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BACKGROUND: Large community-based epidemiological surveys have consistently identified high co-morbidity between major depressive episode (MDE) and generalized anxiety disorder (GAD). Some have suggested that this co-morbidity may be artificial and the product of the current diagnostic system. Because of the added direct and indirect costs associated with co-morbidity, it is important to investigate whether methods of diagnostic classification are artificially increasing the level of observed co-morbidity. METHOD: The item response theory (IRT) log-likelihood ratio procedure was used to test for differential item functioning (DIF) of MDE symptoms between respondents with and without a diagnosis of GAD in the 2001-2002 National Epidemiological Survey on Alcohol and Related Conditions (NESARC). RESULTS: The presence of GAD significantly increased the chances of reporting any symptom of MDE, with odds ratios ranging from 2.54 to 5.36. However, there was no indication of significant DIF of MDE symptoms in respondents with and without GAD. CONCLUSIONS: The lack of any significant DIF indicates that cases with GAD do not present with a distinct MDE symptom profile, one that is consistent with the endorsement of symptoms that are conceptually similar in nature between the two disorders, compared to cases without GAD. This does not support the hypothesis that co-morbidity between MDE and GAD is artificially inflated because of the similar symptom criteria required by the current diagnostic system. Instead, MDE and GAD may be thought of as two distinct diagnostic entities that frequently co-occur because of a shared underlying trait.

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The pharmacokinetics and toxicities of free sodium stibogluconate (SSG) and two vesicular formulations of this drug (a nonionic surfactant vesicular formulation of SSG [SSG-NIV] and SSG-NIV-dextran) were determined after treatment with a single intravenous dose in healthy dogs and were related to their antileishmanial efficacies in mice. Analysis of the curves of the concentrations in plasma after intravenous administration of SSG and SSG-NIV in dogs showed that both formulations produced similar antimony (Sb) pharmacokinetics. In contrast, treatment with SSG-NIV-dextran significantly modified the pharmacokinetics of the drug. The elimination half-life was four times longer (280 min) than that observed after administration of SSG (71 min) (P = 0.01), and the volume of distribution at steady state (V(SS)) was also increased (V(SS) for SSG, 0.21 liters/kg; V(SS) for SSG-NIV-dextran, 0.34 liters/kg [P = 0.02]), thus indicating that drug encapsulation favors the distribution of Sb into organs and increases its residence time in tissues. This would explain the superior antileishmanial efficacy of this formulation compared to those of the free drug in mice. No signs of toxicity were found in dogs after SSG and SSG-NIV administration. However, SSG-NIV-dextran treatment was associated with short-term toxicity, demonstrated by the development of chills and diarrhea, which cleared by 24 h postdosing, and hepatic dysfunction at 24 h postdosing (P < 0.05). The levels of all the biochemical parameters had returned to normal at 1 month postdosing. No signs of toxicity were observed in mice treated with all three formulations.

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A lyophilization process for a pharmaceutical unit dosage form was developed which comprised a container closed with an impermeable membrane pierced with one or more holes through which the material in the container can be lyophilized. The hole or holes in the membrane have to be sufficiently large to allow water vapor to escape but small to ensure that the material is kept within the container. Lyophilization from sealed, perforated, unit-dose package has shown to be feasible. The technique offers a novel convenient means of lyophilizing nonsterile products in their primary pack and increases the potential for the development of lyophilized formulations for nonparenteral applications.

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Peripheral endocrine hormones and local paracrine and autocrine factors contribute, in a coordinated fashion, to the processes of recruitment, development or atresia, selection and ovulation of follicles. Among the local ovarian factors, there is growing evidence from genetic and experimental data that many members of the transforming growth factor (TGFbeta) superfamily have a biological role to play in folliculogenesis. These members include activin, inhibin, TGFbeta, BMP, GDF9 and perhaps MIS. In this review, we discuss the potential roles of the TGFbeta superfamily members, in particular activin, during folliculogenesis. Since the actions of these factors are determined by ligand availability, receptor expression and modulation of their signal transduction pathways, we also collate information on the expression of their signalling components in the follicle. We conclude that the TGFbeta superfamily signalling pathways, in particular activin's pathway, reside in the ovary. Furthermore, follistatin and beta-glycan-components of the accessory binding protein system that modifies activin action-are also present in follicles. In the post-natal rat ovary, the changes in receptor/Smad expression coincide with granulosa cell proliferation and antrum formation. We hypothesise that these pathway components are expressed in a temporal and cell-specific manner to meet the changing demands of cells during follicular development. The analysis of the components of the signal transduction pathways of the TGFbeta family members in populations of defined follicles and the identification of activated pathways in individually stimulated follicles should help clarify the roles of the TGFbeta members in folliculogenesis.

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Evidence to enhance the premise that inhibin and activin are local regulators of ovarian folliculogenesis is presented in this review. Granulosa cells (GC) have been identified as the source of inhibin/activin in the ovary on the basis of mRNA and protein localisation and the measurement of the inhibin forms in GC conditioned media. Expression of the subunit mRNAs changed with follicular development, being maximal in the ovaries of 8-day-old rats, where secondary follicles predominate. The expression of beta subunit mRNAs by GC isolated from diethylstilboestrol (DES)-treated immature rats, was reduced in the absence of any change in alpha subunit mRNA expression. Dimeric inhibin-A, -B and free alpha subunit were produced by ovarian cell cultures prepared from 4- to 12-day-old rats. Inhibin-A production by these cultures was responsive to FSH and TGF-beta, with preantral follicles of day 8 ovaries exerting effects so profound that the inhibin A/alpha subunit ratio increased, most likely due to a stimulation of beta(A) subunit production. In contrast, inhibin-B was not stimulated by TGF-beta until day 8 and FSH until day 12. Fractionation of GC conditioned media revealed a prominence of free alpha subunit and inhibin-A, but little inhibin-B, suggesting that inhibin-B production declines with follicular development. Activin receptor types I and II, Smads 1-8 and betaglycan (beta-glycan) mRNAs were present in the rat ovary and showed distinct patterns of expression between postnatal days 4 and 12. Oocytes and GC localised activin receptor, Smad and beta-glycan proteins, with beta-glycan also present in theca cells (TC). These data indicate that activin/TGF-beta signalling machinery and factors which influence these pathways, are present in the postnatal rat ovary. Our hypothesis that inhibin and activin play important and changing autocrine/paracrine roles in the growth and differentiation of follicles, including the oocyte, has been supported by these studies.

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We tested the hypothesis that ERalpha and ERbeta mRNAs in the rat ovary are regulated during the post-natal period and in immature rats in response to estrogen treatment. Total ovarian ERbeta mRNA was more abundant than ERalpha mRNA and expression of ERbeta increased between post-natal days 4 and 12, coinciding with advancing folliculogenesis and an increase in granulosa cell numbers. In contrast, ERalpha mRNA levels remained relatively constant during this period. In situ hybridisation studies localised both ERalpha and ERbeta to granulosa cells of growing follicles, in 25 day old ovaries, although not all granulosa cells in a follicle or all follicles expressed the ERs. Diethylstilboestrol (DES) administered in vivo to 21 day old rats, for up to 4 days, did not significantly alter the expression of either ER as determined by RT-PCR, despite a 5.5-fold increase in granulosa cell number in these ovaries. In situ hybridisation studies established that DES-treatment down-regulated granulosa cell ER mRNAs. RT-PCR analyses on isolated granulosa cells confirmed that ERalpha was significantly down-regulated by DES. The predominance of ERbeta over ERalpha in the ovary and the regulation of ERbeta mRNA expression during ovarian development, is consistent with an important biological role for ERbeta in granulosa cell proliferation and differentiation.

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Single-dose treatment with sodium stibogluconate solution (SSG) and treatment with a nonionic surfactant vesicular formulation of sodium stibogluconate (SSG-NIV) were compared for the ability to protect BALB/c mice against infection with Leishmania donovani. Prophylactic treatment with SSG-NIV protected against infection, although its effects were time and organ dependent; protection was not obtained with SSG. Protection against reinfection with L. donovani was observed only in mice cured by treatment with SSG-NIV. However, this protective effect was probably due to the presence of residual drug rather than an immune effect, since prophylactic SSG-NIV treatment gave similar results. Transfer of enriched spleen T-cell populations from L. donovani-infected mice or from infected SSG-NIV-treated mice gave no protection against L. donovani infection in the recipients. T cells from infected mice, but not from infected SSG-NIV-treated mice, were infectious to recipients. SSG-NIV treatment was equally effective against visceral leishmaniasis in immunocompetent and SCID mice, whereas SSG treatment was less effective in the latter. The results of this study suggest that the high antileishmanial activity of SSG-NIV is due to favorable modification of SSG delivery and does not require a fully functional immune response. Cure of visceral leishmaniasis by SSG-NIV treatment in the BALB/c mouse did not protect against reinfection.

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In this study, treatment efficacies of a nonionic surfactant vesicle formulation of sodium stibogluconate (SSG-NIV) and of several formulations of amphotericin B were compared in a murine model of visceral leishmaniasis. Treatment with multiple doses of AmBisome, Abelcet, and Amphocil (total dose, 12.5 mg of amphotericin B/kg of body weight) resulted in a significant suppression of parasite burdens in liver (P < 0.0005) and spleen (P < 0.0005) compared with those of controls, with Abelcet having the lowest activity. Only AmBisome and Amphocil gave significant suppression of parasites in bone marrow (compared to control values, P < 0.005). In the acute-infection model, single-dose treatments of SSG-NIV (296 mg of SbV/kg), SSG solution (296 mg of SbV/kg), or AmBisome (8 mg of amphotericin B/kg) were equally effective against liver parasites (compared to control values, P < 0.0005). SSG-NIV and AmBisome treatment also significantly suppressed parasites in bone marrow and spleen (P < 0.005), with SSG-NIV treatment being more suppressive (>98% suppression in all three sites). Free-SSG treatment failed to suppress spleen or bone marrow parasites. Infection status influenced treatment outcome. In the chronic-infection model, the AmBisome single-dose treatment was less effective in all three infection sites and the SSG-NIV single-dose treatment was less effective in the spleen. The results of this study suggest that the antileishmanial efficacy of SSG-NIV compares favorably with those of the novel amphotericin B formulations.

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This article attempts to answer three questions about avoidant personality disorder (AVPD): (a) Is it a coherent unidimensional entity, (b) Is the requirement that four or more of the criteria be met in order to make the diagnosis justified, and (c) Are the changes made in DSM-IV supported? Four hundred thirty-four people presenting for treatment for anxiety were assessed with the Personality Disorder Examination. The criteria met were factor analyzed to indicate the unidimensionality of the diagnosis. Measures of internal consistency were calculated to validate the instruction to diagnose AVPD if four or more criteria were observed. Confirmatory factor analysis showed that a single factor was the best fit to the observed pattern of relationships between the seven AVPD criteria. The internal consistency of the seven criteria was moderate (Cronbach's alpha = .76) with a median intercriterion correlation of .29. The data provided good support for the hypothesis that the seven DSM-III-R AVPD criteria assess a single dimension. Three of the criteria did not reflect this factor as highly as the remaining four and these three have either been dropped in DSM-IV or substantially revised.

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Non-ionic-surfactant vesicular (NIV) formulations of paromomycin have been tested in-vitro and in-vivo for their activity against Leishmania donovani. Production of NIV was dependent both on the surfactant used and on the concentration of paromomycin; only two of the surfactants studied formed vesicles at the highest paromomycin concentration (9 mg mL(-1)). At surfactant-lipid concentrations > or = 1.5 mM, suspensions of NIV (drug- or glucose-loaded) were cytotoxic to macrophages infected with L. donovani; high levels of nitrite were produced in cell supernatants. At surfactant-lipid concentrations < 1.5 mM, drug-loaded NIV were more effective than the same dose of free drug, in terms of the percentage of cells infected and the number of parasites/cell. At surfactant-lipid concentrations < or = 0.15 mM, drug-loaded NIV were ineffective in-vitro. In-vivo, treatment with decaethylene glycol mono n-hexadecyl ether paromomycin NIV was more effective than hexaethylene glycol mono n-hexadecyl ether paromomycin NIV, in terms of suppression of liver and spleen parasite burdens. Against liver parasites, both types of paromomycin-loaded NIV were more effective than free drug. Neither the NIV nor free forms of paromomycin caused significant suppression of bone-marrow parasites. The study shows that entrapment of paromomycin in NIV can be used to increase its antileishmanial activity in-vitro and in-vivo.

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The antileishmanial efficacies of four proprietary amphotericin B (AmB) formulations (Fungizone, AmBisome, Abelcet, and Amphocil) and an experimental nonionic surfactant vesicle (NIV) formulation were compared in a murine model of acute visceral leishmaniasis. By a multiple-dosing regimen, groups of Leishmania donovani-infected BALB/c mice were treated (2.5 mg of AmB per kg of body weight) on days 7 to 11 postinfection with one of the AmB formulations, and parasite burdens were determined on day 18 postinfection. All of the formulations caused significant suppression parasite burdens in spleens (P < 0.01 to 0.0005) and livers (P < 0.0005) compared with those in the spleens and livers of the controls. In addition, a significant suppression of parasite burdens in bone marrow (P < 0.0005) compared to the burdens in the bone marrow of the controls was obtained for all the formulations except Abelcet, which was inactive at this site. On the basis of their overall efficacies (activity against liver, spleen, and bone marrow parasites), the formulations could be ranked as follows: Amphocil = AmBisome > AmB-NIV > Abelcet >> Fungizone. On the basis of spectrophotometric measurements, AmB was shown to exist in a predominantly aggregated state in all of the formulations. Although incubation in 50% serum altered the degree of aggregation, the AmB remained predominantly aggregated, indicating that the AMB-lipid complex in all of the formulations was physically stable. The results of the study showed that antiparasitic efficacy is associated positively with the degree of AmB aggregation in the presence of serum.

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BACKGROUND: A short self-report questionnaire was developed to assess dependence on benzodiazepines (BZDs), the Benzodiazepine Dependence Questionnaire (BDEPQ). The BDEPQ is the first scale to assess dependence on BZDs comprehensively, as all existing scales focus exclusively on withdrawal symptoms. METHOD: To evaluate its internal consistency and construct validity, 302 regular BZD users were recruited from media advertisements and assessed on a number of measures. The BDEPQ was compared with measures of depression, anxiety, sleep quality, BZD withdrawal symptoms and neuroticism to assess its construct validity. A 3-4 month follow-up was conducted to assess the ability of the BDEPQ to predict changes in BZD consumption and future BZD withdrawal. RESULTS: The BDEPQ was found to have high internal consistency and to be relatively stable over the follow-up period. Three subscales were identified, each with good internal consistency and temporal stability. The BDEPQ was able to predict the severity of withdrawal symptoms. CONCLUSION: The BDEPQ was found to be a reliable and valid self-report instrument for the assessment of BZD dependence in samples approximating the general population of people using BZDs.

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The rates (after 12 months' follow-up) of unassisted smoking cessation reported in the literature have varied from 13.8 per cent to 8.5 per cent. A meta-analysis was conducted of the abstinence rates observed in 14 samples of smokers who presented at primary health settings and received either no intervention aimed at smoking or usual care (which involved no deliberate intervention for smoking cessation). The estimated rate of stopping smoking without intervention, over an average 10-month period, was 7.33 per cent. This rate is consistent with others reported in the literature when motivation to quit is taken into account. The estimate provides a baseline to judge the effects of smoking-cessation interventions.

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Five non-ionic surfactants (Surfactants V-IX) were screened for their ability to produce vesicles for the delivery of sodium stibogluconate. Mean vesicle diameter and antimony content were determined prior to in vivo assessment of antiparasitic activity in a mouse model of acute visceral leishmaniasis. V/D suspensions (i.e. stibogluconate loaded vesicles kept in the hydrating drug solution) were more effective against spleen, liver and bone marrow parasites than drug loaded vesicle suspensions that had unentrapped drug removed. A Surfactant IX V/D suspension was the most active antileishmanial preparation causing 74 +/- 10%, 99 +/- 1% and 38 +/- 8% suppression of liver, spleen and bone marrow parasite burdens respectively. Contrary to previous findings, a reduction in splenic and bone marrow parasite burdens was achieved using large vesicles (mean diameter > 800nm). The significance of these results is discussed.

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A meta-analysis of randomized and controlled evaluations of the efficacy of smoking cessation interventions compared 146 estimates of the difference in abstinence rates between treated and control conditions (effect sizes) from 85 publications. Simple advice to quit and other brief intervention techniques, nicotine chewing gum and behavioural techniques were all found to be significantly better than relevant control conditions in promoting abstinence, although the results were not homogeneous. In five studies of acupuncture compared with control, consistent results were found showing no benefit for acupuncture.

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The influence of host genetic background on the response of Leishmania donovani-infected mice to chemotherapy was studied using the H-2d and H-2b haplotypes on a BALB or a B10 genetic background. Animals were treated with free or liposomal sodium stibogluconate and parasite burdens in the liver, spleen and bone marrow were assessed. In all the mouse strains and their congenic derivatives examined, the liver responded best to therapy regardless of drug formulation, whilst the spleen and the bone marrow respectively were increasingly less responsive to chemotherapy. Treatment with free drug was more effective in congenic mice carrying the H-2b haplotype than in those carrying the H-2d haplotype and in mice carrying the same H-2 haplotype, animals from a BALB background were better responders than those from a B10 genetic background. Liposomal drug was more effective than free drug treatment in all four mouse strains and produced a similar significant suppression (> 99%, P < 0.001) in liver parasite burdens to that obtained using a six times greater free drug dose. This liposomal drug dose was more effective than free drug in reducing bone marrow parasite burdens in all four mouse strains and equally (BALB/c mice) or more effective (P < 0.01, BALB/B, B10 and B10.D2 strains) in reducing spleen parasite numbers. Liposomal dependent influences apparent using free sodium stibogluconate. These results are discussed in relation to the genetic factors which are known to control the course of L. donovani infection in mice.

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The pharmacokinetics and tissue distribution of antimony after the administration of sodium stibogluconate in a free form or entrapped in vesicles prepared from non-ionic surfactant were studied in the dog. Animals were given either one or two intravenous bolus injection(s) equivalent to 45 mg Sb kg-1 as free drug or 0.625 or 0.685 mg Sb kg-1 as vesicular drug. Blood samples were taken at various times after dosing and antimony levels in various tissues were determined at 3 h, 48 h and 6 days after dosing. After free stibogluconate antimony clearance from the blood occurred in a rapid elimination phase with a blood half-life of 0.58 +/- 0.08 h. This rapid elimination phase did not occur after vesicular drug. Both drug preparations gave similar antimony levels in the spleen, liver and femur and humerus bone marrow at all time points assessed even though the vesicular dose was one-seventieth of the free drug dose. After the free drug there was marked urinary excretion of antimony and, as a result, increased kidney loading at the expense of other tissue. Vesicle-mediated drug delivery suppressed renal excretion and a much greater proportion of the antimony dose was recovered from tissue than was obtained after free drug. A hypothesis is presented to account for the differences in tissue antimony concentrations produced by the two formulations.

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BALB/c mice with an acute or chronic Leishmania donovani infection were treated with intravenous sodium stibogluconate solution and the parasite suppressions determined in the spleen, liver and femur bone marrow. Antimony concentrations in these and other tissues were determined by hydride generation-atomic absorption spectrophotometry. There was little correlation between tissue antimony levels one hour after treatment and drug efficacy. It would appear that the peak tissue antimony concentration achieved soon after dosing, rather than the lower concentrations which are readily sustained in most tissues, is the most important factor in the antileishmanial activity of stibogluconate. A high peak antimony concentration occurred in the liver, where parasites were significantly suppressed, and was not observed in the two other sites of infection, where the parasites were apparently less susceptible to stibogluconate therapy.

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Drug and alcohol agencies across Australia were asked to describe the services they offer to opiate users. Of the 284 agencies identified as providing treatment, 229 (81%) responded. A standard assessment procedure was used in 72% of agencies. Eighty (35%) agencies offered detoxification and had assisted 7883 clients with detoxification in the 12 months prior to March 1990. Methadone maintenance was offered in 20% of agencies with 5234 clients currently receiving this treatment. Daily doses of methadone in the range of 40-80 mg were described for most (51%) clients receiving methadone and concurrent counselling was provided in 45% of cases. Standard psychosocial interventions were provided by 60% of agencies. Out-patient or non-residential settings were most common (36%), with residential therapeutic communities being the setting for 21% of programmes. Supportive counselling was the most commonly used individual approach, and cognitive-behavioural or 12-step approaches were the most commonly used group approaches. Brief support or referral to Nar-Anon were the most popular family interventions. Procedures aimed at reducing the risk of HIV were in place at 85% of agencies. These findings are discussed in light of research evidence. Briefly, there is a diversity of treatment options available from different treatment agencies which is not reflected within the agencies, little aftercare is offered despite high rates of relapse, and doses of methadone are lower than has been found to be optimal.