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PubMed1994

Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily.

We have identified a member of the steroid receptor superfamily and cloned it from human and rat hypothalamus, prostate, and testis cDNA libraries. The open reading frame between first ATG and terminator TGA can encode 615 (human) and 596 (rat) amino acids with calculated molecular mass of 67.3 (human) and 65.4 (rat) kDa. The amino acid sequence of this protein, called TR4 orphan receptor, is closely related to the previously identified TR2 orphan receptor. The high homology between TR2 and TR4 orphan receptor suggests that these two orphan receptors constitute a unique subfamily within the steroid receptor superfamily. These two orphan receptors are differentially expressed in rat tissues. Unlike TR2 orphan receptors, the TR4 orphan receptor appears to be predominantly located in granule cells of the hippocampus and the cerebellum, suggesting that it may play some role(s) in transcriptional regulation in these neurons.

Amino Acid Sequence↗

PubMed2005

Methods to estimate the number of orphans as a result of AIDS and other causes in Sub-Saharan Africa.

OBJECTIVE: To derive methods to estimate and project the fraction of children orphaned by AIDS and other causes. METHODS: HIV/AIDS affects orphan numbers through increased adult and child mortality and reduced fertility of HIV-positive women. We extend an epidemiologic and demographic model used previously to estimate maternal orphans to paternal orphans. We account for the impact of HIV/AIDS on child survival by modeling the HIV status of the partners of men who die of AIDS or other causes based on data on the concordance of heterosexual partners. Subsequently, the proportion of orphans whose parents have both died is predicted by a regression model fitted to orphanhood data from 34 national demographic and health surveys (DHSs). The approach is illustrated with an application to Tanzania and compared with DHS estimates for the years 1992 and 1999. RESULTS: Projections of the number and age distribution of orphans using these methods agree with survey data for Tanzania. They show the rise in orphanhood over the last decade that has resulted from the HIV epidemic. CONCLUSIONS: The methods allow estimation of the numbers of children whose mother, father, or both parents have died for countries with generalized heterosexual HIV epidemics. These methods have been used to produce orphan estimates for high-prevalence countries published by Joint United Nations Program on HIV/AIDS, World Health Organization, United Nations Children's Fund, and US Agency for International Development in 2002 and 2004.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Assessing the health status of young AIDS and other orphans in Kampala, Uganda.

The huge number of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) orphans is an important feature of the epidemic in sub-Saharan Africa. There are few and conflicting data on the effects of being orphaned on health and nutrition in the highly affected HIV endemic areas of Africa. This study reports findings from a cross-sectional survey on associations between orphan status and health and nutrition parameters in young children of urban Uganda. A high prevalence of orphans was reported from a central Kampala community, with 41% being attributed to HIV/AIDS. Although there was a higher prevalence of self-reported morbidity in orphans than non-orphans, there were no differences in reported treatment seeking behaviour and measured anthropometric parameters. Hence it seems that the extended family system still manages to care for young orphans. Paying school fees for older children should be the primary target for HIV/AIDS impact mitigation programs in urban Uganda.

Acquired Immunodeficiency Syndrome↗

PubMed2006

ORENZA: a web resource for studying ORphan ENZyme activities.

BACKGROUND: Despite the current availability of several hundreds of thousands of amino acid sequences, more than 36% of the enzyme activities (EC numbers) defined by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) are not associated with any amino acid sequence in major public databases. This wide gap separating knowledge of biochemical function and sequence information is found for nearly all classes of enzymes. Thus, there is an urgent need to explore these sequence-less EC numbers, in order to progressively close this gap. DESCRIPTION: We designed ORENZA, a PostgreSQL database of ORphan ENZyme Activities, to collate information about the EC numbers defined by the NC-IUBMB with specific emphasis on orphan enzyme activities. Complete lists of all EC numbers and of orphan EC numbers are available and will be periodically updated. ORENZA allows one to browse the complete list of EC numbers or the subset associated with orphan enzymes or to query a specific EC number, an enzyme name or a species name for those interested in particular organisms. It is possible to search ORENZA for the different biochemical properties of the defined enzymes, the metabolic pathways in which they participate, the taxonomic data of the organisms whose genomes encode them, and many other features. The association of an enzyme activity with an amino acid sequence is clearly underlined, making it easy to identify at once the orphan enzyme activities. Interactive publishing of suggestions by the community would provide expert evidence for re-annotation of orphan EC numbers in public databases. CONCLUSION: ORENZA is a Web resource designed to progressively bridge the unwanted gap between function (enzyme activities) and sequence (dataset present in public databases). ORENZA should increase interactions between communities of biochemists and of genomicists. This is expected to reduce the number of orphan enzyme activities by allocating gene sequences to the relevant enzymes.

Amino Acid Sequence↗

PubMed2006

[Orphans and vulnerable children affected by HIV/AIDS in Brazil: where do we stand and where are we heading?].

This study aimed at identifying human rights' status and situation, as expressed in the United Nations General Assembly Special Session on HIV/AIDS, of children and adolescents living with HIV/AIDS, non-orphans and orphans affected by AIDS, based on local and international literature review. The main study findings did not allow to accurately estimating those children and adolescents living with HIV and non-orphans affected by HIV/AIDS but data was available on those living with AIDS and orphans. The limitations and possibilities of these estimates obtained from surveillance systems, mathematical models and surveys are discussed. Though studies in literature are still quite scarce, there is indication of compromise of several rights such as health, education, housing, nutrition, nondiscrimination, and physical and mental integrity. Brazil still needs to advance to meet further needs of those orphaned and vulnerable children. Its response so far has been limited to providing health care to those children and adolescents living with HIV/AIDS, preventing mother-to-child HIV transmission and financing the implementation and maintenance of support homes (shelters according to Child and Adolescent Bill of Rights) for those infected and affected by HIV/AIDS, either orphans or not. These actions are not enough to ensure a supportive environment for children and adolescents orphaned, infected or affected by HIV/AIDS. It is proposed ways for Brazil to develop and improve databases to respond to these challenges.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor.

From a database containing the published nuclear hormone receptor (NR) sequences I constructed an alignment of the C, D and E domains of these molecules. Using this alignment, I have performed tree reconstruction using both distance matrix and parsimony analysis. The robustness of each branch was estimated using bootstrap resampling methods. The trees constructed by these two methods gave congruent topologies. From these analyses I defined six NR subfamilies: (i) a large one clustering thyroid hormone receptors (TRs), retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptors (VDRs) and ecdysone receptors (EcRs) as well as numerous orphan receptors such as RORs or Rev-erbs; (ii) one containing retinoid X receptors (RXRs) together with COUP, HNF4, tailless, TR2 and TR4 orphan receptors; (iii) one containing steroid receptors; (iv) one containing the NGFIB orphan receptors; (v) one containing FTZ-F1 orphan receptors; and finally (vi) one containing to date only one gene, the GCNF1 orphan receptor. The relationships between the six subfamilies are not known except for subfamilies I and IV which appear to be related. Interestingly, most of the liganded receptors appear to be derived when compared with orphan receptors. This suggests that the ligand-binding ability of NRs has been gained by orphan receptors during the course of evolution to give rise to the presently known receptors. The distribution into six subfamilies correlates with the known abilities of the various NRs to bind to DNA as homo- or heterodimers. For example, receptors heterodimerizing efficiently with RXR belong to the first or the fourth subfamilies. I suggest that the ability to heterodimerize evolved once, just before the separation of subfamilies I and IV and that the first NR was able to bind to DNA as a homodimer. From the study of NR sequences existing in vertebrates, arthropods and nematodes, I define two major steps of NR diversification: one that took place very early, probably during the multicellularization event leading to all the metazoan phyla, and a second occurring later on, corresponding to the advent of vertebrates. Finally, I show that in vertebrate species the various groups of NRs accumulated mutations at very different rates.

Animals↗

PubMed2004

Estimation of the number of authentic orphan genes in bacterial genomes.

Genome annotation produces a considerable number of putative proteins lacking sequence similarity to known proteins. These are referred to as "orphans." The proportion of orphan genes varies among genomes, and is independent of genome size. In the present study, we show that the proportion of orphan genes roughly correlates with the isolation index of organisms (IIO), an indicator introduced in the present study, which represents the degree of isolation of a given genome as measured by sequence similarity. However, there are outlier genomes with respect to the linear correlation, consisting of those genomes that may contain excess amounts of orphan genes. Comparisons of genome sequences among closely related strains revealed that some of the annotated genes are not conserved, suggesting that they are ORFs occurring by chance. Exclusion of these non-conserved ORFs within closely related genomes improved the correlation between the proportion of orphan genes and the IIO values. Assuming that the correlation holds in general, this relationship was used to estimate the number of "authentic" orphan genes in a genome. Using this definition of authentic orphan genes, the anomalies arising from over-assignments, e.g., the percentages of structural annotations, were corrected for 16 genomes, including those of five archaea.

Amino Acid Sequence↗

PubMed2004

Gene silencing by nuclear orphan receptors.

Nuclear orphan receptors represent a large and diverse subgroup in the nuclear receptor superfamily. Although putative ligands for these orphan members remain to be identified, some of these receptors possess intrinsic activating, inhibitory, or dual regulatory functions in development, differentiation, homeostasis, and reproduction. In particular, gene-silencing events elicited by chicken ovalbumin upstream promoter-transcription factors (COUP-TFs); dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1); germ cell nuclear factor (GCNF); short heterodimer partner (SHP); and testicular receptors 2 and 4 (TR2 and TR4) are among the best characterized. These orphan receptors are critical in controlling basal activities or hormonal responsiveness of numerous target genes. They employ multiple and distinct mechanisms to mediate target gene repression. Complex cross-talk exists between these orphan receptors at their cognate DNA binding elements and an array of steroid?nonsteroid hormone receptors, other transcriptional activators, coactivators and corepressors, histone modification enzyme complexes, and components of basal transcriptional components. Therefore, perturbation induced by these orphan receptors at multiple levels, including DNA binding activities, receptor homo- or heterodimerization, recruitment of cofactor proteins, communication with general transcriptional machinery, and changes at histone acetylation status and chromatin structures, may contribute to silencing of target gene expression in a specific promoter or cell-type context. Moreover, the findings derived from gene-targeting studies have demonstrated the significance of these orphan receptors' function in physiologic settings. Thus, COUP-TFs, DAX-1, GCNF, SHP, and TR2 and 4 are known to be required for multiple physiologic and biologic functions, including neurogenesis and development of the heart and vascular system steroidogenesis and sex determination, gametogenesis and embryonic development, and cholesterol?lipid homeostasis.

Animals↗

PubMed2002

Orphan drug product regulation--United States.

The legislative history of the United States Orphan Drug Act began with rare, unanimous approval by the United States Congress. The Act, mid consequently the Regulations, have evolved since then. The two-stage process of Orphan Drug designation and approval is outlined, as well as the incentives that are offered to commercial companies for their implementation. Orphan Drugs are likely to be over-represented among drugs used under "Treatment" INDs. For patent- and "drug-difference" reasons, the benefits under the Orphan Drug Act are especially valuable to those who develop biologics. By any measure, this legislation, which requires only voluntary participation, has been a success; because the human genome is likely to lead to more biologicals than orthodox drugs, this success is likely to continue into the future. But even so, the 18-year experience with Orphan Drugs in the United States has led to some 225 Orphan Product approvals that benefit many millions of patients.

Biological Products↗

PubMed2001

[Orphan drugs: some legal, ethical and economics aspects].

Besides well-known diseases, about 5,000 identified are classed as "orphan" because of the lack of any response in terms of diagnosis, prevention and treatment. The development of drugs for these diseases, intended for a limited number of patients, often requires considerable research, and subsequently, cost. The aim of the present article is to discuss the ethical, political and economic problems relevant to the development and disposal of drugs specifically designed for these diseases, now commonly called "orphan" drugs. These questions have been raised at discussions and dialogues at the European Parliament where European regulations on orphan drugs were adopted on December 15, 1999. These regulations (141/2000/EEC) came into effect in the European Union on January 22, 2000, and are widely inspired from the American model. The regulations stipulate that the criterion for designation of the drug is based on a disease prevalence of 5/10000). Advantages commonly recognized for the orphan drug status concern: community registration (centralized marketing approval), eligibility for grants and national or community fiscal support, lower or canceled registration fees, technical contribution via the European drug agency (EMEA), and exclusive rights for a 10-year period. On May 12, 2000, the European Commission completed the status by adopting rules establishing the criteria used for designating a drug as an orphan drug. This document implements the dispositions available to pharmaceutical firms inciting them to invest in the development of orphan drugs.

Drug Costs↗

PubMed2006

[Hope for patients with rare diseases--"orphan" drugs].

Rare diseases are defined as those affected less than five in every 10 000 person in European Union. The purpose of this paper is to present activities, which make possible to stimulate research development and marketing of appropriate medicine for tretment of rare disease, named "Orphan" medicinal products. EU "Orphan" medicinal products legislation which entered into force in April 2000 is described. Definition of "Orphan" medicinal products as well as the procedure of designation and placing the products into the Community register is presented. Those incentives to industry are described, which are already five years very well implemented oh the European level mostly on the pre-authorisation phase of "Orphan" medicinal products development, but also in the registration process as well as the post-authorisation phase. Finaly, the first twenty "Orphan" medicinal products, which have been given positive opinion in the Community for the grant of a marketing authorisation till April 2005 are mentioned in this work. The real availability of "Orphan" medicinal products in the particular EU member states is analysed.

Drug Approval↗

PubMed1985

Orphan drugs: the question of products liability.

Orphan drugs, essential for the treatment of persons with rare diseases, generally are unprofitable for manufacturers to develop and market. While congressional and administrative efforts to promote the development of orphan drugs have met with modest success, application of products liability doctrine to orphan drug sponsors could subvert those efforts. This Note describes the provisions of the Orphan Drug Act and analyzes products liability law with respect to orphan drug litigation. It argues that the goals of tort law support the imposition of liability for design defect, failure to warn and negligence in testing. Finally, the Note acknowledges that liability costs create disincentives for orphan drug development and suggests mechanisms for reducing manufacturers' liability concerns.

Drug Industry↗

PubMed1993

[Orphan diseases].

Basic investigation in industrial laboratories are mainly addressed to widespread diseases. It follows that: 1) basic research is addressed chiefly to the well known and largely diffuse diseases; 2) rare diseases are not usually studied and therefore little chance is given to their physiopathological or therapeutic knowledge. Hence the name of orphan diseases. The aim of this study is to contribute to the stimulation of innovative and applied basic research of orphan diseases and therefore to gradually confine the number of incurable rare diseases. Our proposal upsets the studies undertaken in some foreign countries and Italy on the orphan drugs (e.g. Orphan Drug Act, issued in the USA in 1982) since we suggest starting from a study on disease more than studies on drug. The planning of studies of disease may be undertaken on various points of view (prevalence, clinical features, prognosis, social cost, etc.), while this may be very hard for the drug. Therefore we suggest starting from a study plane, classification and estimation of rare diseases, shared for apparatus. These studies may be undertaken on a vigorous rationale (more than studies on orphan drugs) and therefore they may bring about to the definition of a national (government) planning for addressing consistent financial resources to the study of pathophysiology and therapy (or prevention) of the major orphan diseases. Adequate studies within the European Community may be planned in the near future, since most rare diseases are presumed to have a common distribution within the Community.

Disease↗

PubMed1998

Orphan neurones and amine excess: the functional neuropathology of Parkinsonism and neuropsychiatric disease.

The aetiology and treatment of Parkinsonism is currently conceptualised within a dopamine (DA) deficiency-repletion framework. Loss of striatal DA is thought to cause motor impairment of which tremor, bradykinaesia and rigidity are prominent features. Repletion of deficient DA should at least minimise parkinsonian signs and symptoms. In Section 2, based on extensive pre-clinical and clinical findings, the instability of this approach to Parkinsonism is scrutinised as the existing negative findings challenging the DA deficiency hypothesis are reviewed and reinterpreted. In Section 3 it is suggested that Parkinsonism is due to a DA excess far from the striatum in the area of the posterior lateral hypothalamus (PLH) and the substantia nigra (SN). This unique area, around the diencephalon/mesencephalon border (DCMCB), is packed with many ascending and descending fibres which undergo functional transformation during degeneration, collectively labelled 'orphan neurones'. These malformed cells remain functional resulting in pathological release of transmitter and perpetual neurotoxicity. Orphan neurone formation is commonly observed in the PLH of animals and in man exhibiting Parkinsonism. The mechanism by which orphan neurones impair motor function is analogous to that seen in the diseased human heart. From this perspective, to conceptualise orphan neurones at the DCMCB as 'Time bombs in the brain' is neither fanciful nor unrealistic [E.M. Stricker, M.J. Zigmond, Comments on effects of nigro-striatal dopamine lesions, Appetite 5 (1984) 266-267] as the DA excess phenomenon demands a different therapeutic approach for the management of Parkinsonism. In Section 4 the focus is on this novel concept of treatment strategies by concentrating on non-invasive, pharmacological and surgical modification of functional orphan neurones as they affect adjacent systems. The Orphan neurone/DA excess hypothesis permits a more comprehensive and defendable interpretation of the interrelationship between Parkinsonism and schizophrenia and other related disorders.

Acute Disease↗

PubMed2003

Dimensions of the emerging orphan crisis in sub-Saharan Africa.

This study uses recent Demographic and Health Survey (DHS) data to examine levels, trends, and differentials in orphan prevalence in sub-Saharan Africa. The first part of the analysis presents direct estimates of orphan prevalence in 17 countries during the period 1995-2000. We find a strong correlation between orphanhood prevalence and national adult HIV prevalence estimates lending support to the interpretation of the orphan crisis as, in large part, AIDS-related. The second part of the analysis consists of an in-depth study of trends and age-patterns in orphan prevalence and welfare in the 1990s for five countries that have had widely divergent HIV prevalence levels (Zimbabwe, Kenya, Tanzania, Ghana, and Niger). The vulnerability of orphans with respect to their situation in households and educational opportunities is evaluated in relation to non-orphans' experience. The results of the analysis indicate that losing one or both parents is significantly associated with diminished chances of being at the appropriate grade level for age. Our results are interpreted in the context of societal responses to the crisis, and potential recommendations for intervention.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Dependence symptoms but no diagnosis: diagnostic 'orphans' in a community sample.

To receive a DSM-IV diagnosis of alcohol dependence, an individual must manifest at least three out of seven possible dependence criteria. Thus, individuals may manifest one or two dependence criteria yet not receive the dependence diagnosis. In a sense, these latter individuals may be seen as diagnostic 'orphans', since they have individual symptoms of dependence but no diagnoses. A study of these individuals sheds light on the validity of the three-symptom severity threshold for a diagnosis of DSM-IV alcohol dependence. Thus, we investigated the meaning of the 'orphan' status through cross-sectional and longitudinal research in a general population sample. Three groups were compared at baseline, subjects with no symptoms of any alcohol use disorder (148), diagnostic 'orphans' with one or two symptoms of dependence (136) and subjects who met full criteria for DSM-IV alcohol dependence (140). Several variables significantly differentiated the three groups, including binge drinking and family history of alcoholism. At a 1-year follow-up point, very few of the 'orphans' met criteria for DSM-IV alcohol dependence. The proportion of new onsets from the 'orphan' group and the group with no symptoms did not differ significantly. Binge drinking predicted chronicity of 'orphan' status, but family history of alcoholism did not. The results support the decision to require a minimum of three symptoms to make a diagnosis of alcohol dependence.

Adult↗

PubMed1999

Identification of the histamine H1 receptor gene as a differentially repressed target of the human TR2 orphan receptor.

We have identified a DNA response element (TR2RE-HR) in the 3' flanking region of the human histamine H1 receptor gene as a target for the TR2 orphan receptor, a member of the steroid/thyroid hormone receptor superfamily. The application of both tetracycline inducible and improved differential display systems has allowed us to isolate a cDNA fragment differentially regulated by the expression of the TR2 orphan receptor. Northern blot and sequencing analysis demonstrated that the expression of the human histamine H1 receptor gene was differentially repressed by the TR2 orphan receptor. Electrophoretic mobility shift assay further revealed a specific binding (dissociation constant = 26.2 nM) between the TR2 orphan receptor and the wildtype TR2RE-HR, but not the mutant TR2RE-HR. In addition, reporter gene expression assay indicated that the TR2 orphan receptor may suppress the expression of luciferase activities in a dose-dependent manner via the TR2RE-HR in HeLa cells. Our results demonstrate that the histamine H1 receptor gene could represent one of the target genes directly regulated by the human TR2 orphan receptor.

Base Sequence↗

PubMed2005

The orphans of Eritrea: what are the choices?

The authors examined the emotional well-being, adaptability, and emotional distress of 10-13 year-old Eritrean war orphans cared for in 3 different social environments and 1 group of home-reared children using 2 scales of the Behavioral Assessment System for Children and informal interviews with the children. Orphans reunified with extended families had greater adaptive skills than institutional orphans but as many signs and symptoms of emotional distress as orphanage children. Group-home orphans had fewer signs and symptoms of emotional distress and greater adaptive skills than either reunified or institutional orphans, and they had fewer symptoms of emotional distress than home-reared children. However, placing orphans in small group homes was far more expensive than reunifying them with extended families. The public policy implications of the findings for the protection of unaccompanied children in impoverished developing countries are discussed.

Adaptation, Psychological↗