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A number of researchers have observed that response biases, defined as when subjects respond to items in research instruments in ways that do not coincide with the intent or content of the instrument, suffuse measurements and assessments of mental disorders. They cautioned that the response bias problem has been neglected in mental health research at the price of substantial error. Have the cautions been heeded? Or does the neglect of response bias continue? Articles published in 1998 in three major psychiatric journals were examined: Archives of General Psychiatry, American Journal of Psychiatry, and the Journal of Nervous and Mental Disease. The articles were examined to determine whether response biases were mentioned and whether systematic efforts were made to attend to their influence on the findings of the study. Each article was assessed twice by independent raters. The examination indicates that a very small minority of the articles reviewed mentioned response bias and that among those mentioning it, a minority attempted to control for bias effects. Cautions offered about response bias have not been heeded. Accordingly, the issue is one of how to incorporate concerns about response bias into the institutional structures that influence the culture of mental health research.

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HBC-3 hepatic stem cells maintained in the undifferentiated state can be induced to differentiate along the hepatocyte lineage in response to DMSO (Rogler, 1997). In order to understand the complex transcriptional regulatory mechanisms associated with the differentiation of these somatic stem cells and to identify novel candidate stem cell and differentiation associated genes, we have begun to characterize the transcriptome of HBC-3 cells during a 7-day differentiation protocol. This analysis showed that differentiating HBC-3 cells undergo biphasic bursts of gene regulation peaking at 3 hours and 120 hours of DMSO treatment. In the undifferentiated state, HBC-3 cells express muscle, neuron, myeloid, and lymphoid specific genes that are rapidly downregulated during hepatocytic differentiation. Cluster analysis has revealed large groups of genes with different temporal regulation profiles demonstrating complex and widespread transcriptional changes. Specifically, we discovered a multifaceted downregulation of the Wnt/beta-catenin pathway accompanied by the repression of TCF target genes during HBC-3 differentiation. In addition, there is downregulation of cellular receptors for fibronectin and laminin and other extracellular matrix molecules indicative of widespread cell surface alterations. DMSO induces cell cycle arrest, and this is reflected in upregulation of growth inhibitory proteins such as cyclin I and p18 and downregulation of cyclins B1 and D. Genes needed for hepatocytic functions, such as apolipoprotein C-IV, phosphoenolpyruvate carboxykinase, alcohol dehydrogenase, and asialoglycoprotein receptor were upregulated. Finally, transcriptional regulators including Twist, Snail, HNF1a, and GATA6 were upregulated during differentiation of HBC-3 cells. The significance of these findings is that our genome-based approach has allowed the parallel identification of multiple regulatory pathways that is needed to begin to fully understand the complex differentiation process.

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Insulin-like growth factor binding protein 2 (IGFBP-2) is one member of the family of IGF binding proteins believed to have both endocrine functions elicited by modulating serum IGF half-life and transport as well as autocrine/paracrine functions that result from blocking or enhancing the availability of IGFs to bind cell surface receptors. To clarify the in vivo role of IGFBP-2, we have used gene targeting to introduce a null IGFBP-2 allele into the mouse genome. Animals homozygous for the altered allele are viable and fertile, contain no IGFBP-2 mRNA, and have no detectable IGFBP-2 in the adult circulation. Heterozygous and homozygous animals showed no significant differences in prenatal or postnatal body growth. Analyses of organ weights in adult males, however, revealed that spleen weight was reduced and liver weight was increased in the absence of IGFBP-2. In addition, ligand blot analyses of sera from adult IGFBP-2 null males showed that IGFBP-1, IGFBP-3, and IGFBP-4 levels were increased relative to wild-type mice. These results demonstrate that up-regulation of multiple IGFBPs accompanies the absence of IGFBP-2 and that IGFBP-2 has a critical role, either directly or indirectly, in modulating spleen and liver size.

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The unprecedented inclusion of culture-bound syndromes in DSM-IV provides the opportunity for highlighting the need to study such syndromes and the occasion for developing a research agenda to study them. The growing ethnic and cultural diversity of the U.S. population presents a challenge to the mental health field to develop truly cross-cultural approaches to mental health research and services. In this article, the authors provide a critique of previous analyses of the relationship between culture-bound syndromes and psychiatric diagnoses. They highlight the problems in previous classificatory exercises, which tend to focus on subsuming the culture-bound syndromes into psychiatric categories and fail to fully investigate these syndromes on their own terms. A detailed research program based on four key questions is presented both to understand culture-bound syndromes within their cultural context and to analyze the relationship between these syndromes and psychiatric disorders. Results of over a decade of research on ataques de nervios, a Latino-Caribbean cultural syndrome, are used to illustrate this research program. The four questions focus on the nature of the phenomenon, the social-cultural location of sufferers, the relationship of culture-bound syndromes to psychiatric disorders, and the social and psychiatric history of the syndrome in the life course of the sufferer.

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The concept of procedural norms, which is taken from the analysis of science as an institutionally structured social process, is used to explain the persistence of cultural insensitivity in research. The concept refers to the canons of research that tell scientists what should be studied and how, and they are taught to successive generations of researchers. An examination of cross-cultural studies in mental health reveals that cultural insensitivity stems from procedural norms in the development of content validity based on experts' rational analysis of concepts, in linguistic translations that try to conform to the exact terms of standardized instruments, and in the uncritical transferring of concepts across cultures. We need a wide-ranging examination of our procedural norms, with the objective of keeping such norms from suppressing, biasing, or deflecting cultural understandings. This article proposes a dialogue on the intricate connections between culture and our customary methodologies.

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Mechanisms regulating cell type-specific gene expression are not completely understood. We utilized hepatitis B virus (HBV) enhancer I and preS1 promoter sequences, which exhibit cell type specificity, to analyze transcriptional control in pluripotential murine embryonic stem (ES) cells, bipotential HBC-3 progenitor liver cells, mature hepatocytes, and fibroblasts. In transient transfection assays, HBV sequences were most active in primary hepatocytes, followed by HBC-3 and ES cells, and became inactive in fibroblasts. Cotransfections with HNF-3 or C/EBP plasmids increased expression of HBV sequences in hepatocytes and HBC-3 cells. However, increased HBV expression was not observed in ES cells and HBV remained inactive in fibroblasts, suggesting different transcriptional controls, which was compatible with alterations in the abundance of endogenous transcription factors. Analysis in somatic hybrid cells created from NIH 3T3 fibroblasts and Hepa1-6 mouse hepatocytes with expression of albumin and selected hepatic transcription factors showed that HBV sequences were expressed weakly but without increased expression following transfection of HNF-1, HNF-3, and C/EBP plasmids. These findings indicated that repression of HBV in nonpermissive cells involved inactivation of transcription factor activity. Expression of HBV in stem cells is relevant for mechanisms concerning viral persistence and oncogenesis, as well as analysis of hepatocytic differentiation in progenitor cells.

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The Insulin like growth factor 2 (IGF2) gene is expressed in several types of tumors in humans and mice and has been implicated as an important growth factor in tumor progression. IGF2 expression in the TGF alpha transgenic mice was analysed in liver and tumors from animals which also contained one or two functional IGF2 alleles. In a two by two mating experiment using transgenic mice containing either a TGF alpha transgene or a IGF2 gene knockout, we have investigated whether IGF2 imprinting is reversed during hepatocarcinogenesis and the consequences of IGF2 expression for tumor growth. We observed that: (1) 100% of the hepatocellular carcinomas expressed IGF2 (2) the normally imprinted maternal allele is active in the tumors in which the paternal allele is knocked out and (3) all three of the murine IGF2 promoters upstream of the reactivated maternal alleles are transcriptionally active in tumors. We also observed that the total tumor burden of animals with two wild type IGF-2 alleles (paternal and maternal) was the same as the tumor burden in animals which contained only a single reactivated maternal allele. The 100% incidence of reactivation of the imprinted maternal allele suggests that IGF2 expression is selected during murine hepatocarcinogenesis and can substitute for the paternal allele when it is inactivated.

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From the first to the current fourth edition, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) has grown considerably in size and complexity. The DSM-III (1980) represented a paradigm shift in psychiatric diagnoses and is the main focus of the article's five propositions attempting to make sense of basic historical changes in the manual. The first two propositions concern theoretical changes in the manual; they critically examine the effort to evict unverified etiological assumptions from diagnoses, the adoption of formulations of disorders as discretely constituted, and the role of the multiaxial context in diagnoses. The next two propositions attempt a new development: a set of concepts designating the structural changes in the DSM histories of individual disorders. The fifth proposition examines historical forces supporting the neo-Kraepelinian psychiatrists' efforts to produce the DSM-III. The conclusion brings the propositions together to explain the DSM's growth in size and complexity and to show that the general pattern of the DSM changes are aimed at remedicalizing the profession of psychiatry.

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A line of hepatic endoderm cells, hepatoblast cell line 3 (HBC-3), was derived from the liver diverticulum of the mouse on day 9.5 of gestation by culture on a mitomycin C treated STON+ feeder layer in a hepatoblast culture medium consisting of Dulbecco's modified Eagle's medium, nonessential amino acids, fetal calf serum, and beta-mercaptoethanol. This line, HBC-3, stains positively for alpha-fetoprotein, albumin, and cytokeratin 14 (CK-14), protein markers expressed by the embryonic liver diverticulum, indicating that HBC-3 cells retain an undifferentiated hepatoblast phenotype. HBC-3 cells acquire hepatocyte-like ultrastructural characteristics, including bile canaliculi, peroxisomes, and glycogen granules, when maintained in culture for 3 weeks without passage. Treatment with dimethylsulfoxide or sodium butyrate induces a rapid hepatocytic differentiation. The cells cease to express alpha-fetoprotein and CK-14, maintain albumin expression, and become positive for glucose-6-phosphatase activity (a profile consistent with differentiation along the hepatocyte lineage). On Matrigel, HBC-3 cells form elaborate ductular structures, which are positive for gamma-glutamyl transpeptidase and CK-14 and CK-19 and do not express detectable amounts of albumin, a phenotypic change consistent with differentiation along the bile ductular lineage. Thus, HBC-3 cells behave in culture as bipotential hepatoblasts and provide a model system to identify factors that regulate bipotential differentiation in the liver.

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In reaching to serve the mental health needs of new catchment neighborhoods, the 1963 federally funded Community Mental Health Center (CMHC) program stimulated culturally oriented research on the effectiveness of mental health services for Hispanics. The research, at first scattered and diffuse, has converged on a number of targets. This article examines four of the targets of research and how they can be brought into a unified perspective if they are viewed in temporal order as sequenced disadvantages Hispanics confront in using mental health services. The targets can be arrayed longitudinally: reasons for Hispanics' underutilization of professional mental health services, difficulties in retaining Hispanics in such services, errors in evaluating their mental health, and the problems of adapting treatment modalities to their needs.

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The fourth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association 1994) treats the concept of culture as directly relevant to the diagnostic task. In contrast, its predecessor, the DSM-III-R, restricted its coverage to two paragraphs of the concept, cautioning that when the manual was used with clients from different cultural groups, cultural factors could interfere with diagnosis. I believe that the adequacy of the cultural insertions in the DSM-IV should be debated but I also believe that the changes will be considered important. The premise of this article is that they are important. The objective is to show that the cultural insertions in DSM-IV can be organized and focused on important issues of research.

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This study was conducted to analyze determinants of depression among Puerto Ricans by replicating and expanding earlier studies of depression among Cuban Americans and Mexican Americans. Data from the Hispanic Health and Nutrition Examination Survey, 1982-1984, were employed to examine depression and associated characteristics among Puerto Ricans. We utilized descriptive and multivariate statistics to examine the Center for Epidemiologic Studies Depression Scale (CES-D)-assessed depressive symptomatology and the DSM-III/DIS specification of major depression. The findings indicated that CES-D-assessed depressive symptomatology among Puerto Ricans was associated with female gender, disrupted marital status, poor health, and lower socioeconomic status as indicated by low education, low household income, age, and unemployment. For both 6-month and 1-month DIS major depression, age, disrupted marital status, and income of less than $5,000 were significant risk factors. For 6-month DIS major depression, never married persons had a higher risk for depression. For 1-month diagnoses, writing Spanish better than English was associated with lower risk. In general, our findings for Puerto Ricans were similar to studies of depression among other Hispanic groups. We remained unable to explain the relatively extreme levels of depression among Puerto Ricans in New York, though several probable explanations are elaborated. We emphasized the general need to expand the range of research designs and current risk models in epidemiology in an effort to capture the complexity of psychosocial and cultural processes relevant to psychological distress.

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Identified the concept of acculturation as a cornerstone of immigration research, while questioning assumptions about zero-sum cultural change in acculturation scales and in procedures assessing biculturality. Involvements in the host society culture and the culture of origin should be assessed separately in order to reflect the complexities of the cultural interactions immigrants and their offspring experience. To evaluate this prescription, we convened focus groups of Puerto Rican adults to discuss their cultural experiences in Puerto Rico and in the United States. Discussions were content analyzed to develop acculturation items. Factor analysis of the responses of 403 first- and second-generation adults yielded two general factors, involvement in American culture and involvement in Puerto Rican culture, which demonstrated modest reliability, relative independence, and moderate correlations with traditional acculturation scale validators. Results of the study challenge the assumption of mutual cultural exclusivity in acculturative change; enable the measurement of degree of biculturality; and provide future directions for the assessment of acculturation in domains other than language usage. The concept of acculturation is integrated with recent formulations in community psychology which advocate a deeper and more extensive commitment to studying the implications of cultural phenomena and greater focus on the growing cultural diversity in the United States.

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Current, large-scale, cross-cultural migrations offer promising research targets for the study of human adaptations. The opportunities for such research, however, remain substantially unused in the mainstream of psychology. The purpose here is to provide a framework encompassing components of the migration experience to aid such research. Contextual factors in the sending and receiving societies impinge on the components of the migration experience: social networks, socioeconomic status, and culture. The components, treated as intertwining transitional experiences in migration, should be juxtaposed in research to examine their effects. Gender and age mediate the effects. The framework aims to benefit research that implicates, directly or heuristically, the experiences of persons exposed to rapid sociocultural change and the consequences of such changes in their lives.

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Cultural sensitivity in mental health research is enhanced by examining the collective perceptions of members of ethnic groups about their own idiomatic expressions of distress. Such an examination was conducted with Puerto Ricans living in New York City, beginning with focus group discussions. Their prevailing idioms of distress, based upon themes of anger and injustice, were correlated widely with professionally developed measures of anxiety, depression, and somatization and with utilization of professional mental health care. By examining the relationship between idioms of distress, saliently volunteered by members of the ethnic ingroup, on the one hand, and professional care and assessments of mental health, on the other, we increase our culturally based understanding of mental health in the community.

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The revised version of the third edition of the American Psychiatric Association's (1987) Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) gives scant attention to the significance of culture. Two paragraphs in the Introduction advising caution when using the Manual in different cultures (pp. xxvi-xxvii) are followed by more than 500 pages in which the relevance of culture remains basically unrecognized. This neglect is problematical: Ethnological research has repeatedly demonstrated the cultural plasticity of human behavior, so much so, in fact, as to controvert the unqualified attribution of psychiatric meaning to symptoms or sets of symptoms (Rogler, 1993). Yet, despite the scant attention given to culture, the DSM-III and its revised version are more widely used cross-nationally in teaching, research, and clinical practice than any other system for classifying mental illnesses (Maser et al. 1991).

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The convergence between the demystification of psychiatric diagnosis and the increasing professional awareness of a cultural viewpoint offers the opportunity for research to systematically address issues of culturally valid diagnosis. To organize such research, a three-level hierarchical framework is developed which integrates hypotheses about the role of culture, beginning with symptom assessment, then the configuring of symptoms into disorders, and finally the interpersonal situation of the diagnostic interview. An examination of cross-cultural research and research on cultural minorities shows how errors accumulate from the first to the third level because of the neglect of culture or through misconceptions of the concept. The framework is premised upon the need to make programs of research the driving force behind long-range efforts to culturally sensitize psychiatric diagnosis.

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Challenged Shrout et al.'s (1992) comparisons of mental health characteristics of island Puerto Ricans to Mexican Americans and non-Hispanic whites from the Los Angeles Epidemiological Catchment Area Study. The hypothesis tested by Shrout et al.--higher symptom counts but lower DSM-III prevalence rates among Puerto Ricans--was misattributed to Rogler (1989). We also question the validity of assessing lifetime prevalence and reaffirm the need for psychiatric epidemiological research to consider the role of culture in diagnostic criteria.

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The authors argue that the concept of help-seeking pathways, defined generically, oriented toward institutional structures, and put at the forefront of research, can help integrate much of what we know about the use of mental health care and how to make such care more accessible and effective among underserved populations. They focus the concept of help-seeking pathways on current issues and research findings pertinent to the onset of psychological distress, the contacting of mental health care facilities, and treatment in such facilities. Pathways are not random; they are structured by the convergence of psychosocial and cultural factors and have sufficient integrity to be studied directly as unfolding processes.

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