtained by direct aspiration, and antibiotic levels were assayed using an agar well diffusion method. MK-787 penetrated uninflamed intraocular fluids, including vitreous humor, although vitreous concentrations achieved (0.1-0.2 micrograms/ml) were significantly lower than the mean peak plasma (15 micrograms/ml) and aqueous concentrations (7 micrograms/ml). Nevertheless, the intraocular levels attained approached or exceeded the MIC90 for most sensitive organisms including some gram-negative bacilli important in bacterial endophthalmitis. When administered in combination with the renal enzyme inhibitor MK-791, plasma and aqueous concentrations of MK-787 were markedly potentiated, although vitreous concentrations were minimally affected. The potential usefulness of MK-787 in conjunction with MK-791 in the infected eye should be examined further in an animal model of bacterial endophthalmitis.

Patient satisfaction and discussion of smoking cessation during clinical visits.

OBJECTIVE: To learn whether patients who smoke and who receive smoking cessation information during medical office visits were less likely to be satisfied with the smoking cessation help they received than patients who smoke but who did not receive such information. PATIENTS AND METHODS: A total of 3703 current cigarette smokers were identified by a mailing in November 1998 to 163,596 members of 2 Minnesota health plans, and 2714 (77.3%) responses to a 44-item questionnaire were available for analysis. Using hierarchical analysis to control confounding variables, we assessed the relationship between patient-reported smoking cessation support actions at the last physician visit and satisfaction "with the help received from your doctor about quitting smoking." RESULTS: Smokers were very satisfied (12.0%), satisfied (25.3%), neutral (48.6%), and dissatisfied or very dissatisfied (13.5%) with physician help. After controlling for other characteristics, the 1898 patients who reported that they had been asked about tobacco use or advised to quit during the latest visit had 10 percentage point greater satisfaction ratings and 5 percentage point less dissatisfaction than those not reporting such discussions (P<.001). Smokers reporting no interest in quitting at the time of the latest visit also demonstrated greater satisfaction in association with these actions. CONCLUSION: Smoking cessation interventions during physician visits were associated with increased patient satisfaction with their care among those who smoke. This information should reduce concerns of physicians or nurses about providing tobacco cessation assistance to patients during office visits.

Liver AMP-activated protein kinase and acetyl-CoA carboxylase during and after exercise.

Exercise induces a decline in liver malonyl-CoA, an inhibitor of carnitine palmitoyltransferase-1. The purpose of these experiments was to determine whether this decrease in malonyl-CoA is accompanied by an activation of AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase (ACC). Rats were killed at rest, after 10 min of running at 32 m/min up a 15% grade or at 0, 15, or 60 min postexercise after 120 min of running at 16 m/min. There was no significant difference in AMPK and ACC activities after 120 min of exercise, although a trend toward a decrease in ACC and an increase in AMPK was noted 15 min postexercise. After 10 min at 32 m/min, however, maximal ACC activity decreased from 487 +/- 27 to 280 +/- 39 nmol. g-1. min-1, and the activation constant for citrate activation of ACC increased from 5.9 to 12.5 mM. AMPK activity increased from a resting value of 4.7 +/- 0.4 to 9.8 +/- 2.0 pmol. mg-1. min-1 after exercise. These data provide indirect evidence of phosphorylation and inactivation of liver ACC during heavy exercise. In contrast, the decrease in malonyl-CoA during long-term, low-intensity exercise may occur by mechanisms other than phosphorylation of ACC.

Attenuation of skeletal muscle and strength in the elderly: The Health ABC Study.

Although loss of muscle mass is considered a cause of diminished muscle strength with aging, little is known regarding whether composition of aging muscle affects strength. The skeletal muscle attenuation coefficient, as determined by computed tomography, is a noninvasive measure of muscle density, and lower values reflect increased muscle lipid content. This investigation examined the hypothesis that lower values for muscle attenuation are associated with lower voluntary isokinetic knee extensor strength at 60 degrees/s in 2,627 men and women aged 70-79 yr participating in baseline studies of the Health ABC Study, a longitudinal study of health, aging, and body composition. Strength was higher in men than in women (132.3 +/- 34.5 vs. 81.4 +/- 22.0 N x m, P < 0.01). Men had greater muscle attenuation values (37.3 +/- 6.5 vs. 34.7 +/- 7.0 Hounsfield units) and muscle cross-sectional area (CSA) at the midthigh than women (132.7 +/- 22.4 vs. 93.3 +/- 17.5 cm(2), P < 0.01 for both). The strength per muscle CSA (specific force) was also higher in men (1.00 +/- 0.21 vs. 0.88 +/- 0.21 N x m x cm(-2)). The attenuation coefficient was significantly lower for hamstrings than for quadriceps (28.7 +/- 8.7 vs. 41.1 +/- 6.9 Hounsfield units, P < 0.01). Midthigh muscle attenuation values were lowest (P < 0.01) in the eldest men and women and were negatively associated with total body fat (r = -0.53, P < 0.01). Higher muscle attenuation values were also associated with greater specific force production (r = 0.26, P < 0.01). Multivariate regression analysis revealed that the attenuation coefficient of muscle was independently associated with muscle strength after adjustment for muscle CSA and midthigh adipose tissue in men and women. These results demonstrate that the attenuation values of muscle on computed tomography in older persons can account for differences in muscle strength not attributed to muscle quantity.

Gender differences in ADHD: a meta-analysis and critical review.

OBJECTIVE: To quantitatively review and critically evaluate literature examining gender differences in attention-deficit hyperactivity disorder (ADHD). METHOD: A meta-analysis of relevant research based on 18 studies meeting inclusion criteria was performed. Domains evaluated included primary symptomatology, intellectual and academic functioning, comorbid behavior problems, social behavior, and family variables. RESULTS: Gender differences were not found in impulsivity, academic performance, social functioning fine motor skills, parental education, or parental depression. However, compared with ADHD boys, ADHD girls displayed greater intellectual impairment, lower levels of hyperactivity, and lower rates of other externalizing behaviors; it was not possible to evaluate the extent to which referral bias affected these findings. Some gender differences were clearly mediated by the effects of referral source; among children with ADHD identified from nonreferred populations, girls with ADHD displayed lower levels of inattention, internalizing behavior, and peer aggression than boys with ADHD, while girls and boys with ADHD identified from clinic-referred samples displayed similar levels of impairment on these variables. CONCLUSIONS: The need for future research examining gender differences in ADHD is strongly indicated, with attention to methodological limitations of the current literature, including the potential confounding effects of referral bias, comorbidity, developmental patterns, diagnostic procedures, and rater source.

Gender differences in children with ADHD, ODD, and co-occurring ADHD/ODD identified in a school population.

OBJECTIVE: To examine gender differences among children with disruptive behavior disorders (DBDs) from an ethnically diverse school sample. METHOD: From 2,984 children, children with attention-deficit/hyperactivity disorder, combined type (ADHD-C) (46 boys, 11 girls), oppositional defiant disorder (ODD) (59 boys, 35 girls), and co-occurring ADHD-C/ODD (76 boys, 27 girls), diagnosed by teacher-rated DSM-IV symptoms, were compared with each other and with 254 controls on teacher ratings of symptoms, social functioning and Achenbach Teacher's Report Form scales. RESULTS: Children with ADHD-C/ODD received the poorest ratings on all variables. In "pure" groups, children with ODD were rated as learning more, working harder, and being less inattentive than children with ADHD-C; only the ODD group showed more internalizing problems than controls. For ADHD-C and ODD groups, ratings of aggression and some individual symptoms were higher in boys than girls. Girls with ODD were rated as more appropriate and less inattentive, but unhappier and more socially impaired than boys with ODD. Overall, girls received higher peer dislike scores than boys. CONCLUSIONS: Comorbidity and gender issues affect the correlates of DBDs, with learning problems higher in ADHD-C, internalizing problems associated only with ODD, and greatest impairment for ADHD-C/ODD groups. Despite having similar or less behavioral dysfunction, girls with DBDs may have more social problems than boys with DBDs.

Do men become infertile after having sexually transmitted urethritis? An epidemiologic examination.

OBJECTIVE: To critically assess the possibility that gonorrhea or chlamydia causes male infertility. DESIGN: Comprehensive literature review structured to evaluate the epidemiologic tenets for causality, including biologic plausibility, strength of association, dose response, consistency, temporality, and treatment effect. RESULT(S): It is biologically plausible that gonorrhea and/or chlamydia could cause male infertility. There is clinical and pathologic evidence linking these pathogens to urethritis, linking urethritis to epididymo-orchitis, and linking epididymo-orchitis to infertility. Retrospective epidemiologic results also support an association between chlamydia serologies and male infertility, which in most of these small studies does not reach the level of statistical significance. However, there is no consistent epidemiologic evidence that these pathogens alter sperm characteristics. We discuss the methodologic limitations of previous epidemiologic studies and suggest strategies for future research. CONCLUSION(S): Whether gonorrhea and/or chlamydia cause male infertility is currently unclear. Sound methodologic research strategies must be applied to future studies.

Developmental neurotoxicity of polybrominated biphenyls.

Female F0 generation Sprague-Dawley rats received daily oral doses of 0, 0.2, or 2 mg/kg polybrominated biphenyls (PBB) as fireMaster BP-6 from Day 6 of gestation through Day 24 postpartum. Maternal parameters were assessed, and F1 generation offspring were evaluated for growth and survival, as well as physical and behavioral development. No adverse maternal effects were observed nor were there PBB-related effects on survival of the F1 generation or acquisition of developmental landmarks. Crown-rump length of 0.2 and 2 mg/kg male offspring was significantly less than that of controls and 2 mg/kg male and female offspring gained significantly less weight than did controls for the entire 60-day postnatal observation period. An overall evaluation of behavior by multivariate analysis of variance revealed significant PBB-related effects for acquisition of forward locomotion, cliff avoidance, cage emergence, and open-field activity of male and female offspring from dams administered 2 mg/kg. Delays in acquisition of forward locomotion and suppressed open-field activity were the most prominent effects. These indications of growth retardation and neurobehavioral toxicity occurred at concentrations of PBB in offspring body fat in the range of those which have been reported for highly exposed human subjects with neurological sequelae.

Behavioral characteristics of DSM-IV ADHD subtypes in a school-based population.

From an ethnically diverse sample of 2,744 school children, 221 attention deficit hyperactivity disorder (ADHD) [123 (4.5%) predominantly inattentive (IA), 47 (1.7%) predominantly hyperactive/impulsive (HI), and 51 (19%) combined type (C)] were identified using teacher ratings on a Diagnostic and Statistical Manual of Mental Disorders (4th ed.)(DSM-IV) symptom checklist. Subjects were compared to 221 controls on teacher ratings of behavioral, academic, and social functioning. The results revealed relatively independent areas of impairment for each diagnostic group. The IA children were impaired in all areas, but were rated as displaying more appropriate behavior and fewer externalizing problems than HI or C children. The HI group displayed externalizing and social problems, but was rated as no different than controls in learning or internalizing problems. The C group demonstrated severe and pervasive difficulties across domains. These findings support the validity of the DSM-IV ADHD subtypes; all ADHD groups demonstrated impairment relative to controls, but show different patterns of behavioral characteristics.

Peer assessment of the social behavior of accepted, rejected, and neglected children.

Positive and negative sociometric nominations were used with second and fifth-grade children to select 26 socially accepted, 32 rejected, and 28 neglected children. A total of 358 of their classmates evaluated these children by indicating whether each of 19 descriptions of social behavior was characteristic of each child. Rejected children were perceived by their peers as being more aggressive, disruptive, irritable, domineering , dishonest , and selfish than accepted and/or neglected children. Neglected children, in contrast, differed from accepted children only in being less likely to brag about physical prowess . While the low sociometric status of rejected children appears to be related to the negative impact of their behavior on peers, this does not appear to be the case for neglected children. Females were generally perceived as behaving more positively with peers, but no interactions were found between sex and sociometric status. In general, the test-retest reliability of peer evaluation items was higher for fifth- than for second-grade children, but significant grade by sociometric status interactions were found for only two items.

Effects of methylphenidate on the persistence of ADHD boys following failure experiences.

We examined the effects of methylphenidate on the task persistence of 21 boys with attention-deficit hyperactivity disorder (ADHD), after they had been exposed to both solvable and insolvable problems. The boys attempted to solve 10 different find-a-word puzzles on each of 4 days, involving the crossing of medication (placebo vs. 0.3 mg/kg) and prior task difficulty (solvable vs. insolvable). The results revealed that medication prevented the decrement in performance following the insolvable problems that was evident with the placebo days. In addition, on medication compared with placebo, the boys were more likely to make external attributions for failure and internal attributions for success. The results are discussed in terms of the impact of medication on ADHD boys' performance as mediated by cognitive-motivational state mechanisms.

Single and combined effects of methylphenidate and behavior therapy on the classroom performance of children with attention-deficit hyperactivity disorder.

Twenty-four boys with attention deficit-hyperactivity disorder (ADHD) participating in an intensive summer treatment program each received b.i.d. placebo and two doses of methylphenidate (MPH, 0.3 mg/kg and 0.6 mg/kg) crossed with two classroom settings: a behavior modification classroom including a token economy system, time out and daily home report card, and a "regular" classroom setting not using these procedures. Dependent variables included classroom observations of on-task and disruptive behavior, academic work completion and accuracy, and daily self-ratings of performance. Both MPH and behavior modification alone significantly improved children's classroom behavior, but only MPH improved children's academic productivity and accuracy. Singly, behavior therapy and 0.3 mg/kg PMH produced roughly equivalent improvements in classroom behavior. Further, the combination of behavior therapy and 0.3 mg/kg MPH resulted in maximal behavioral improvements, which were nearly identical to those obtained with 0.6 mg/kg MPH alone.

Sociometric status of clinic-referred children with attention deficit disorders with and without hyperactivity.

Peer sociometric nominations of clinic-referred children given the diagnosis of Attention) Deficit Disorder with Hyperactivity (ADD/H) or Attention Deficit Disorder without Hyperactivity (ADD/WO) were compared to one another and to those of normal control children. Only children with ADD diagnoses in the absence of other major diagnoses were included. Both children with ADD/H (n = 16) and ADD/WO (n = 11) received significantly fewer "liked most" nominations, more "liked least" nominations, and lower social preference scores than normal control (n = 45) children. These results confirm previous findings of social deficits in children with ADD/H, even when codiagnoses are excluded. In addition, they support the validity of the diagnostic category of ADD/WO by demonstrating that the ADD/WO behavior pattern is apparently "psychopathological" in being associated with peer unpopularity after codiagnoses are excluded. When larger groups including all codiagnoses (primarily Conduct Disorder) of children with ADD/H (n = 36) and ADD/WO (n = 20) were compared, identical patterns of peer unpopularity were found, except that children with ADD/H also were significantly more likely to be nominated as a child who "fights most."

Attention-deficit/hyperactivity disorder, predominantly inattentive subtype.

This article reviews research on the DSM-IV attention deficit/hyperactivity disorder inattentive (ADHD/IA) subtype. Data examining demographic characteristics, comorbidity, social functioning, and cognitive/attentional components are presented. Children with ADHD/IA show different patterns of demographic characteristics and comorbid symptomatology than those with ADHD/C, with suggestive evidence that they may differ in attentional style, as well. The implications of these results for treatment planning are discussed, along with suggestions that future research further examine attentional components, mechanisms contributing to impairment domains, and the role of sluggish cognitive tempo.

HIV-related services for persons with severe mental illness: policy and practice in New Hampshire community mental health.

Rates of HIV and HIV risk behaviors are elevated among people with severe mental illnesses (SMI). Little is known about the extent to which community mental health (CMH) centers screen, refer, and educate their clients regarding HIV and sexually transmitted diseases (STDs). The authors surveyed CMH administrators and clinicians in New Hampshire regarding HIV/STD policy, practices, knowledge, and attitudes. HIV/STD service availability varied, and the amount of services provided was unrelated to the prevalence of HIV and AIDS in that region. Clinicians were knowledgeable about general HIV information but lacked specific knowledge about HIV related to persons with SMI. CMH staff had positive attitudes about helping clients with HIV issues. Administrators were interested in receiving training. Policy leadership, CMH practice guidelines, and training are warranted in light of the pressing public health implications of HIV/STDs among people with SMI.

Differences in heterosocial behavior and outcomes of ADHD-symptomatic subtypes in a college sample.

The purpose of this study was to explore heterosocial relational outcomes in a college-aged sample showing symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). Using questionnaires and a behavioral observation task, dating, sexual, and social outcomes were examined in three groups: 24 non-ADHD controls, 27 ADHD-Combined (ADHD/C) Type, and 13 ADHD-Primarily Inattentive (ADHD/IA) Type. The ADHD/IA group showed a consistent pattern of passivity and inexperience and was perceived relatively negatively by female confederates, whereas the ADHD/C group reported increased sexual drive and early dating experience. The effects of externalizing comorbidity differed by DSM-IV ADHD subtype. These findings indicate that ADHD-symptomatic adults differ by DSM-IV subtype in the manifestation of heterosocial deficits. Results suggest specific and divergent types of psychosocial intervention with ADHD/C versus ADHD/IA clients.

Validity of the diagnostic category of attention deficit disorder without hyperactivity: a review of the literature.

The validity of the diagnostic category of Attention Deficit Disorder Without Hyperactivity (ADD/WO) has been the subject of debate since it was first introduced in DSM-III. The differentiation of two syndromes of ADD is supported by factor analytic studies that indicate two dimensions of maladjustment: (1) inattention and disorganization, and (2) motor hyperactivity and impulsive responding. Cluster analyses of these two dimensions have yielded two profiles of deviance that correspond to the DSM-III subtypes. Furthermore, clinic-referred children who meet DSM-III criteria for ADD/WO have been shown to exhibit less serious conduct problems, are less impulsive, are more likely to be characterized as sluggish and drowsy, are less rejected by peers but more socially withdrawn, and are more likely to exhibit depressed mood and symptoms of anxiety disorder than children with Attention Deficit Disorder with Hyperactivity (ADD/H).

Social functioning and emotional regulation in the attention deficit hyperactivity disorder subtypes.

Compared 16 children with attention deficit hyperactivity disorder (ADHD) combined type (ADHD-C), 14 children with ADHD predominantly inattentive type (ADHD-I), and 17 controls on parent and teacher ratings of social status and performance, self-report of social knowledge and performance, and observations of behavior on an emotional regulation task. Analyses revealed distinct patterns of social dysfunction between ADHD subgroups. Children with ADHD-C were rated as showing more aggressive behavior; furthermore, they displayed emotional dysregulation characterized by high intensity and high levels of both positive and negative behavior. In contrast, children with ADHD-I were perceived as displaying social passivity and showed deficits in social knowledge on the self-report measure but did not evidence problems in emotional regulation. Regression analyses revealed that social performance, emotional regulation, and, to a lesser degree, social knowledge, were predictive of social status. The application of these findings to understanding the nature of the social deficits in the ADHD subtypes and directions for future research are discussed.