The functional effect of pathogenic mutations in Rab escort protein 1.

Choroideremia (CHM) is a chorioretinal degeneration with an X-linked pattern of inheritance. Affected males experience progressive atrophy of the choroid, retinal pigment epithelium and retina leading to eventual blindness. The CHM gene encodes Rab escort protein 1 (REP-1). REP-1 is involved in trafficking of Rab proteins in the cell. To date, the majority of reported mutations in the CHM gene cause a complete loss of REP-1 function. Here we report pathogenic mutations: a novel missense mutation, L550P; a truncation c.1542T>A, STOP; and two deletions (c.525_526delAG and c.1646delC) in the CHM gene and their phenotypic effect. To analyze the effect of mutations, the 3D structure of human REP-1 and the proteins associated with REP-1 function were modeled using sequence homology with rat proteins. In silico analysis of the missense mutation L550P suggests that the proline residue at position 550 destabilizes the beta-structural elements, and the REP-1 tertiary structure. Truncation and deletion mutants are associated with a partial or total loss of the REP-1 essential activity and protein-protein interactions as predicted by the analysis of the structure and stability of these protein products. The presumptive loss of protein was confirmed by Western Blot analysis of protein from mononuclear cells and fibroblasts (FB) from CHM patients.

Noninvasive cardiac absolute pressure sensing: a fundamentally new approach.

Noninvasive cardiac pressure sensing using an imaging modality to ascertain changes in absolute pressure would be of immense benefit as a replacement for the Swan-Ganz catheter in current use. However, very little research has been published in this area. This paper reviews the small number of relevant studies to date, points out the many gaps in the research record, and discusses possible new avenues of approach in solving the problem.

The role of sequential stream segregation and frequency selectivity in the perception of simultaneous sentences by listeners with sensorineural hearing loss.

The purpose of this study was to determine the role of frequency selectivity and sequential stream segregation in the perception of simultaneous sentences by listeners with sensorineural hearing loss. Simultaneous sentence perception was tested in listeners with normal hearing and with sensorineural hearing loss using sentence pairs consisting of one sentence spoken by a male talker and one sentence spoken by a female talker. Listeners were asked to repeat both sentences and were scored on the number of words repeated correctly in each sentence. Separate scores were obtained for the first and second sentences repeated. Frequency selectivity was assessed using a notched-noise method in which thresholds for a 1,000 Hz pure-tone signal were measured in noise with spectral notch bandwidths of 0, 300, and 600 Hz. Sequential stream segregation was measured using tone sequences consisting of a fixed frequency (A) and a varying frequency tone (B). Tone sequences were presented in an ABA_ABA_... pattern starting at a frequency (B) either below or above the frequency of the fixed 1,000 Hz tone (A). Initially, the frequency difference was large and was gradually decreased until listeners indicated that they could no longer perceptually separate the two tones (fusion threshold). Scores for the first sentence repeated decreased significantly with increasing age. There was a strong relationship between fusion threshold and simultaneous sentence perception, which remained even after partialling out the effects of age. Smaller frequency differences at fusion thresholds were associated with higher sentence scores. There was no relationship between frequency selectivity and simultaneous sentence perception. Results suggest that the abilities to perceptually separate pitch patterns and separate sentences spoken simultaneously by different talkers are mediated by the same underlying perceptual and/or cognitive factors.

Why adolescent boys dream of becoming professional athletes.

A review of studies which investigated drawings of the ideal man and the occupational aspirations of boys (ages 11-18 years) from several countries indicated that becoming a professional athlete was a popular but unrealistic aspiration for many adolescent boys. Boys who were athletes and nonathletes from diverse ethnic groups and nationalities dreamed of becoming professional athletes. In two additional studies in the United States of America, adolescents were asked why they thought boys most often selected professional athlete as a possible future occupation. Adolescents perceived professional athletes as rich, famous, and glorified. Enhancement of status and financial gain were ranked as more important than the desire to play sports.

Specialty mental health services in metropolitan and nonmetropolitan areas: 1983 and 1990.

This paper provides information about the changes between 1983 and 1990 in the availability and volume of specialty mental health services in counties with different levels of metropolitanization and urbanization. The analysis uses the 1983 county metropolitan and urbanization designations for both 1983 and 1990 in order to obtain an accurate determination of the changes that occurred in the 7-year period. The results indicate that during the study period, metropolitan counties experienced increasing availability of specialty mental health services, while nonmetropolitan counties did not. Implications for future rural mental health policy are discussed.

Adolescents' opposite-sex ideal in four countries.

Six hundred young adolescents (11 to 16 years old) from 4 countries (Guatemala, Iceland, Mexico, and the United States) ranked the importance of 10 qualities of the opposite-sex ideal person. Those from the United States responded in an individualistic fashion; they ranked being fun, being sexy, and having considerable money as important for the ideal. Those from Guatemala responded in a collectivistic fashion; they ranked liking children as important, but being fun and good looking as unimportant. Adolescents from Mexico and Iceland reported patterns of values not clearly associated with either collectivism or individualism.

Girls' relational self in Sri Lanka and the United States.

The self-conceptions of 100 girls (11-17 years old) from Sri Lanka and the United States were studied from the traditional Western perspective of identity development as a process in which adolescents become increasingly independent and autonomous. This perspective is based on male development in Western countries and may not adequately describe the experience of girls of non-Western adolescents, for whom relationships with others may be central to identity formation. The participating girls drew self-portraits and either answered the question "How would you describe yourself to yourself?" or completed the sentence "I am..." 20 times. The results indicate that relationships and independence are important themes for the girls from the United States and from Sri Lanka. Older girls differed from younger girls in that greater maturity was associated with greater interest in interpersonal relationships and future lives.

Interleukin-1 contributes to increased concentrations of soluble tumor necrosis factor receptor type I in sepsis.

Studies were done in baboons and humans to assess the role of interleukin (IL)-1 on the release of soluble tumor necrosis factor receptors (sTNFRs) during sepsis. In baboons, IL-1 alpha induced increased levels of sTNFR types I and II. Infusion of Escherichia coli into baboons also led to higher sTNFR levels. Treatment with IL-1 receptor antagonist (ra) attenuated the rise in sTNFR-I, which was positively correlated with a partial preservation of renal function by IL-1ra. In patients with sepsis, treatment with IL-1ra also was associated with lower levels of sTNFR-1 but did not influence plasma creatinine levels. IL-1ra did not affect sTNFR-II in baboons or humans. These data suggest that IL-1 produced during sepsis is involved in increases in sTNFR-I. Such increases during rapidly fatal septic shock may in part be explained by an effect on the renal clearance of sTNFR-I.

Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropin concentrations in man.

Interleukin-1 (IL-1) has been implicated as a mediator of the euthyroid sick syndrome. The effects of IL-1 can be blocked by the naturally occurring IL-1 receptor antagonist (IL-1ra). In the present study, iv administration of endotoxin was used as a human model of the euthyroid sick syndrome. To assess the role of endogenous IL-1 in endotoxin-induced changes in plasma thyroid hormone and TSH concentrations, 18 healthy postabsorptive humans were studied on a control study day, followed 3 days later by a study day on which they were randomly assigned to one of three treatments: a 6-h infusion of recombinant human IL-1ra alone (133 mg/h), endotoxin alone (lot EC-5; 20 U/kg), or both endotoxin and IL-1ra. Administration of IL-1ra alone did not affect the plasma concentrations of thyroid hormones or TSH compared with those on the control day. Endotoxin injection was associated with decreases in T4 (P = 0.06 vs. the control day), free T4 (P = 0.02), T3 (P < 0.001), and TSH (P < 0.0001) and a rise in rT3 (P < 0.001), reproducing the major features of the euthyroid sick syndrome. Coinfusion of IL-1ra did not influence these endotoxin-induced changes. Our results suggest that endogenous IL-1 does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.

Influence of IL-1 receptor blockade on the human response to endotoxemia.

Although the experimental administration of IL-1 induces several aspects of the inflammatory response, such as fever, tachycardia, and acute phase proteinemia, the contribution of IL-1 to the human responses to injury or infection remains unclear. A specific IL-1R antagonist (IL-1ra), which effectively blocks the actions of IL-1, was utilized to evaluate the influence of endogenous IL-1 during experimental human endotoxemia. Eighteen healthy volunteers each underwent one control study day, followed 3 days later by one of three randomly chosen treatments: a 6-h infusion of IL-1ra alone (133 mg/h), 20 U/kg national reference endotoxin alone, or both endotoxin and IL-1ra infusion. IL-1ra administration alone was not associated with any observable response. Despite achieving high circulating levels of IL-1ra (34 +/- 3 micrograms/ml), there were no significant differences in hemodynamic parameters, core temperature, or resting energy expenditure in those endotoxemic volunteers receiving IL-1ra when compared with those who did not. Furthermore, leukocyte kinetic and circulating cytokine, acute phase protein, and endocrine responses were similar in both endotoxemic groups. However, IL-1 blockade did significantly reduce the subjective severity of symptoms experienced by the endotoxemic volunteers (p < 0.05). This study demonstrates that an endogenous IL-1 response does not play a significant role in the hemodynamic, immunologic, and metabolic responses to mild endotoxemia in humans.

Video display terminal operators: technology's biopsychosocial stressors.

1. Professional nurses can contribute significantly to the implementation of a multidisciplinary team to solve biopsychosocial stress issues in the "high tech" workplace. 2. Educating workers about risk factors, ergonomics, and self management measures is one of the most important aspects of preventing video display terminal related disorders. 3. The evaluation of biopsychosocial stress involves examination of workers' physical health, psychological demands, decision latitude, social support, workstation design, and other special considerations such as electronic performance monitoring.

Adolescents' views of work and leisure in The Netherlands and the United States.

During early adolescence, youth begin to make choices about their future. Sundberg and Tyler (1970) found differences between adolescents in the Netherlands and the United States as to their possibilities for future occupations and leisure activities. Since there have been many changes in both countries over the past twenty-five years, the present study was designed as a replication and expansion of that research. Participants were 522 14- and 15-year-olds in the Netherlands and the United States who filled out the Sundberg and Tyler questionnaire (in the original Dutch and English forms) and drew a picture of the ideal man or woman engaged in an activity. Two-way (country by gender) ANOVAs indicated that the number of occupations listed was greater for adolescents in the Netherlands than in the United States, and that girls listed more occupations than did boys, but considered fewer occupations as actual possibilities for themselves. There was an apparent increase in the number of leisure activities listed by adolescents in the Netherlands. In the U.S., the ideal person was more often drawn as being at work (44.9%) as compared with the Netherlands (20.4%). U.S. students seemed more inclined to glamorize work; popular drawings had themes which linked work and success, achievement and wealth. Dutch students seemed to be interested in quality of life; their drawings depicted sports, relaxation, attractiveness, and humor.

Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans.

A phase I study of human recombinant interleukin-1 receptor antagonist (IL-1ra) was conducted in healthy males between the ages of 18 and 30. Twenty-five volunteers received a single, 3 h continuous intravenous infusion of doses ranging between 1 mg/kg and 10 mg/kg IL-1ra. At 3 h into the infusion, plasma IL-1ra levels were 3.1 micrograms/ml and 29 micrograms/ml for the 1 mg/kg and 10 mg/kg doses, respectively. Post-infusion plasma IL-1ra levels declined rapidly, exhibiting an initial half-life of 21 min and a terminal half-life of 108 min. Clinical, hematological, biochemical, endocrinological and immunomodulatory effects were monitored over 72 h and compared to those of four subjects receiving a 3 h infusion of saline. There were no clinically significant differences between the drug and saline groups in symptoms, physical examinations, complete blood counts, mononuclear cell phenotypes, blood chemistry profiles, serum iron and serum cortisol levels. Peripheral blood mononuclear cells (PBMC) obtained after completion of the IL-1ra infusion synthesized significantly less interleukin 6 ex vivo than PBMC from saline-injected controls. These data suggest that transient blockade of interleukin 1 receptors is safe and does not significantly affect homeostasis.

Girls' identity formation in the changing social structure of Sri Lanka.

Adolescent girls (N = 118) from diverse social backgrounds in Sri Lanka described their views of womanhood. Qualities of the ideal woman considered most important were kindness and honesty, liking children, intelligence, and having a good job. Although the traditional role of the Sri Lankan woman is that of homemaker, most girls in the study (55%) drew the ideal woman working outside the home, often as a teacher or a doctor. Nevertheless, adolescent girls emphasized traditional qualities of the woman at both work and home as self-sacrificing and serving others.

Racial congruity as a contextual correlate of mental disorder.

The effects of exposure to racially dissonant residential environments on depressive psychopathology are explored. Epidemiological survey data are shown to support the hypothesis that an inverse relationship exists between racial congruity and depression. Limitations of the analysis are discussed, as are the social implications of the findings.

The food crisis and environmental conservation in Africa.

PIP: In spite of good rains in Africa in 1985, 30-35 million people suffered the effects of famine. Much of Africa is still dependent on food aid. The main causes of insufficient food production are land degradation--desertification--and high population growth. Distribution of the US $2.9 billion in food and non-food aid has been hampered by transport and logistical problems. The major challenge for 1986 is non-food support. Only US $460 million (15.3%) of non-food aid had been received as of March. Country profiles of Angola, Chad, Ethiopia, Mozambique, Somalia, Sudan, Lesotho, Mali, Mauritania, Niger, Rwanda, Tanzania, and Zambia show a pattern of high food assistance needs and displaced refugee populations. The 1st 6 of the group suffer from civil strife. There is some good news; e.g. Niger, which is embarking on agressive agricultural development, and Tanzania, which has enjoyed bumper crops, but the crisis is clearly far from over. Few African Governments have been willing to face the population problem; population in the area will probably continue to increase at 3% yearly. It is shown that desertification: reducing the biological potential of the land through over-exploitation, animal husbandry, and deforestation, is a wordwide problem particularly acute in Africa. Lost production totals $26 billion annually. Straightforward cost-benefit analysis of projects to halt or reverse the problem does not adequately take factors such as human attachment to the land into account. Unfortunately halting desertification does not receive the attention it should receive from donor agencies. Investment goes towards high-return projects, e.g. power dams; sugar factories, when a more careful study reveals that returns from afforestations are much more long-term. There has been increased consciousness of the long-term benefits of dryland rehabilitation, which will hopefully impact policy in the future. But since desertification is a self-accelerating process, there is a need for very rapid action.^ieng