Efficacy over time of LHRH analogs in the treatment of PCa--a prospective analysis using serum testosterone to determine dosing intervals.

OBJECTIVES: To examine the duration of serum testosterone and prostate-specific antigen suppression after each dose of a 4-month depot leuprolide acetate for 18 months and to assess the potential for using serum testosterone as a guide for redosing the luteinizing hormone-releasing hormone analogs instead of using fixed dosing intervals. Luteinizing hormone-releasing hormone analogs are well established for the treatment of prostate cancer (PCa). However, many open questions remain regarding the optimal dosing. METHODS: Thirteen patients with PCa were enrolled in a longitudinal study. Serum testosterone levels were obtained at baseline and then monthly beginning 4 months after the first injection and every 2 months after the subsequent injections, for a total of 18 months. The median number of days from injection to the first serum testosterone level > or = 50 ng/dL was estimated using the Kaplan-Meier product-limit method. RESULTS: The median duration of effect was 159, 189, and 163 days for the first, second, and third treatment cycle, respectively. The prostate-specific antigen values from entry to completion decreased in all subjects. The total number of injections was reduced in all but one subject who completed the 18-month trial. One patient developed hormone-refractory PCa. CONCLUSIONS: Serum testosterone measurement might be a useful method for redosing luteinizing hormone-releasing hormone analogs. Using testosterone levels to determine the time of reinjection has a significant economic impact. Monitoring serum testosterone not only helps to identify patients who fail to achieve testosterone suppression but also provides close monitoring for the potential development of hormone-refractory PCa.

Gilbert N. Lewis and the chemical bond: the electron pair and the octet rule from 1916 to the present day.

We describe the development of Lewis's ideas concerning the chemical bond and in particular the concept of the electron pair bond and the octet rule. We show that the concept of the electron pair bond has endured to the present day and is now understood to be a consequence of the Pauli principle. In contrast the octet rule is now regarded as much less important than was originally generally believed, although Lewis himself knew several exceptions and regarded it as less important than what he called the rule of two (the electron pair). The octet rule was more strongly promoted by Langmuir who is also responsible for the term covalent bond. However, many more exceptions to the octet rules than were known to Lewis are now known and the terms hypervalent and hypovalent used to describe such molecules are no longer particularly useful. Today it is realized that bonding electron pairs in many molecules are not as well localized as Lewis believed, nevertheless resonance structures, i.e., plausible alternative Lewis structures, are still often used to describe such molecules. Moreover electrons are not always found in pairs, as for example in linear molecules, which can, however, be satisfactorily described by Linnett's double quartet theory. The electron density distribution in a molecule can now be analyzed using the ELF and other functions of the electron density to show where electron pairs are most probably to be found in a molecule.

The geometry of nonmetal hydrides and the ligand radius of hydrogen.

The aim of this paper was to investigate why the geometries of nonmetal hydrides are often not in accordance with the VSEPR model. From a consideration of interligand distances in a variety of BX(4), CX(4), and NX(4) molecules where X is a ligand or a lone pair and in which there are at least two H ligands we have shown that the hydrogen ligands are essentially close-packed. For each of the central atoms we have obtained a value for the ligand radius of hydrogen. These radii decrease with decreasing negative charge and increasing positive charge of the hydrogen ligand as the electronegativity of the central atom increases, as has been found previously for other ligands such as F and Cl. We show that ligand-ligand intractions are an important factor in determining bond angles in hydrides and that the ligand close-packing (LCP) model gives a better explanation of bond angles than the VSEPR model according to which bond angles depend on the electronegativity of the ligand rather than on its size. For example, although the very small angles in PH(3) and SH(2) are not in accord with the VSEPR model, they are consistent with the LCP model in that they are a consequence of the small size of hydrogen ligands which are pushed together by the lone pairs until they are almost close-packed.

Ligand close packing and the geometry of the fluorides of the nonmetals of periods 3, 4, and 5.

This paper discusses the geometry of the fluorides of the nonmetals of periods 3, 4, and 5 in terms of the ligand close packing (LCP) model according to which molecular geometry is determined primarily by ligand-ligand repulsions (Pauli closed shell repulsions) rather than by the bonding and lone pair Pauli repulsions of the VSEPR model. The LCP model becomes the dominant factor in determing geometry when the ligands are sufficiently crowded that they may be regarded as essentially incompressible. Ligand close packing is a modification of the VSEPR model in which ligand-ligand repulsion (Pauli closed shell repulsion) is given more emphasis than bonding and nonbonding electron pair Pauli repulsion. The nonmetals of period 3 are large enough to form octahedral six coordinated molecules in which the ligands are close packed. The larger nonmetals of period 4 also have a maximum coordination number of six and an octahedral geometry although the ligands are not close packed. Ligand radii derived from the interligand distances in the molecules of period 3 depend only on the charge of the fluorine ligands and are consistent with the previously derived radii obtained from the fluorides of the close packed tetrahedral molecules of the period 2 elements. Although the ligands in the molecules of the period 4 nonmetals are not close packed, these elements are not large enough to form molecules with a higher coordination number. However, the larger period 5 nonmetals may have coordination numbers of seven and eight. The seven coordinated molecules have a pentagonal bipyramidal geometry in which the equatorial ligands are close packed. The eight coordinated molecules have a square antiprism geometry, which is not a close packed geometry although the fluorine interligand distances are only a little larger than expected for close packing. The difference between the axial and equatorial bond lengths in the trigonal bipyramidal pentafluorides and the pentagonal bipyramidal pentafluorides can be understood on the basis of ligand close packing. Ligand packing prevents the lone pair in AF(6)E molecules from fully entering the valence shell and thereby exerting its full stereochemical effect so that these molecules have a C(3)(v)() distorted octahedral geometry rather than a geometry based on pentagonal bipyramidal seven coordination.

Explaining unexpected gender differences in hostility among persons seeking treatment for substance use disorders.

OBJECTIVE: Gender differences in depression and anxiety are found among patients seeking treatment for substance use disorders, but few data exist on differences in hostility. As part of a larger study describing substance abuse treatment seekers, analyses investigated whether women would be more depressed and anxious than men, but less hostile. METHOD: Data were collected at baseline from 336 outpatients (62% men) at an addiction treatment agency. Most of the outpatients (81%) had DSM-IV chart diagnoses of alcohol dependence or abuse. RESULTS: On the depression, anxiety and hostility subscales of the Brief Symptom Inventory, women had significantly higher scores than did men. When scores were converted to gender-keyed T scores standardized on a normal sample, differences in depression and anxiety were no longer significant. However, differences in hostility remained. A regression analysis indicated that hostility scores were explained not by gender, but by greater severity of adverse consequences from substance use, insomnia, lack of social support, and being married. A childhood history of physical or sexual abuse, although more common in women than men, did not explain gender differences in hostility after controlling for other variables. CONCLUSIONS: The women in this study did not appear to be more anxious and depressed than did the men after controlling for gendered population norms. However, the women were more hostile than the men. Women's greater hostility was explained not by gender per se, but by personal and social factors that were differentially distributed across genders. Treatment implications are reviewed.

Insomnia, self-medication, and relapse to alcoholism.

OBJECTIVE: This study was an investigation of the frequencies of insomnia and its self-medication with alcohol in a group of alcoholic patients, as well as the relationship of these variables to alcoholic relapse. METHOD: The subjects were 172 men and women receiving treatment for alcohol dependence. They completed a sleep questionnaire, measures of alcohol problem severity and depression severity, and polysomnography after at least 2 weeks of abstinence. RESULTS: On the basis of eight items from the Sleep Disorders Questionnaire, 61% of the subjects were classified as having symptomatic insomnia during the 6 months before treatment entry. Compared to patients without insomnia, patients with insomnia were more likely to report frequent alcohol use for sleep (55% versus 28%), had significantly worse polysomnographic measures of sleep continuity, and had more severe alcohol dependence and depression. Among 74 alcoholics who were followed a mean of 5 months after treatment, 60% with baseline insomnia versus 30% without baseline insomnia relapsed to any use of alcohol, a significant difference. Insomnia remained a robust predictor of relapse after application of logistic regression analysis to control for other variables. A history of self-medicating insomnia with alcohol did not significantly predict subsequent relapse. CONCLUSIONS: The majority of alcoholic patients entering treatment reported insomnia symptoms. Given the potential link between insomnia and relapse, routine questions about sleep in clinical and research settings are warranted.

When a family member has a schizophrenic disorder: practice issues across the family life cycle.

Viewing individuals with schizophrenic disorders within a family life-cycle context promotes recognition of the range of family roles, particularly partnership and parenting roles, in clients' lives. Knowledge of clients' stage of family development allows practitioners to view the client more holistically--as a family member with roles and responsibilities--instead of as an isolated, ill individual. Gender differences--in family roles and in manifestation of the illness--are considered.

Platelet production methods in the United Kingdom.

Platelets had traditionally been produced in the United Kingdom (U.K.) either from random donor blood by centrifugation of the platelet rich plasma or by plateletpheresis using various apheresis machines. The proportions of apheresis versus non-apheresis derived platelets varying from centre to centre depending on local policy. The production of platelets from random donor blood is labour intensive and in the late 1980s and early 1990s, biotechnology manufacturers developed newer automated techniques to derive platelets from buffy coats aiming to produce a more standard product and reduce the labour intensity of platelet production. At the same time, apheresis technology has continued to develop with the aim of maximising platelet yields from single donors by yielding 4-6 single unit equivalent of platelets per donor while eliminating the need for further laboratory processing. The trend in some European countries and in North America has been to move away from platelets recovered from whole blood either by buffy coat method or by centrifugation of platelet-rich plasma to plateletpheresis. Intense pressure is being put on blood centres to introduce newer technologies which are inevitably more expensive methods of platelet production. Since 1992, centres in the U.K. have gradually changed their method of platelet production and a survey was conducted to examine the status of platelet production within the U.K. This has shown that many centres are moving away from the production of random donor unit platelets derived by secondary centrifugation of platelet rich plasma (25%) towards buffy-coat derived platelets (45.3%) while plateletpheresis remains fairly static (29.7).

Initial route of antigen administration alters the T-cell cytokine profile produced in response to the mouse pneumonitis biovar of Chlamydia trachomatis following genital infection.

A Th1-type response develops following vaginal infection with the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn). Since the type of response, i.e., Th1 versus Th2, can be influenced by factors present during T-cell activation, we examined the effects of different routes of MoPn administration on the cytokine profile and resistance against infection following a MoPn vaginal challenge. A dominant Th1-type cytokine profile developed in mice given live MoPn via the intranasal, oral, and vaginal routes with ratios of gamma interferon-secreting cells to interleukin 4-secreting cells greater than 10. In contrast, mice injected subcutaneously produced a Th2-type profile with a gamma interferon/interleukin 4 ratio of only 0.7. These mice also had significantly higher anti-MoPn immunoglobulin G1 serum titers, confirming a Th2-type cytokine profile. Exposure of mice to live MoPn, by any route prior to vaginal challenge, resulted in a shortened course of infection. However, the subcutaneous group resolved the vaginal infection more slowly, with 60% (6 of 10 mice) of the mice still isolation positive 12 days after challenge compared with only 20% of mice given live MoPn by other routes. Administration of UV-inactivated MoPn did not provide protection against a vaginal challenge. The decreased ability to clear infection was not associated with a shift in the cytokine profile, since intranasal and oral administration of UV-inactivated MoPn resulted in a predominant Th1-type response. Taken together, these data indicate that the initial route of MoPn administration can direct the type of response produced after a local MoPn infection and thus influence the ability of the immune response to protect against subsequent infection.

Casual attributions about mental illness: relationship to family functioning.

The relationship between causal attributions about mental illness and family functioning was investigated in 39 individuals with chronic mental illness and their families. Among parents and siblings, poor family functioning was associated with attribution to a person as the cause of the illness. Unexpectedly, no relationship was found between family functioning and causal attributions to genetics, biology, God, or chance.

Parents' attitudes to self-medication by their asthmatic children.

Parents have previously been underconsulted concerning their attitudes to asthma self-medication in the primary school. Parents have a wealth of experience to contribute to asthma care. This should be acknowledged while the child is in school. Parents' practices concerning self-medication by their child may differ from their beliefs and attitudes. Parents' recommendations or support for school practice concerning self-medication may be at variance with attitudes and practice in the home. The health-promoting school has an important role to play in encouraging self-medication and self-responsibility for health from the earliest possible age. Parents should be involved with school staff in formulating and implementing school medications policies.