Substance use stigma: A systematic review of measures and their psychometric properties.

Background: Instruments to measure substance use stigma are emerging, however little is known regarding their psychometric properties. While research has evolved to view substance use stigma as a context sensitive international phenomenon that is embedded within cultures, validated self-report measures are lacking and comprehensive reviews of the existing measures are extremely limited. In this systematic review of substance use stigma and shame measures, we aim to contextualize results from existing research, lay the groundwork for future measurement development research, and provide a thorough resource for research scientists currently designing studies to measure substance use stigma. Methods: We searched three databases using Boolean search terms for psychometric evaluations of measures of substance use stigma and shame and evaluated the quality/psychometric properties using an adaptation of the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) systematic review guidelines. Results: We identified 18 measures of substance use stigma. Overall, most measures had minimal psychometric assessments and none of the measures met all domains of the COSMIN measure quality criteria. However, most studies reported satisfactory factor analyses and internal consistency scores. Conclusions: Most measures of substance use stigma and shame had psychometric assessment across a limited range of criteria and no measures of structural substance use stigma were found. The most reported psychometric properties were structural validity and convergent validity. We suggest future researchers investigate test-retest reliability and cross-cultural validity for existing substance use stigma measures, as well as develop and evaluate novel measures assessing structural stigma of substance use.

Trauma cognitions as intervening variables in the relation of chronic child abuse and thwarted interpersonal needs.

OBJECTIVE: Chronic childhood trauma is consistently linked to negative mental health outcomes in adulthood, but research exploring specific paths of risk remains limited. The aims of the current study were to examine trauma cognitions as intervening variables in the relation of chronic victimization with perceived burdensomeness and thwarted belongingness, variables implicated in transdiagnostic risk for psychopathology. METHOD: Semistructured interviews were used to identify university students reporting exposure to systematic physical and/or sexual violence prior to age 18 (n = 101) versus those experiencing other Criterion-A events (n = 254). Trauma cognitions (self, world, and self-blame) and thwarted interpersonal needs (burdensomeness and thwarted belongingness) were measured using scores from the posttrauma cognitions inventory (PTCI) and the Interpersonal Needs Questionnaire-10 (INQ-10). Path models in these cross-sectional data were evaluated to assess the indirect effects of chronic abuse on burdensomeness and thwarted belongingness through self, world, and blame cognitions. RESULTS: An initial model indicated associations of chronic victimization on self (p = .044) and world (p = .005) scales of the PTCI and a unique effect of self-beliefs on INQ-10 burdensomeness (p < .001). An indirect effect of abuse on burdensomeness through self-beliefs was supported (p = .050). A second model identified direct effects of PTCI self (p < .001) and world (p < .001) scores on thwarted belongingness as well as an indirect effect of chronic abuse on belongingness through world beliefs (p = .026). CONCLUSIONS: While typically assessed within the context of posttraumatic stress disorder, results suggest that shifts in fundamental beliefs about the self and the world may have more general impacts on perceptions of burdensomeness and belonging in survivors of early, systematic abuse. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Social anxiety and MDMA-assisted therapy investigation: a novel clinical trial protocol.

Background: Social anxiety disorder (SAD) is a serious and prevalent psychiatric condition that heavily impacts social functioning and quality of life. Though efficacious treatments exist for SAD, remission rates remain elevated and a significant portion of those affected do not access effective treatment, suggesting the need for additional evidence-based treatment options. This paper presents a protocol for an open-label pilot study of MDMA-assisted therapy (MDMA-AT) for social anxiety disorder. The study aims to assess preliminary treatment outcomes, feasibility and safety, and psychological and physiological processes of change in the treatment of SAD with MDMA-AT. A secondary aim includes the development of a treatment manual for MDMA-AT for SAD. Method: The outlined protocol is a randomized, open-label delayed treatment study. We will recruit 20 participants who meet criteria with moderate-to-severe social anxiety disorder (SAD) of the generalized subtype. Participants will be randomly assigned to an immediate treatment (n = 10) or delayed treatment condition (n = 10). Those in the immediate treatment condition will proceed immediately to active MDMA-AT consisting of three preparation sessions, two medicine sessions in which they receive oral doses of MDMA, and six integration sessions over approximately a 16-week period. The delayed treatment condition will receive the same intervention after a 16-week delay. Our primary outcome is SAD symptom reduction as measured by the Liebowitz Social Anxiety Scale administered by blinded raters at post-treatment and 6 month follow up. Secondary outcomes include changes in functional impairment, feasibility and safety measures, and novel therapeutic processes of change including shame and shame-related coping, belongingness, self-concealment, and self-compassion at post-treatment. Exploratory outcomes are also discussed. Discussion: The results of this pilot trial advance the field's understanding of the acceptability and potential effectiveness of MDMA-AT for social anxiety disorder and provide an overview of relevant therapeutic mechanisms unique to SAD. We hope findings from this protocol will inform the design of subsequent larger-scale randomized controlled trials (RCT) examining the efficacy of MDMA-AT for SAD. Clinical trial registration: https://clinicaltrials.gov/, NCT05138068.

Moderating effects of brooding on the link between functional impairment and interpersonal needs in survivors of serious trauma.

OBJECTIVES: Trauma and resulting functional limitations demonstrate associations with perceived burdensomeness and thwarted belongingness, factors contributing to elevated risk for suicidal ideation. However, survivors display differential risk in response to impairment, highlighting the need for research on exacerbating factors. The current study examined the impact of brooding on the association of functional impairment with burdensomeness and belongingness among trauma-exposed undergraduates (N = 262). METHOD: Trauma was assessed via clinical interview with questionnaires for study variables. Regression models examined the unique and interactive effects of physical impairment, emotional impairment, and brooding on burdensomeness and thwarted belongingness. RESULTS: An interaction of brooding and impairment due to emotional difficulties was observed for burdensomeness with impairment linked to elevated burdensomeness at high (ß = -0.46; p < 0.001), but not low (ß = -0.07; p = 0.476) brooding. Impairment due to emotional difficulties (ß = -0.38; p < 0.001) and brooding (ß = 0.25; p < 0.001) were associated with belongingness. CONCLUSIONS: Findings identify brooding as a potential target for assessment and intervention in trauma-exposed individuals.

A systematic review of self-report measures of generalized shame.

OBJECTIVE: Shame is a transdiagnostic emotion of strong clinical and research interest. Yet, there is a lack of consensus on the definition and varying methods employed across self-report measures, potentially affecting our ability to accurately study shame and examine whether clinical interventions to alter shame are effective. This paper offers a systematic review of self-report measures of generalized shame. METHODS: PubMed, PsycInfo, and Web of Science were searched. Studies were included when they were available in English and the primary aim was to evaluate measurement properties of scales or subscales designed to measure generalized shame in adults. RESULTS: Thirty-six papers examining 19 scales were identified, with measures of trait shame more common than state shame. Construct validity, internal consistency, and structural validity were relative strengths. Development and content validity studies were lacking and suffered from low methodological quality. CONCLUSIONS: All measures evaluated needed additional research to meet criteria for recommended use.

Potential processes of change in MDMA-Assisted therapy for social anxiety disorder: Enhanced memory reconsolidation, self-transcendence, and therapeutic relationships.

OBJECTIVE: Researchers have suggested that psychotherapy may be enhanced by the addition of 3,4-methylenedioxymethamphetamine (MDMA), particularly in the treatment of disorders wherein interpersonal dysfunction is central, such as social anxiety disorder. We review literature pertaining to three potential processes of change that may be instigated during sessions involving MDMA administration in the treatment of social anxiety disorder. DESIGN: This is a narrative review that integrates research on the etiology and maintenance of social anxiety disorder and mechanisms of action of MDMA to examine how MDMA may enhance psychotherapy outcomes. RESULTS: We first outline how MDMA may enhance memory reconsolidation in social anxiety disorder. We then discuss how MDMA may induce experiences of self-transcendence and self-transcendent emotions such as compassion, love, and awe; and how these experiences may be therapeutic in the context of social anxiety disorder. We subsequently discuss the possibility that MDMA may enhance the strength and effectiveness of the therapeutic relationship which is a robust predictor of outcomes across many disorders as well as a potential key ingredient in treating disorders where shame and social disconnection are central factors. CONCLUSION: We discuss how processes of change may extend beyond the MDMA dosing sessions themselves.

MDMA-Assisted Therapy as a Means to Alter Affective, Cognitive, Behavioral, and Neurological Systems Underlying Social Dysfunction in Social Anxiety Disorder.

Social anxiety disorder (SAD) is a prevalent and often debilitating psychiatric disorder that can assume a chronic course even when treated. Despite the identification of evidence-based pharmacological and behavioral treatments for SAD, much room for improved outcomes exists and 3,4-methylenedioxymethamphetamine (MDMA) has been proposed as a promising adjunctive treatment to psychological interventions for disorders characterized by social dysfunction. A small randomized, placebo-controlled trial of MDMA-assisted therapy (MDMA-AT) for social anxiety in autistic adults offered encouraging results, but more research is sorely needed to explore the potential for MDMA-AT in treating SAD. This review aims to stimulate future study by summarizing research on disruptions in neurological, perceptual, receptive, and expressive systems regulating social behavior in SAD and proposing how MDMA-AT may alter these systems across four domains. First, we review research highlighting the roles of social anhedonia and reduced social reward sensitivity in maintaining SAD, with specific attention to the reduction in positive affect in social situations, infrequent social approach behaviors, and related social skills deficits. We posit that MDMA-AT may enhance motivation to connect with others and alter perceptions of social reward for an extended period following administration, thereby potentiating extinction processes, and increasing the reinforcement value of social interactions. Second, we review evidence for the central role of heightened social evaluative threat perception in the development and maintenance of SAD and consider how MDMA-AT may enhance experiences of affiliation and safety when interacting with others. Third, we consider the influence of shame and the rigid application of shame regulation strategies as important intrapersonal processes maintaining SAD and propose the generation of self-transcendent emotions during MDMA sessions as a mechanism of shame reduction that may result in corrective emotional experiences and boost memory reconsolidation. Finally, we review research on the role of dysfunctional interpersonal behaviors in SAD that interfere with social functioning and, in particular, the development and maintenance of close and secure relationships. We discuss the hypothesized role of MDMA-AT in improving social skills to elicit positive interpersonal responses from others, creating a greater sense of belonging, acceptance, and social efficacy.

The Interaction of Compliance and Activation on the Force-Length Operating Range and Force Generating Capacity of Skeletal Muscle: A Computational Study using a Guinea Fowl Musculoskeletal Model.

A muscle's performance is influenced by where it operates on its force-length (F-L) curve. Here we explore how activation and tendon compliance interact to influence muscle operating lengths and force-generating capacity. To study this, we built a musculoskeletal model of the lower limb of the guinea fowl and simulated the F-L operating range during fixed-end fixed-posture contractions for 39 actuators under thousands of combinations of activation and posture using three different muscle models: Muscles with non-compliant tendons, muscles with compliant tendons but no activation-dependent shift in optimal fiber length (L0), and muscles with both compliant tendons and activation-dependent shifts in L0. We found that activation-dependent effects altered muscle fiber lengths up to 40% and increased or decreased force capacity by up to 50% during fixed-end contractions. Typically, activation-compliance effects reduce muscle force and are dominated by the effects of tendon compliance at high activations. At low activation, however, activation-dependent shifts in L0 are equally important and can result in relative force changes for low compliance muscles of up to 60%. There are regions of the F-L curve in which muscles are most sensitive to compliance and there are troughs of influence where these factors have little effect. These regions are hard to predict, though, because the magnitude and location of these areas of high and low sensitivity shift with compliance level. In this study we provide a map for when these effects will meaningfully influence force capacity and an example of their contributions to force production during a static task, namely standing.

A Interação de Conformidade e Ativação na Faixa de Operação Força-Comprimento e Capacidade de Geração de Força do Músculo Esquelético: Um Estudo Computacional Usando um Modelo Musculoesquelético de Galinhas-D'angola O desempenho muscular é influenciado por onde ele opera na sua curva de força-comprimento. Aqui, exploramos como a ativação e a conformidade do tendão interagem para influenciar os comprimentos musculares e a capacidade de geração de força. Para estudar isso, construímos um modelo musculoesquelético do membro inferior da galinha-d'angola e simulamos a faixa de operação força-comprimento durante contrações fixas de postura e extremidade para 39 atuadores sob milhares de combinações de ativação e postura usando três modelos musculares diferentes: músculos com tendões não-complacentes, músculos com tendões complacentes, mas sem desvio dependente de ativação no comprimento ideal de fibra (L0), e músculos com tendões complacentes e desvios dependentes de ativação em L0. Descobrimos que os efeitos dependentes da ativação alteraram os comprimentos da fibra muscular em até 40% e aumentaram ou diminuíram a capacidade de força em até 50% durante as contrações de extremidade fixas. Normalmente, os efeitos de ativação e conformidade reduzem a força muscular e são dominados pelos efeitos de complacência do tendão em altas ativações. Em baixa ativação, no entanto, desvios dependentes de ativação em L0 são igualmente importantes e podem resultar em mudanças de força relativas de até 60% para músculos de baixa complacência. Existem regiões da curva de força-comprimento em que os músculos são mais sensíveis à complacência e há baixas de influência onde esses fatores têm pouco efeito. Essas regiões são difíceis de prever porque a magnitude e a localização dessas áreas de alta e baixa sensibilidade mudam com o nível de conformidade. Neste estudo, fornecemos um mapa para quando esses efeitos influenciarão significativamente a capacidade de força e um exemplo de suas contribuições para a produção de forças durante uma tarefa estática, ou seja, em pé. Translated to Portuguese by G. Sobral (gabisobral@gmail.com).

Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones.

The Bicaudal C Homolog 1 (BICC1) gene, which encodes an RNA binding protein, has been identified by genome wide association studies (GWAS) as a candidate gene associated with major depressive disorder (MDD). We explored the hypothesis that MDD associated single-nucleotide polymorphisms (SNPs) affected the ability of cis-regulatory elements within intron 3 of the BICC1 gene to modulate the activity of the BICC1 promoter region. We initially established that the BICC1 promoter drove BICC1 mRNA expression in amygdala, hippocampus and hypothalamus. Intriguingly, we provide evidence that MDD associated polymorphisms alter the ability of the BICC1 promoter to respond to PKA signalling within amygdala neurones. Considering the known role of amygdala PKA pathways in fear learning and mood these observations suggest a possible mechanism through which allelic changes in the regulation of the BICC1 gene in amygdala neurones may contribute to mood disorders. Our findings also suggest a novel direction for the identification of novel drug targets and the design of future personalised therapeutics.The Pharmacogenomics Journal advance online publication, 6 October 2015; doi:10.1038/tpj.2015.62.

A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases.

Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxy-tamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation. The PCD features were observed only at high (µM) concentrations of CQ. The use of a new synthetic coumarin-labeled chloroquine (CM-CQ) showed that these features may be associated with concentration-dependent differences in drug localization. By further using cysteine protease inhibitors z-Asp-Glu-Val-Asp-fmk (zDEVD), z-Phe-Ala-fmk (zFA), z-Phe-Phe-fmk (zFF), z-Leu-Leu-Leu-fmk (zLLL), E64d and CA-074, we were able to implicate clan CA cysteine proteases in CQ-mediated PCD. Finally, CQ induction of two CQ-resistant parasite strains, 7G8 and K1, reveals the existence of PCD features in these parasites, the extent of which was less than 3D7. The use of the chemoreversal agent verapamil implicates the parasite digestive vacuole in mediating CQ-induced PCD.

Screening for psychosocial risk in an urban prenatal clinic population: a retrospective practice-based research study.

Recognition of the need for early identification of risk factors led a "practice-based research" (Epstein, 1995) team of social workers in the prenatal clinic at Mount Sinai to develop a standardized, comprehensive screening, monitoring and evaluation instrument for all patients in their service. To explore the effects of psychosocial risk factors empirically, available information collected from 435 women screened with the original instrument between 1992-93 was converted into a quantitative data-base. The intention was to conduct a retrospective study of the prenatal patient population, including demographic characteristics, problems presented, social work interventions, and treatment outcomes. Among the findings anxiety and ambivalence related to pregnancy were significant risk factors. This model of social work service delivery is consistent with the focus of prenatal care as clinical preventative medicine.

In vivo pharmacology and anti-tumour evaluation of the tyrphostin tyrosine kinase inhibitor RG13022.

Amplification and increased expression of many growth factor receptors, including the epidermal growth factor receptor (EGFR), has been observed in human tumours. One therapeutic strategy for overcoming EGF autocrine control of tumour growth is inhibition of EGFR protein tyrosine kinase (PTK). A series of low molecular weight molecules have been identified which inhibit the EGFR PTK in vitro and demonstrate antiproliferative activity against human cancer cell lines with high expression of EGFR. A significant growth delay in squamous cancer xenografts has been reported for one of these compounds, the tyrphostin RG13022. Based on these encouraging results, we sought to confirm the activity of RG13022 in vivo and relate the effects to the in vivo plasma disposition. RG13022 and three additional peaks were detected by HPLC following intraperitoneal administration of 20 mg kg-1 RG13022 in MF1 nu/nu mice. RG13022 demonstrated rapid biexponential elimination from plasma with a terminal half-life of 50.4 min. RG13022 plasma concentrations were less than 1 microM by 20 min post injection. A primary product was identified as the geometrical isomer (E)-RG13022. Both RG13022 and its geometrical isomer inhibited DNA synthesis in HN5 cells after a 24 h in vitro incubation (IC50 = 11 microM and 38 microM respectively). Neither RG13022 nor its geometrical isomer displayed significant cytotoxicity. RG13022 had no influence on the growth of HN5 tumours when administered chronically, starting either on the day of tumour inoculation or after establishment of tumour xenografts. The rapid in vivo elimination of RG13022 has potential significance to the development of this and other related tyrphostin tyrosine kinase inhibitors, as plasma concentrations fell below that required for in vitro activity by 20 min post injection. The lack of in vivo tumour growth delay suggests that a more optimal administration schedule for RG13022 would include more frequent injections or continuous administration. An improved formulation for RG13022 is therefore required before further development of this or other similar protein tyrosine kinase inhibitors can be made. Alternative strategies should also be sought which display longer lasting in vivo exposures.

Synthesis and antiproliferative activity of tyrphostins containing quinoline moieties.

Tyrphostins are a series of benzylidenemalononitrile derivatives synthesized by condensing aromatic aldehydes with malononitrile derivatives. The use of heteroaromatic aldehydes in this process has received little attention. Accordingly, 27 tyrphostins containing a 2-, 3- or 4-substituted quinoline moiety were synthesized, of which 21 are novel compounds Compounds containing the 2-aminoethene-1, 1-dinitrile moiety in each series were the most potent inhibitors of the EGF receptor kinase in a cell-free enzyme assay (compounds 2, 11 and 20), having IC50 values of 1.7, 27.0 and 4.7 microM respectively. For each R group substitution the order of potency was 2-quinolines > 4-quinolines > 3-quinolines. Compounds 2, 11 and 20 were unable to inhibit the epidermal growth factor (EGF) receptor autophosphorylation in intact cells; however, they were able to inhibit the EGF-dependent phosphorylation of a 50 kDa protein. These three compounds were able to inhibit EGF-dependent proliferation in a fibroblast cell more efficiently than serum-stimulated proliferation, suggesting that their mechanism of action may be linked to the EGF receptor signalling pathway. Compound 2 exhibited a degree of cell line selectivity in the US National Cancer Institute in vitro human tumour cell line panel. The majority of non-small cell lung cancer lines were relatively resistant to compound 2, while most of the colon, CNS, melanoma and renal lines were relatively sensitive. Further work is required to elucidate the mechanism of action of this interesting group of substituted-quinoline compounds and to determine whether for compounds 2, 11 and 20 this is related to inhibition of EGF receptor function.

Synthesis and biological evaluation of a series of tyrphostins containing nitrothiophene moieties as possible epidermal growth factor receptor tyrosine kinase inhibitors.

A series of 36 nitrothiophene tyrphostins were synthesized, 32 of which were novel structures. Their ability to inhibit the epidermal growth factor (EGF) receptor tyrosine kinase was assessed in a cell-free assay. Compounds containing a dinitrile, 2-aminoethene-1, 1-dinitrile or a thioamide group were good inhibitors of the receptor tyrosine kinase. Although anti-proliferative and cytotoxic activity was seen, no evidence of inhibition of EGF receptor autophosphorylation in intact cells was observed. The compounds showed no preferential inhibition of EGF-dependent proliferation of fibroblasts transfected with the EGF receptor. Furthermore, in a panel of squamous cell carcinoma cell lines with varying levels of EGF receptor expression, there was no selective cell kill of lines with the highest EGF receptor expression. The 2-nitro-5-substituted-thiophenes and the 2-nitro-3-substituted-thiophenes showed reduction potentials falling within the range likely to be reduced by cellular reducing agents, while the 2-nitro-4-substituted-thiophenes and 4-nitro-2-substituted-thiophenes did not. Compounds from the 2-nitro-5-substituted-thiophene series were shown to induce DNA damage, while no evidence of DNA damage was demonstrated with compounds from the 2-nitro-4-substituted-thiophene series. The 2-nitro-5-substituted-thiophene compound 4 showed significant tumour-type selectivity in the US National Cancer Institute human tumour cell line panel. The leukaemia cell lines were particularly sensitive to the compound, as were the majority of the colon cancer, melanoma and breast cancer cell lines, while the central nervous system-derived lines and the non-small cell lung cancer lines were particularly resistant. Further work is required to determine the precise mechanisms involved in these effects.

Synthesis and antiproliferative activity of tyrphostins containing heteroaromatic moieties.

A series of benzylidenemalononitrile derivatives previously synthesized by condensing aromatic aldehydes with malononitrile derivatives are known as tyrphostins. In this study, 32 tyrphostins were synthesized, 19 of which are novel compounds. Both hydroxylated derivatives and compounds containing heteroaromatic moieties were prepared. We have confirmed and extended the observation that the tyrphostins displayed an enhancement in their ability to inhibit the epidermal growth factor (EGF) receptor tyrosine kinase domain as the number of hydroxyl groups on the aromatic portion was increased. IC50 values of 1-5 microM were readily achieved. Some inhibitory activity was seen with the heteroaromatic structures, with two compounds exhibiting IC50 values of 56 and 77 microM. However, these derivatives were poor inhibitors of the EGF receptor tyrosine kinase activity as compared to the hydroxylated derivatives. The ability of the 32 tyrphostins synthesized in the present study to inhibit proliferation of a human breast adenocarcinoma cell line (MCF-7) was determined using [3H]thymidine incorporation as a measure of DNA synthesis. Some of the compounds containing pyridine, imidazole or thiophene portions displayed antiproliferative activity comparable to that of tyrphostins prepared from 3,4,5-trihydroxybenzaldehyde. The lack of inhibitory effect of these heteroaromatic compounds on the EGF receptor tyrosine kinase activity suggests that their antiproliferative activity is not related to inhibition of EGF receptor function. As the growth of the MCF-7 cell line is governed by other factors, such as the insulin-like growth factors (IGFs) and oestradiol, it is also still to be established whether the antiproliferative activity of the hydroxylated tyrphostins is directly related to inhibition of the EGF receptor tyrosine kinase activity.

'Awake for an operation'.

It seems likely that every single patient coming into hospital for surgery feels some apprehension, if not fear. Part of this concern comes from what is unknown, some from the prospect of pain and perhaps from the prospect of 'something going wrong'.

Total cellular activity and distribution of a subpopulation of galactosyl receptors in isolated rat hepatocytes are differentially affected by microtubule drugs, monensin, low temperature, and chloroquine.

We studied the effects of low temperature (20-37 degrees C), monensin, chloroquine, and microtubule drugs on the cellular distribution and activity of galactosyl (Gal) receptors in isolated rat hepatocytes. After equilibration at 37 degrees C, hepatocytes were incubated at 37 degrees C, 31 degrees C, 25 degrees C, or 20 degrees C or treated with or without inhibitors at 37 degrees C in the absence of ligand. The cells were then assayed at 4 degrees C for 125I-asialo-orosomucoid binding, to measure receptor activity, or 125I-anti-Gal receptor IgG binding, to measure receptor protein. Surface or total (surface and intracellular) Gal receptor activity and protein were measured on intact or digitonin-permeabilized cells, respectively. These inhibitors fell into two categories. Type I inhibitors (sub-37 degrees C temperatures or colchicine) induced receptor redistribution but not inactivation. Treated cells lost up to 40% of surface Gal receptor activity and protein. Lost surface receptors were recovered intracellularly with no loss of receptor activity. Type II inhibitors (monensin or chloroquine) induced receptor inactivation but not redistribution. Treated cells lost 50-65% of their surface Gal receptor activity but only less than or equal to 15% of their surface receptor protein. These cells lost up to 60% of total cellular Gal receptor activity with no loss of total receptor protein. Of the total inactive Gal receptors, up to 50% and 75%, respectively, were present intracellularly in monensin- and chloroquine-treated cells. Loss of ligand binding to permeable treated cells was not due to changes in receptor affinity. A third category, Type III inhibitors (metabolic energy poisons that deplete ATP) induce both Gal receptor redistribution and inactivation (Biochemistry 27:2061, 1988). We conclude that only one of the two previously characterized subpopulations of Gal receptors on hepatocytes, termed State 2 receptors (J Biol Chem 265:629, 1990), recycles constitutively. The activity and distribution of State 2 but not State 1 Gal receptors are differentially affected by these specific drugs or treatments.

Influence of fetal growth patterns on sonographic estimation of fetal weight.

Six published fetal weight estimating regression models proposed for clinical use were evaluated in 259 pregnant women who delivered within 72 h of an ultrasound evaluation performed with sector scanner. The patient sample included 89 (33.2%) fetal weights that were below the 10th or above the 90th percentile for menstrual age. The actual mean percent error (systematic error), standard deviation (random error), and the number of large errors of prediction for all equations were greatest in fetuses that were small- and large-for-gestational age. Whereas there were no significant differences between equations for the patient sample as a whole, equation AC,BPD (Shepard) had the smallest systematic error in intrauterine growth retarded, premature, and normal-term fetuses less than 4000 g. Conversely, the systematic error of the models that included femur length was smallest at the upper end of the weight scale and in macrosomic fetuses in general. In that regard, the accuracy of fetal weight prediction could be increased by selecting the appropriate model for the proper clinical indications. Although these findings can be explained by the limitations of the current regression models in estimating fetal soft tissue mass, a subtle effect of the use of the sector scanner on the results of this study cannot be completely excluded and requires further investigation.