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PubMed1985

A method to assess the environment for genetic studies: the Common Environment Index and the Household Relationships Interview.

Genetic and environmental influences in causing a disease are difficult to measure because of lack of precision in identification of relevant nongenetic variables. The Household Relationships Interview and Schedule was developed to measure shared common environment in families (Common Environment Index) and to take into account developmental stages throughout the life cycle and separation/disruption. Seven trained persons interviewed three individuals who reported fictitious interrelated life histories varying in length and complexity. Discrepancies between the recorded data and the true data were analyzed. Overall 96.1% of the items were recorded correctly. Thus, the method has shown good face and construct validity and reliability for measuring quantity of time shared by relatives in a common household. Common environment as measured by this instrument should be a particularly useful tool in behavior-genetic studies.

Environment↗

PubMedDate not supplied

Evidences on weaknesses and strengths from health financing after decentralization: lessons from Latin American countries.

OBJECTIVE: The main objective was to identify trends and evidence on health financing after health care decentralization. STUDY DESIGN: Evaluative research with a before-after design integrating qualitative and quantitative analysis. Taking into account feasibility, political and technical criteria, three Latin American countries were selected as study populations: Mexico, Nicaragua and Peru. DATA SOURCES: The methodology had two main phases. In the first phase, the study referred to secondary sources of data and documents to obtain information about the following variables: type of decentralization implemented, source of finance, funds of financing, providers, final use of resources and mechanisms for resource allocation. In the second phase, the study referred to primary data collected in a survey of key personnel from the health sectors of each country. FINDINGS: The trends and evidence reported in all five financing indicators may identify major weaknesses and strengths in health financing. CONCLUSIONS: Weaknesses: a lack of human resources trained in health economics who can implement changes, a lack of financial resource independence between the local and central levels, the negative behavior of the main macro-economic variables, and the difficulty in developing new financing alternatives. Strengths: the sharing between the central level and local levels of responsibility for financing health services, the implementation of new organizational structures for the follow-up of financial changes at the local level, the development and implementation of new financial allocation mechanisms taking as a basis the efficiency and equity principles, new technique of a per-capita adjustment factor corrected at the local health needs, and the increase of financing contributions from households and local levels of government.

Decision Making, Organizational↗

PubMed1991

Growth factors and tyrosine protein kinases in normal and malignant melanocytes.

Melanomas are highly variable with respect to aberrant gene expression and chromosomal lesions but share a common characteristic of an acquired independence from environmental growth factors that are needed for proliferation of normal melanocytes. Receptors with tyrosine kinase activity play a critical role in normal melanocyte proliferation and in the uncontrolled growth of melanomas. Normal human melanocytes depend on exogenous peptide growth factors such as basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), or mast cell growth factor (MGF), all of which stimulate receptors with tyrosine kinase activity. In contrast, human melanoma cells from primary nodular and metastatic lesions grow autonomously partially because of inappropriate production of bFGF and continuous activation of the bFGF-receptor kinase. Animal models also provide evidence for the importance of receptor-tyrosine kinases in normal melanocyte proliferation and in malignant transformation. In the mouse, genes residing in three loci in which inactivation mutations lead to piebaldism, the dominant spotting (W), patch (Ph), and Sl encode, respectively, the receptor-kinases c-kit and platelet derived growth factor receptor, and the ligand for c-kit: MGF. In vivo transformation of mouse melanocytes to melanoma, due to constitutive expression of a transmembrane tyrosine kinase, the oncogene ret, was recently demonstrated in transgenic mice. Studies on a fish model, Xiphophorus, in which melanoma is inherited, showed that the dominant tumor inducing gene, Tu, encodes an EGF-receptor related tyrosine kinase which is expressed only in melanomas and not in normal tissues. Taken together, the results suggest that the uncontrolled growth of melanomas is due, in large part, to constitutive activation of receptors with tyrosine kinase activity.

Animals↗

PubMed1987

Biological differences among MCF-7 human breast cancer cell lines from different laboratories.

MCF-7 human breast cancer cells are used widely for studies of tumor biology and hormone mechanism of action. Conflicting results have often been obtained in studies reported from different laboratories. In this report several biological properties were studied in four MCF-7 cell lines obtained from different laboratories. MCF-7 (ATCC), MCF-7, MCF-7 (KO), and MCF-7 (S) demonstrated similar morphology in monolayer culture. Chromosome analysis revealed that three of the lines shared several structural chromosome alterations and marker chromosomes; however, MCF-7 (ATCC) was distinctly different with virtually no chromosomal alterations shared in common with the other lines. All four lines contained variable amounts of estrogen receptor (ER) and progesterone receptor (PgR). The growth rate of MCF-7 (ATCC) was 50% slower than that of the other lines, and, unlike the other three lines, cell proliferation was unaffected by estrogen or antiestrogen treatment despite the presence of receptors. Cloning efficiency of the four lines varied over a 10-fold range. Tumorigenicity in athymic nude mice also varied considerably among these lines. MCF-7 (ATCC) grew well in ovariectomized nude mice, while the other lines required estrogen supplementation. MCF-7 (S) and MCF-7 grew rapidly with estrogen supplementation; MCF-7 (KO) grew very slowly. Antiestrogen therapy inhibited growth of MCF-7, MCF-7 (S), and MCF-7 (KO) tumors, but it had no effect on MCF-7 (ATCC). These data demonstrate that MCF-7 lines from different laboratories may have unique biological properties, despite having a similar karyotype (MCF-7, MCF-7 (S), MCF-7 (KO]. The fundamental differences in karyotype and biological properties of the MCF-7 (ATCC), and the previously reported differences in DNA restriction fragment polymorphism analyses, demonstrate that this line is derived from an entirely different patient. Investigators should carefully document the source and identity of MCF-7 cells used in published experiments.

Agar↗

PubMed1996

Comparison of the new atypical antipsychotics olanzapine and ICI 204,636 with clozapine on behavioural responses to the selective "D1-like" dopamine receptor agonist A 68930 and selective "D2-like" agonist RU 24213.

The effects of the putative atypical antipsychotics olanzapine and ICI 204,636 on behavioural responses to the selective "D2-like" dopamine receptor agonist RU 24213 and to the selective "D1-like" agonist A 68930 were compared with those of the prototype atypical antipsychotic clozapine, the selective D1-like antagonist SCH 23390 and the selective D2-like antagonist YM 09151-2. Olanzapine (0.4-2.0 mg/kg) and ICI 204,636 (4.0-36.0 mg/kg), like clozapine (4.0-36.0 mg/kg) and SCH 23390 (0.01-1.0 mg/kg), effected at best modest reduction in typical sniffing and locomotor responses and, with the exception of ICI 204,636, released episodes of atypical myoclonic jerking to RU 24213 (12.5 mg/kg); a high dose of olanzapine (10.0 mg/kg), like YM 09151-2 (0.005-0.5 mg/kg), blocked all responsivity to RU 24213. Conversely, olanzapine (0.4-2.0 mg/kg) and ICI 204,636 (4.0-36.0 mg/kg), like clozapine (4.0-12.0 mg/kg) and SCH 23390 (0.01-0.1 mg/kg), readily blocked typical grooming responses to A 68930 (0.5 mg/kg); YM 09151-2 failed to block grooming and exerted more variable effects. Olanzapine and, to a lesser extent, ICI 204,636 share with clozapine a preferential action to attenuate D1-mediated function; given their lack of selective affinity for D1-like receptors, this common effect may be exerted at an alternative level of synaptic function. The action of olanzapine and particularly ICI 204,636 to release additional episodes of atypical vacuous chewing to A 68930 indicates some deviation from a wholly clozapine-like profile, the clinical significance of which remains to be specified.

Animals↗

PubMed1995

Expression of extracellular domain peptides of the FSH receptor and their effect on receptor-ligand interactions in vitro.

Follicle-stimulating hormone receptor (FSH-R) displays considerable homology to luteinizing hormone receptor (LH-R) in structure and amino acid sequence. Comparison of the sequences of the extracellular domains (ECD) of the receptors reveals two regions (amino acids 4-56 and 265-319 in FSH-R) that share relatively little amino acid sequence similarity. This suggests that these variable regions may be important in providing specificity of ligand binding. We have expressed overlapping ECD peptides containing one or both of these regions (RFI, amino acids 5-125; RF2, amino acids 201-319; and RF3, amino acids 5-319) as fusion proteins in E. coli using pRSET vector. The presence of polyhistidine at the N-terminal end allowed substantial purification of the expressed proteins by a single step of affinity chromatography. The purified peptides were characterized for direct binding of hormone and their ability to block the binding of FSH and LH to the receptors. None of the peptides bound labelled hormone, while all peptides inhibited the binding of FSH to its receptor in a dose-dependent manner. However, only RF2 peptide inhibited ligand binding in a hormone-specific manner. These data suggest there is a site between amino acids 201-319 of the FSH-R ECD that is involved in FSH binding.

Amino Acid Sequence↗

PubMed2006

Nucleotide variability of HV-I in Afro-descendents populations of the Brazilian Amazon Region.

The analysis of genetic variation in the nucleotide sequences of mitochondrial DNA, provides unique information about the population diversity and human identification. In this study, the mitochondrial DNA sequences of the first hypervariable region (HV-I) were analyzed in 243 unrelated individuals of seven Afro-descendents populations of the Amazon Region. Sequence polymorphisms were detected using PCR and direct sequencing analysis. A total of 133 different haplotypes were found determined by 97 variable nucleotides. Each one of the three more frequent haplotypes was shared by 9 samples and 91 sequences were unique. The genetic diversity was estimated to 0.9898+/-0.0016 and the probability of two random individuals showed identical mitochondrial DNA (mtDNA) haplotypes were 1.2%.

Black People↗

PubMed2026

Multi-omics integration and colocalization analyses prioritize candidate molecular loci associated with hypothermia.

BACKGROUND: Hypothermia is a life-threatening condition lacking specific pharmacological treatments. This study aimed to prioritize genetically supported molecular loci associated with hypothermia and to explore their pharmacological tractability using multi-omics data. METHODS: Initially, 2532 druggable genes were curated from the Drug-Gene Interaction Database and established literature. These were cross-referenced with cis-eQTL and cis-pQTL datasets, encompassing 870,655 and 114,281 SNPs for blood, respectively, alongside 2379 shared SNPs across adipose, skeletal muscle, and heart tissues. Matched instrumental variables were integrated with hypothermia GWAS summary statistics for two-sample Mendelian randomization (MR) and Bayesian colocalization. Transcriptomic differential expression analysis (DEA) was subsequently conducted as an exploratory analysis of cold-exposure-associated expression changes. Database-derived compound annotations were systematically re-evaluated according to target specificity, established pharmacological mechanism, and concordance with the direction of the MR estimates. RESULTS: Among 671 gene-level MR tests, 36 genes reached nominal significance, whereas only ABCC8 remained significant after FDR correction. Colocalization was evaluable for 8 of these 36 genes, and 4 loci (COL18A1, SLC1A7, ADIPOQ, and MERTK) met the prespecified PP.H4>0.90 threshold. The remaining 28 loci were not evaluable because sufficient overlapping regional variants were unavailable after harmonization. Transcriptomic analysis identified altered expression of SLC1A3 and SLCO4A1 under cold exposure, although these findings did not directly validate the colocalization-supported loci. Re-evaluation of database-derived compound annotations did not identify any direct, selective, and directionally concordant drug-repurposing candidate for hypothermia. CONCLUSIONS: COL18A1, SLC1A7, ADIPOQ, and MERTK showed colocalization support among the 8 evaluable nominal MR-associated loci. Because colocalization coverage was limited, these genes should be regarded as preliminary candidate loci rather than established therapeutic targets. The pharmacological annotations were indirect, non-selective, unsupported, or directionally inconsistent and should be interpreted solely as hypothesis-generating information.

Bayesian colocalization↗

PubMed2004

Role of environment and behaviour in familial resemblances of Plasmodium falciparum infection in a population of Senegalese children.

Despite the importance of both environment and behaviour in vector-borne disease epidemiology, these factors are unable to explain alone the distribution of cases in a community and the diversity of clinical presentations, suggesting the involvement of more individual factors such as age, sex, immunity or genetic background. The existence of a genetic factor involved in the susceptibility/resistance to a disease can be suspected by the demonstration of a familial aggregation of cases or by the stability over time of infectious status (infected vs. uninfected; mean level of parasite density (PD), etc.). These familial resemblances can be explained by shared environment, family habits and behaviours (use of bed nets, field activities, etc.). In this preliminary study, we essentially investigated the influence of environment and behaviour on Plasmodium falciparum infection levels and reported the effects of these factors on the existence of familial resemblances. Our results are consistent with the existence of familial resemblances for both the level of P. falciparum infection and the qualitative infection status (QIS) (infected vs. uninfected) that seem to be more related to shared behaviour and environment than to a genetic factor. However, although familial resemblances decreased significantly when adjusted for shared behaviour and environment, this decrease is around 12% for the variability between families, against only 4.5% of that within families. Furthermore, we also demonstrated that the QIS is remarkably stable over time. Both these results are consistent with the hypothesis of the existence of a strong and complex individual factor involved in the control of infection status.

Adolescent↗

PubMed1996

Characterization of noble metal implant cylinders: as-received cylinders and cast interfaces with noble metal alloys.

A common procedure in the fabrication of implant prostheses is the use of premade wrought cylinders in cast frameworks. Although manufacturers outline some precautions in the use of these components, detailed information about the metal interface between cylinders and cast alloys is lacking. This article, following a previous report that compared titanium-based implant cylinders used with two different classes of cast alloys, compares conventional noble metal cylinders from three different manufacturers combined with these two classes of cast noble alloys. Analysis of the as-received cylinders revealed that the implant cylinders as a group are predominantly composed of metals commonly found in noble dental alloys, namely, platinum, palladium, gold, and silver. The interfaces created by casting both high-fusing and low-fusing alloys around the cylinders exhibited a general elemental concentration variability compared with the bulk alloy regions, but continuous concentrations for shared elements suggested alloy-cylinder compatibility. Vickers hardness values, which ranged from 212 to 276 for the as-received cylinders, decreased from 12% to 43% for the various cylinders after casting. This study suggests characteristics of an ideal cast interface that include maintenance of the cylinder and casting alloy microstructures up to the interface, absence of interfacial reaction regions, lack of porosity created by volatilization of components from either alloy or the casting process, and sufficient strength to maintain anticipated loads.

Dental Alloys↗

PubMed1987

Frequency, levels, and significance of blood eosinophilia in systemic sclerosis, localized scleroderma, and eosinophilic fasciitis.

Blood eosinophilia is a common feature of eosinophilic fasciitis and is variably reported in systemic sclerosis and localized scleroderma. Since these diseases share cutaneous fibrosis as the final outcome and have other clinical and pathologic features that are difficult to differentiate, the presence of blood eosinophilia may be a further source of confusion. In this study, we examined the frequency and level of blood eosinophilia in 715 patients with systemic sclerosis, 72 patients with localized scleroderma, and 22 patients with clinically active eosinophilic fasciitis. When defined as greater than 400 cells/mm3, eosinophilia was present in 7% of patients with systemic sclerosis, 31% of patients with localized scleroderma, and 83% of patients with eosinophilic fasciitis. Greater than 1000 eosinophils/mm3 were present less frequently in systemic sclerosis (1%) and localized scleroderma (8%) than in eosinophilic fasciitis (61%). No difference in the frequency of eosinophilia was present in patients with the limited cutaneous CREST syndrome or the diffuse cutaneous variety of systemic sclerosis, and in these patients the presence of eosinophilia did not correlate with the extent of cutaneous or internal organ involvement or with other laboratory abnormalities. Among patients with localized scleroderma, eosinophilia was more common in those with linear scleroderma and generalized morphea than in those with morphea, and both the frequency and level of eosinophilia were greater in individuals with clinically active disease (p less than 0.02). Eosinophilia was a persistent feature in untreated patients with active eosinophilic fasciitis, even up to 30 months of disease duration.

Eosinophilia↗

PubMed1994

HMG domain proteins induce sharp bends in cisplatin-modified DNA.

Circularly permuted linear DNAs of approximately 100 bp were constructed containing the major adduct of the anticancer drug cisplatin, a cis-[Pt(NH3)2[d(GpG)-N7(1),-N7(2)]] intrastrand cross-link, at a specific site. Gel electrophoresis mobility shift assays with these probes were used to investigate the effects of binding of HMG domain proteins to the platinated DNAs. The site-specifically platinated duplexes were recognized by six different HMG domain proteins--HMG1, mtTFA, Ixr1, and HMG domains from HMG1 (domain B), mSRY, and LEF-1--with comparable binding affinities (Kd approximately 10(-6) to 10(-7) M). In the presence of the HMG domain proteins, the platinated DNAs were bent significantly more than in their absence, the values being 86 +/- 2 degrees, 87-90 +/- 5 degrees, and 68 +/- 6 degrees, respectively, for the proteins and 65-74 +/- 4 degrees, approximately 50 degrees, and 72 +/- 6 degrees, respectively, for the domains. The variability in bend angles suggests that, although the HMG domain proteins share a common ability to bend platinated DNA, specific contacts between the proteins and the platinated duplex are different. The assay further revealed the bend loci to be centered quite near the platinum adduct. The methodology employed in the present study should be generally applicable for synthesizing other small, circularly permuted, covalently modified DNAs which cannot otherwise be readily obtained.

Base Sequence↗

PubMed1986

The roles of typicality, instance dominance, and category dominance in verifying category membership.

Four experiments examined the relationships between category verification reaction time (RT), exemplar typicality, instance dominance, category selection time (an RT measure of category dominance), and three production measures of category dominance. The category dominance measures were obtained in two experiments for use in two nearly identical category verification experiments. In one category verification experiment, the category name was presented 800 ms before the exemplar name; in the other, the exemplar name preceded the category name by 800 ms. Multiple regression analyses of the yes and no category verification RTs indicated that category dominance produced large and highly significant effects in all conditions, whereas instance dominance produced marginally significant and selective effects. Typicality had no effect beyond its shared effect with the dominance measures except as a possible suppressor variable. Category selection time was the best predictor, although all of the category dominance measures were better predictors than typicality or instance dominance. It is concluded that typicality may be an inappropriate independent variable for RT tasks studying the memory representation of natural-world knowledge.

Classification↗

PubMed2005

A short guided tour through functional and structural features of saposin-like proteins.

SAPLIPs (saposin-like proteins) are a diverse family of lipid-interacting proteins that have various and only partly understood, but nevertheless essential, cellular functions. Their existence is conserved in phylogenetically most distant organisms, such as primitive protozoa and mammals. Owing to their remarkable sequence variability, a common mechanism for their actions is not known. Some shared principles beyond their diversity have become evident by analysis of known three-dimensional structures. Whereas lipid interaction is the basis for their functions, the special cellular tasks are often defined by interaction partners other than lipids. Based on recent findings, this review summarizes phylogenetic relations, function and structural features of the members of this family.

Amino Acid Sequence↗

PubMed2002

Patient autonomy: evolution of the doctor-patient relationship.

In recent years, much has been said about the shifting locus of control in clinical practice. This article discusses the influence on the physician-patient relationship of recent social and political history, patient culture and experience, and advances in medical practice. I suggest that effective partnerships between physicians and patients are possible in a supportive institutional environment in which the participants acknowledge and fulfil their roles and responsibilities in shared decision-making. While I recognize that there is considerable variability in practices across cultures and in individual behaviour, the scope of this article is based on literature and my knowledge, which is representative primarily of the North American experience.

Communication↗

PubMed2002

Adrenergic inducibility of AP-1 binding in the rat pineal gland depends on prior photoperiod.

The main known function of the pineal gland in mammals is the temporal synchronization of physiological rhythms to seasonal changes of day length (photoperiod). In rat, the transcription factor activating protein-1 (AP-1) displays a circadian rhythm in its DNA binding in the pineal gland, which results from the rhythmic expression of Fra-2. We postulated that, if AP-1 is an important component of pineal gland functioning, then variations in photoperiodic conditions should lead to an adaptation of the AP-1 binding rhythm. Here we show that AP-1 binding patterns adapt to variations in lighting conditions, in the same way as the rhythm of arylalkylamine-N-acetyltransferase (AA-NAT) activity. This adaptation appeared to result from photoperiodic adaptation of the rhythmic fra-2 gene expression and was reflected by an adapted delay between the onset of night and the acrophase of the nocturnal peak. We further showed that photoperiodic adaptation of both the AP-1 binding and AA-NAT activity rhythms resulted from adapted changes in adrenergic inducibility of both variables at night onset. We finally provided evidence that AP-1 shared with the CREM gene encoding the transcriptional repressor protein inducible cAMP early repressor (ICER) the ability to be hypersensitive or subsensitive to adrenergic stimuli, depending on prior photoperiod.

Adaptation, Physiological↗

PubMed2001

The genetic contribution to hip joint morphometry and relationship to hip cartilage thickness.

A twin study approach was used to explore the genetic determinants of hip joint morphometry and their relationship to hip cartilage thickness. Our analysis used data on anthropometric characteristics and radiographic features of a group of 222 monozygotic (MZ) and 240 dizygotic (DZ) twins. We confirmed that genetic factors account for most of the variation in minimal joint space (MJS) and acetabular anatomy. This genetic variation was largely due to factors unique to MJS itself and not explained by anthropometric variables or measurements of acetabular morphology. Only a small proportion was shared with genetic factors underlying acetabular shape, mainly the centre edge angle.

Adult↗

PubMed2002

Single-nucleotide polymorphisms and haplotype analysis in beta-defensin genes in different ethnic populations.

Beta-defensins are cationic antimicrobial peptides expressed by epithelial cells and exhibit antibacterial, antifungal, and antiviral properties. The defensins are part of the innate host defense network and may have a significant protective role in the oral cavity and other mucosa. Defects or alteration in expression of the beta-defensins may be associated with susceptibility to infection and mucosal disorders. We examined the occurrence of single-nucleotide polymorphisms (SNPs) in the human beta-defensin genes DEFB1 and DEFB2 encoding human beta-defensin-1 and -2 (hBD-1, hBD-2), respectively, in five ethnic populations and defined haplotypes in these populations. Fifteen SNPs were identified in both DEFB1 and DEFB2. Coding region SNPs were found in very low frequency in both genes. One nonsynonymous DEFB1 SNP, G1654A (Val --> Ile), and one nonsynonymous DEFB2 SNP, T2312A (Leu --> His), were identified. Seven sites in each gene exhibited statistically significant differences in frequency between ethnic groups, with the greatest variation in the promoter and in the 5'-untranslated region of DEFB1. DEFB1 displayed 10 common haplotypes, including one cosmopolitan haplotype. Eight common haplotypes were found in DEFB2, including one cosmopolitan haplotype shared among all five ethnic groups. Our results show that genotypic variability among ethnic groups will need to be addressed when performing associative genetic studies of innate defense mechanisms and susceptibility to disease.

Haplotypes↗