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PubMed2003

Children orphaned by AIDS: a global perspective.

Internationally, the orphan crisis caused by the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pandemic remains a serious issue with long-term social consequences. At the end of 2001, an estimated 14 million children worldwide had lost their mother or both parents to AIDS or related causes. Sub-Saharan Africa is the most severely affected, accounting for more than 80 percent of those orphaned as a result of AIDS. Without the care of parents or an appointed caregiver, children are likely to face extraordinary risks of malnutrition, poor health, inadequate schooling, migration, homelessness, and abuse. Strengthening existing family and community capacity to assist orphans in Africa should be the first priority. Community support must be coupled with support for education for orphans. Combining local and international responses to deliver protection and services to all orphans and vulnerable children is critical. In addition, saving the lives of parents through access to antiretroviral therapies in resource-poor countries in conjunction with bold support for alleviation of poverty and education must be an integral part of the global response to the orphan crisis in sub-Saharan Africa.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Suppression of the human erythropoietin gene expression by the TR2 orphan receptor, a member of the steroid receptor superfamily.

A DNA response element, TR2RE-EPO (5'-TCTGACCTCTCGACCTAC-3') has been identified in the 3-minimal hypoxia-inducible enhancer of the human erythropoietin gene for the TR2 orphan receptor, an androgen-repressed transcription factor and a member of the steroid/thyroid hormone receptor superfamily. Electrophoretic mobility shift assay showed a specific binding with high affinity (Kd = 0.14 nM) between the TR2 orphan receptor and the TR2RE-EPO. Our data further indicated that this specific binding is not due to the homo-dimerization of the TR2 orphan receptor. In addition, reporter gene expression using chloramphenicol acetyltransferase assay demonstrated that the TR2 orphan receptor may suppress the expression of the chloramphenicol acetyltransferase activities via the TR2RE-EPO in the hypoxic/normoxic human hepatoma HepG2 cells. Finally, our in situ hybridization data also indicated that the TR2 orphan receptor and the erythropoietin transcripts can be co-expressed in mouse kidney and liver. Together, our data suggest that the human erythropoietin gene could represent the first human target gene regulated directly by the human TR2 orphan receptor.

Animals↗
PubMed1996

Two receptor interaction domains in the corepressor, N-CoR/RIP13, are required for an efficient interaction with Rev-erbA alpha and RVR: physical association is dependent on the E region of the orphan receptors.

Rev-erbA alpha and RVR/Rev-erb beta/BD73 are orphan steroid receptors that have no known ligands in the 'classical sense'. These 'orphans' do not activate transcription, but function as dominant transcriptional silencers. The thyroid hormone receptor (TR) and the retinoic acid receptor (RAR) act as transcriptional silencers by binding corepressors (e.g. N-CoR/RIP13 and SMRT/TRAC-2) in the absence of ligands. The molecular basis of repression by orphan receptors, however, remains obscure, and it is unclear whether these corepressors mediate transcriptional silencing by Rev-erbA alpha and RVR. Recently, two new variants of N-CoR have been described, RIP13a and RIP13delta1. The characterisation of these splice variants has identified a second receptor interaction domain (ID-II), in addition to the previously characterised interaction domain (ID-I). This investigation utilised the mammalian two hybrid system and transfection analysis to demonstrate that Rev-erbA alpha and RVR will not efficiently interact with either ID-I or ID-II separately from RIP13a or RIP13delta1. However, they interact efficiently with a domain composed of ID-I and ID-II from RIP13a. Interestingly, the interaction of Rev-erbA alpha and RVR is strongest with ID-I and ID-II from RIP13delta1. Detailed deletion analysis of the orphan receptor interaction with RIP13/N-CoR rigorously demonstrated that the physical association was critically dependent on an intact E region of Rev-erbA alpha and RVR. Over-expression of the corepressor interaction domains (i.e. dominant negative forms of N-CoR/RIP13) could alleviate orphan receptor-mediated repression of transactivation by GALVP16. This demonstrated that these regions could function as anti-repressors. In conclusion, these data from two independent approaches demonstrate that repression by Rev-erbA alpha and RVR is mediated by an interaction of ID-I and ID-II of N-CoR, RIP13a and delta1 with the putative ligand binding domain of the orphan receptors.

DNA-Binding Proteins↗
PubMed1998

The orphans of Eritrea: are orphanages part of the problem or part of the solution?

OBJECTIVE: This study compared the mental health and cognitive development of 9- to 12-year-old Eritrean war orphans living in two orphanages that differed qualitatively in patterns of staff interaction and styles of child care management. METHOD: The directors and several child care workers at each institution were asked to complete staff organization and child management questionnaires. The psychological state of 40 orphans at each institution was evaluated by comparing their behavioral symptoms and performance on cognitive measures. RESULTS: Orphans who lived in a setting where the entire staff participated in decisions affecting the children, and where the children were encouraged to become self-reliant through personal interactions with staff members, showed significantly fewer behavioral symptoms of emotional distress than orphans who lived in a setting where the director made decisions, daily routines were determined by explicit rules and schedules, and interactions between staff members and the children were impersonal. CONCLUSIONS: When orphanages are the only means of survival for war orphans, a group setting where the staff shares in the responsibilities of child management, is sensitive to the individuality of the children, and establishes stable personal ties with the children serves the emotional needs and psychological development of the orphans more effectively than a group setting that attempts to create a secure environment through an authoritative style of management with explicit rules and well-defined schedules.

Adaptation, Psychological↗
PubMed1998

Antisense TR3 orphan receptor can increase prostate cancer cell viability with etoposide treatment.

In androgen-responsive LNCaP human prostatic cancer cells, human TR3 orphan receptor, a member of the steroid receptor superfamily, can be rapidly induced by androgen. In contrast, ablation of androgen by castration can induce the expression of the TR3 orphan receptor gene in rat ventral prostate that has undergone apoptosis. This phenomenon prompted us to further analyze the potential role of human TR3 orphan receptor in prostate cancer cells in which apoptosis had been induced. Northern blot analysis shows that human TR3 orphan receptor expression can be induced rapidly after treatment of LNCaP and PC-3 prostate cancer cells with calcium ionophore or etoposide. Our data further demonstrate that a much higher concentration of etoposide was needed to kill the same number of cells in LNCaP and PC-3 cells transfected stably with antisense TR3 orphan receptor compared with that in control vector transfectants. Together, our data suggest that the human TR3 orphan receptor may play an important role in modulating drug-induced prostate apoptosis.

Androgens↗
PubMed2004

Orphans in Africa: parental death, poverty, and school enrollment.

We examine the impact of orphanhood on children's school enrollment in 10 sub-Saharan African countries. Although poorer children in Africa are less likely to attend school, the lower enrollment of orphans is not accounted for solely by their poverty. We find that orphans are less likely to be enrolled than are nonorphans with whom they live. Consistent with Hamilton's rule, the theory that the closeness of biological ties governs altruistic behavior, outcomes for orphans depend on the relatedness of orphans to their household heads. The lower enrollment of orphans is largely explained by the greater tendency of orphans to live with distant relatives or unrelated caregivers.

Adolescent↗
PubMed2003

A five-year prospective study of diagnostic orphans for alcohol use disorders.

OBJECTIVE: One consequence of the DSM-IV diagnostic system for substance abuse and dependence is that there are individuals who might endorse one or two of the criterion items for dependence but not meet criteria for abuse. These persons have been referred to as "diagnostic orphans." The aim of the analyses presented here is to further understanding about this potentially important group. METHOD: The DSM-IV categorical approach was used to determine alcohol-related diagnoses for 439 young adult men. Structured face-to-face follow-up interviews were administered 5 years later. RESULTS: At the beginning of the evaluation period, 14.6% (n = 64) of the men were alcohol dependent, 18.2% (n = 80) fulfilled criteria for alcohol abuse, 16.4% (n = 72) did not meet criteria for an alcohol use disorder but endorsed one or two of the dependence criteria and 50.8% (n = 223) reported none of the dependence items. At the initial interview, and again 5 years later, the diagnostic orphans reported alcohol and drug use histories that fell between the histories of those with dependence and those with no alcohol-related difficulties. The orphans were most similar to the men with abuse, although they had lower quantities and frequencies of alcohol use, endorsed fewer additional alcohol-related problems and reported less involvement with drugs compared with that group. CONCLUSIONS: Although the diagnostic orphans were more similar to the subjects with alcohol abuse than they were to those with dependence or no diagnosis, the data do not necessarily support combining the orphans with those with abuse. These diagnostic orphans do, however, constitute an important group that carries an enhanced risk for alcohol use disorders and should be closely followed.

Adult↗
PubMed1996

AIDS orphans in Louisiana in the year 2000: the potential economic impact on the foster care system.

This study estimates the number of AIDS orphans in Louisiana and projects the fiscal demand on the state's foster care system in the year 2000. The Michaels and Levine model is used to estimate the number of orphans, and state foster care data are used to project the placement cost of those AIDS orphans. Between 1992 and the year 2000, the AIDS orphan count in Louisiana is estimated to range between 1,242 and 2,627 infants and children. Black children are estimated to comprise the overwhelming majority of this population. If only 50% of the AIDS orphans this study projects for the year 2000 require foster care services, the state of Louisiana would need additional revenues for that year alone, ranging from $308,112 to $624,546, to serve those new entrants. This study provides a critical starting point for state policy planning. The AIDS orphan population in Louisiana is growing each year and the needs of these infants and children must be anticipated and accommodated.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Radiopharmaceuticals as orphan drugs.

Rare diseases and conditions are defined as diseases or conditions that affect less than 200,000 individuals in the United States. Because of the limited population suffering from any given rare disorder, there is little economic motivation for the development of drug products for its diagnosis or treatment. Also, frequently these rare diseases are misdiagnosed or undiagnosed due to a lack of familiarity with their symptoms and course. Thus, these rare disorders are commonly referred to as orphan diseases or conditions. To address this problem, legislation has been enacted that provides for incentives for the development of drug products for rare diseases or conditions (i.e., orphan drug products). Nuclear medicine scientists can take advantage of these incentives in the development of orphan radiopharmaceuticals for the treatment or diagnosis of rare diseases or conditions. Nuclear medicine physicians should know where information on orphan diseases and orphan radiopharmaceuticals can be obtained to maximize the care of their patients.

Disease↗
PubMed1992

Evolution and current status of the Orphan Drug Act.

The 1983 Orphan Drug Act was designed in response to market and regulatory disincentives that limited industrial interest in developing drugs needed by people in the United States with rare diseases and conditions. These disincentives evolved from changes in the pharmaceutical industry and in regulatory testing requirements. In the eight years since the Act and subsequent amendments have been in effect, the law has been associated with the new development and approval of 40 marketed drugs and 12 biologicals to treat rare (orphan) diseases. An additional 281 drugs and 141 biologicals have been entered into development and designated as orphans. Finally, the law has mandated exploration of whether the incentives of the Act are necessary and appropriate for stimulating industrial development of orphan medical drugs and devices. Despite this progress, controversies have arisen over three profitable orphan products that have benefited from the law's provisions. This has created the need for continued assessment of the Act's benefits and costs.

Drug Approval↗
PubMed2002

Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study.

As new lead discovery technologies of high throughput screening and rational drug design have been incorporated into pharmaceutical and biotechnology drug discovery programs, researchers have focused on the applying these new technologies in diseases traditionally neglected by for-profit drug discovery efforts. This article reviews general trends in orphan disease lead discovery, identifies best practices of orphan market drug discovery and provides an overview of recent ALS lead discovery programs and drug development according to these metrics. Best practices in orphan market drug discovery embodied by programs like the NIH Anticonvulsant Screening Program include the (1) management of timelines and priorities, (2) engagement of for-profit partners, (3) creative application of technology, (4) collaboration, and (5) flexibility. Recent trends in ALS lead discovery have been shaped not only by the predominance of animal models of disease over in vitro models, but also by the successes and best practices of these earlier orphan market drug discovery programs. The ALS Treatment Initiative, the Johns Hopkins Center for ALS Research, the ALS Association, and the ALS Therapy Development Foundation have all initiated lead discovery programs in the past several years which seek to utilize existing experimental models of the disease and challenge assumptions about the linear nature of the lead discovery and development process. The compounds currently in clinical evaluation for ALS were identified as leads from a variety of sources, further reinforcing the transforming effect these new lead discovery programs have had on drug discovery and development in ALS. We conclude our review with an overview of the challenges and opportunities lead discovery in ALS currently faces, ultimately concluding that ALS lead discovery, and indeed orphan market drug discovery in general, would most benefit from more centralized lead discovery management, expanded national access to core facilities for lead discovery, and matrixed simultaneous screening of multiple compounds for multiple neglected diseases.

Amyotrophic Lateral Sclerosis↗
PubMedDate not supplied

[Orphan drugs and metabolic disorders].

INTRODUCTION: Over the past twenty years the legal and philosophical concept of orphan diseases has developed to include the diseases with an incidence in the general population of less than 1/5,000. Treatment of these conditions, which is very specific, requires drugs which will be used by a very small number of patients and are therefore not profitable from the financial point of view. This gives rise to the concept of orphan drugs which lack sponsorship, are expensive to investigate and develop, are little used and therefore there is little incentive to market them. All metabolic disorders due to genetic defects may be considered to be orphan diseases , since their incidence in the population is less than 1/5,000 and there may be only a negligible incidence of 1/37,000,000. DEVELOPMENT: In this study we discuss the treatment of three orphan metabolic diseases, which severely affect the central nervous system by different mechanisms, by three orphan drugs which solve the problems of only a few patients. We describe the treatment of: (1) the deficiency of the synthesis of tetrahydrobiopterin, which causes neurotransmitter deficiency, with tetrahydrobiopterin, (2) N acetylglutamate sythetase deficiency, which causes severe hyperammonaemia and cerebral oedema, with N carbamyl glutamate (3) cystathionine synthetase deficiency which causes hyperhomocyteinaemia and a high risk of thromboembolic accidents, with Betaine.

Acetyltransferases↗
PubMed1993

The use of a DNA-binding domain replacement method for the detection of a potential TR3 orphan receptor response element in the mouse mammary tumor virus long terminal repeat.

TR3 orphan receptor is a human homologue of the mouse nur77, N10 and rat NGFI-B, TIS1 genes which may represent an early response gene involved in the control of cell proliferation. We have studied potential target genes for TR3 orphan receptor using the DNA-binding domain replacement method. We found that mouse mammary tumor virus long terminal repeat-linked chloramphenicol acetyltransferase expression can be activated in transfected cells by a chimeric androgen receptor/TR3 orphan receptor/androgen receptor construct (AR/TR3/AR) in the presence of androgen. By deletion analysis, a region with 20 nucleotides in length between positions -1178 and -1159 of the mouse mammary tumor virus long terminal repeat was confirmed as a potential TR3 orphan receptor response element. These results suggest that feasibility of using the DNA-binding domain replacement method to detect target sequences of orphan receptors.

Androgens↗
PubMed2000

Cloning and characterization of human NTT5 and v7-3: two orphan transporters of the Na+/Cl- -dependent neurotransmitter transporter gene family.

Orphan transporters form a growing subfamily of genes related by sequence similarity to the Na+/Cl- -dependent neurotransmitter superfamily. Using a combination of database similarity searching and cloning methods, we have identified and characterized two novel human orphan transporter genes, v7-3 and NTT5. Similar to other known orphan transporters, v7-3 and NTT5 contain 12 predicted transmembrane domains, intracellular N- and C-terminal domains, and large extracellular loops between transmembrane (TM) domains 3 and 4 and between TM domains 7 and 8. Residues within the extracellular loops are also predicted to contain sites for N-linked glycosylation. Human v7-3, the species orthologue of rat v7-3, contains an open reading frame (ORF) of 730 amino acids. Human NTT5 is a new member of the orphan transporter family and has an ORF of 736 amino acids. The amino acid sequences of human v7-3 and NTT5 are greater than 50% similar to other known orphan neurotransmitter transporters and also show sequence similarity to the human serotonin and dopamine transporters. Radiation hybrid mapping located the human v7-3 and NTT5 genes on chromosomes 12q21.3-q21.4 and 19q13.1-q13.4, respectively. Human mRNA distribution analysis by TaqMan reverse transcription-polymerase chain reaction showed that v7-3 mRNA is predominantly expressed in neuronal tissues, particularly amygdala, putamen, and corpus callosum, with low-level expression in peripheral tissues. In contrast, NTT5 mRNA was highly expressed in peripheral tissues, particularly in testis, pancreas, and prostate. Transient transfection with epitope-tagged transporter constructs demonstrated v7-3 to be expressed at the cell surface, whereas NTT5 was predominantly intracellular, suggestive of a vesicular location. Although the substrates transported by these transporters remain unknown, their specific but widespread distribution suggests that they may mediate distinct and important functions within the brain and the periphery.

AMP-Activated Protein Kinases↗
PubMed2001

Local brain functional activity following early deprivation: a study of postinstitutionalized Romanian orphans.

Early global deprivation of institutionalized children may result in persistent specific cognitive and behavioral deficits. In order to examine brain dysfunction underlying these deficits, we have applied positron emission tomography using 2-deoxy-2-[(18)F]fluoro-D-glucose in 10 children (6 males, 4 females, mean age 8.8 years) adopted from Romanian orphanages. Using statistical parametric mapping (SPM), the pattern of brain glucose metabolism in the orphans was compared to the patterns obtained from two control groups: (i) a group of 17 normal adults (9 males, 8 females, mean age 27.6 years) and (ii) a group of 7 children (5 males and 2 females, mean age 10.7 years) with medically refractory focal epilepsy, but normal glucose metabolism pattern in the contralateral hemisphere. Consistent with previous studies of children adopted from Romanian orphanages, neuropsychological assessment of Romanian orphans in the present study showed mild neurocognitive impairment, impulsivity, and attention and social deficits. Comparing the normalized glucose metabolic rates to those of normal adults, the Romanian orphans showed significantly decreased metabolism bilaterally in the orbital frontal gyrus, the infralimbic prefrontal cortex, the medial temporal structures (amygdala and head of hippocampus), the lateral temporal cortex, and the brain stem. These findings were confirmed using a region-of-interest approach. SPM analysis showed significantly decreased glucose metabolism in the same brain regions comparing the orphans to the nonepileptic hemisphere of the childhood epilepsy controls. Dysfunction of these brain regions may result from the stress of early global deprivation and may be involved in the long-term cognitive and behavioral deficits displayed by some Romanian orphans.

Adoption↗
PubMed1999

The quest for novel bioactive peptides utilizing orphan seven-transmembrane-domain receptors.

Various sorts of bioactive molecules including hormones, neurotransmitters, and chemokines transmit signals into cells by binding to so-called seven-transmembrane-domain receptors (7TMRs). The recent progress in cDNA and genome DNA analyses has brought the discovery of numerous genes encoding ligand-unknown "orphan" 7TMRs. We have developed a strategy to identify the ligands of orphan 7TMRs by monitoring specific signal transductions induced in cells expressing orphan 7TMRs. Employing this method, we succeeded in identifying the natural ligands of the orphan 7TMRs, hGR3, and APJ. The ligand peptide identified for hGR3 was found to show a specific prolactin release promoting activity in rat anterior pituitary cells in in vitro culture and was therefore named "prolactin-releasing peptide." We named another novel bioactive peptide "apelin," for "APJ endogenous ligand." Although the biological functions of apelin are still under investigation, APJ reportedly acts as a coreceptor in the process of human immunodeficiency virus infection. We believe that the identification of orphan 7TMR ligands will provide clues to reveal the unknown regulatory mechanisms of various physiological phenomena and opportunities for novel drug discovery in the future.

Animals↗
PubMed2003

Changing patterns of orphan care due to the HIV epidemic in western Kenya.

The HIV/AIDS epidemic has given rise to major demographic changes including an alarming number of orphans in sub-Saharan Africa. The study describes a rural community in western Kenya in which one out of three children below 18 years of age had lost at least one biological parent-and one out of nine had lost both. The main problems these children faced were lack of school fees, food and access to medical care. The high number of orphans has overwhelmed the traditional mechanisms for orphan care, which were based on patrilineal kinship ties. Thus, 28% of the orphans were looked after by culturally "inappropriate" categories such as matrilineal kin or strangers. Furthermore, many of the caretakers were themselves not capable due to ill health or old age. Factors such as poverty, negative attitudes, and traditional funeral customs made the orphans' situation even worse. The authors conclude that though community-based interventions are urgently needed as the most appropriate way to address the issue, the complex, local reality in which cultural factors, kinship ties, and poverty are interwoven needs to be taken into consideration if sustainable solutions are to be found.

Adolescent↗
PubMed2003

An ultra-HTS process for the identification of small molecule modulators of orphan G-protein-coupled receptors.

G-protein-coupled receptors (GPCRs) are the most successful target proteins for drug discovery research to date. More than 150 orphan GPCRs of potential therapeutic interest have been identified for which no activating ligands or biological functions are known. One of the greatest challenges in the pharmaceutical industry is to link these orphan GPCRs with human diseases. Highly automated parallel approaches that integrate ultra-high throughput and focused screening can be used to identify small molecule modulators of orphan GPCRs. These small molecules can then be employed as pharmacological tools to explore the function of orphan receptors in models of human disease. In this review, we describe methods that utilize powerful ultra-high-throughput screening technologies to identify surrogate ligands of orphan GPCRs.

Drug Design↗