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PubMed1999

Microtubule-associated protein-2 in the hypothalamo-neurohypophysial system: low-molecular-weight microtubule-associated protein-2 in pituitary astrocytes.

Microtubule-associated protein-2 is the most abundant microtubule-associated protein in the brain and is responsible for morphogenesis and maintenance of the nervous system. In the present experiments, we have examined the localization of microtubule-associated protein-2 in the hypothalamo-neurohypophysial system of the rat using western blots and immunohistochemistry. Two monoclonal antibodies against microtubule-associated protein-2, antibody C and AP20, were used: antibody C recognizes both the high- and low-molecular-weight isoforms of microtubule-associated protein-2; antibody AP20 specifically detects high-molecular-weight microtubule-associated protein-2 only. Western blot analysis revealed expression of high-molecular-weight microtubule-associated protein-2 in the whole brain, hippocampus and whole hypothalamus. While the supraoptic nucleus expressed only high-molecular-weight microtubule-associated protein-2, the adult posterior pituitary predominantly expressed low-molecular-weight microtubule-associated protein-2, which was also seen in the embryonic whole brain. Light microscopic immunohistochemistry revealed that both antibody C and AP20 intensely stained dendrites of the dendritic and somatic zones in the supraoptic nucleus. Double labeling with antibodies against microtubule-associated protein-2 and oxytocin (or vasopressin) demonstrated that microtubule-associated protein-2 was localized in dendrites of magnocellular neurons in the supraoptic nucleus. In the posterior pituitary, however, antibody C stained fine processes and cell bodies of astrocytes, which were identified by an antibody against glial fibrillary acidic protein. Antibody AP20 also stained fine processes of some astrocytes in the posterior pituitary, but the intensity of immunoreactivity with antibody AP20 was weaker than that with antibody C. This result suggests that microtubule-associated protein-2 in astrocytes of the posterior pituitary is predominantly of the low-molecular-weight type. Moreover, western blots revealed low-molecular-weight microtubule-associated protein-2 of the posterior pituitary at a molecular weight slightly higher than embryonically expressed low-molecular-weight microtubule-associated protein-2, indicating that low-molecular-weight microtubule-associated protein-2 in the posterior pituitary is possibly the isoform microtubule-associated protein-2d. The present results demonstrate that astrocytes in the posterior pituitary of adult rats still retain the ability to express the immature variant of microtubule-associated protein-2, low-molecular-weight microtubule-associated protein-2, and its expression is probably linked to structural plasticity.

Animals↗
PubMed2004

Characteristic clinical features of hepatocellular carcinoma associated with Budd-Chiari syndrome: evidence of different carcinogenic process from hepatitis B virus-associated hepatocellular carcinoma.

OBJECTIVE: Budd-Chiari syndrome (BCS) is a known risk factor for hepatocellular carcinoma (HCC). Considering the pathophysiological mechanism of BCS, BCS-associated HCC may have a different carcinogenic process to hepatitis B virus (HBV)-associated HCC, resulting in different characteristic clinical features. METHODS: The clinical, radiological and histopathological characteristics of 15 HCCs associated with BCS were analysed and compared with 211 HBV-associated HCCs. RESULTS: HCC associated with BCS showed a female predominance in contrast to a male predominance in HCC associated with HBV infection. Child classes of BCS-associated HCC patients were not different from the classes of HBV-associated HCC. BCS tended to be associated with the single nodular type of HCC. Only one BCS-associated HCC patient had portal vein invasion at the time of diagnosis, compared with 96 patients with HBV-associated HCC. No HCC patients with BCS showed biliary invasion, compared with 47 HBV-associated HCC patients. The median survival period of HCC patients associated with BCS was 58 months, which was much longer than the median survival period of 10 months in HBV-associated HCC. All of the three BCS-associated HCCs available for histological examination were well differentiated. CONCLUSIONS: Patients with HCC associated with BCS seemed to survive for much longer periods than those with HBV due to the low invasiveness of the tumour. Such unique clinical features may be evidence of different carcinogenic processes in BCS-associated and HBV-associated HCC.

Adolescent↗
PubMed2006

Association of connexin36 and zonula occludens-1 with zonula occludens-2 and the transcription factor zonula occludens-1-associated nucleic acid-binding protein at neuronal gap junctions in rodent retina.

Most gap junctions between neurons in mammalian retina contain abundant connexin36, often in association with the scaffolding protein zonula occludens-1. We now investigate co-association of connexin36, zonula occludens-1, zonula occludens-2 and Y-box transcription factor 3 (zonula occludens-1-associated nucleic acid-binding protein) in mouse and rat retina. By immunoblotting, zonula occludens-1-associated nucleic acid-binding protein and zonula occludens-2 were both detected in retina, and zonula occludens-2 in retina was found to co-immunoprecipitate with connexin36. By immunofluorescence, the four proteins appeared as puncta distributed in the plexiform layers. In the inner plexiform layer, most connexin36-puncta were co-localized with zonula occludens-1, and many were co-localized with zonula occludens-1-associated nucleic acid-binding protein. Moreover, zonula occludens-1-associated nucleic acid-binding protein was often co-localized with zonula occludens-1. Nearly all zonula occludens-2-puncta were positive for connexin36, zonula occludens-1 and zonula occludens-1-associated nucleic acid-binding protein. In the outer plexiform layer, connexin36 was also often co-localized with zonula occludens-1-associated nucleic acid-binding protein. In connexin36 knockout mice, labeling of zonula occludens-1 was slightly reduced in the inner plexiform layer, zonula occludens-1-associated nucleic acid-binding protein was decreased in the outer plexiform layer, and both zonula occludens-1-associated nucleic acid-binding protein and zonula occludens-2 were markedly decreased in the inner sublamina of the inner plexiform layer, whereas zonula occludens-1, zonula occludens-2 and zonula occludens-1-associated nucleic acid-binding protein puncta persisted and remained co-localized in the outer sublamina of the inner plexiform layer. By freeze-fracture replica immunogold labeling, connexin36 was found to be co-localized with zonula occludens-2 within individual neuronal gap junctions. In addition, zonula occludens-1-associated nucleic acid-binding protein was abundant in a portion of ultrastructurally-defined gap junctions throughout the inner plexiform layer, and some of these junctions contained both connexin36 and zonula occludens-1-associated nucleic acid-binding protein. These distinct patterns of connexin36 association with zonula occludens-1, zonula occludens-2 and zonula occludens-1-associated nucleic acid-binding protein in different sublaminae of retina, and differential responses of these proteins to connexin36 gene deletion suggest differential regulatory and scaffolding roles of these gap junction accessory proteins. Further, the persistence of a subpopulation of zonula occludens-1/zonula occludens-2/zonula occludens-1-associated nucleic acid-binding protein co-localized puncta in the outer part of the inner plexiform layer of connexin36 knockout mice suggests close association of these proteins with other structures in retina, possibly including gap junctions composed of an as-yet-unidentified connexin.

Animals↗
PubMed2006

The future of cardiovascular imaging and non-invasive diagnosis. A joint statement from the European Association of Echocardiography, the Working Groups on Cardiovascular Magnetic Resonance, Computers in Cardiology, and Nuclear Cardiology, of the European Society of Cardiology, the European Association of Nuclear Medicine and the Association for European Paediatric Cardiology.

Advances in medical imaging now make it possible to investigate any patient with cardiovascular disease using multiple methods which vary widely in their technical requirements, benefits, limitations and costs. The appropriate use of alternative tests requires their integration into joint clinical diagnostic services where experts in all methods collaborate. This statement summarises the principles that should guide developments in cardiovascular diagnostic services.

Cardiovascular Diseases↗
PubMed1997

The anatomy of an OPTI: Part 2. The CORE system. Ohio Osteopathic Hospital Association. Ohio Association of Osteopathic Medical Directors. Ohio Osteopathic Association.

In July 1995, the American Osteopathic Association (AOA) Board of Trustees passed new regulations regarding the accreditation of osteopathic graduate medical education (GME) by establishing the Osteopathic Postdoctoral Training Institutions (OPTI) system. This system must be phased in by July 1999. The principal changes resulting from the OPTI system include establishing requirements for college cosponsorship of GME programs and for the number of residency programs, interns, and residents to be trained by the OPTI. In essence, OPTI is an osteopathic acronym for consortium. Each OPTI must include at least one college of osteopathic medicine (COM) and one AOA-accredited hospital. The OPTIs will be subject to interval AOA inspections and will be required to demonstrate a governing system, mission statement, organizational structure, and the presence of faculty development programs. The first article in this two-part series, published in the October JAOA, provided a general blueprint for OPTI building and presented both positive and negative issues germane to the formation of OPTIs. Part 2 reinforces the considerations outlined in Part 1 by describing the formation of a large OPTI--the Ohio University College of Osteopathic Medicine (OU-COM) Centers of Osteopathic Regional Education (CORE) system. Key features are described, including the mission statement, organizational structure, committee system, governance, GME programs, operations, and budget.

Accreditation↗
PubMed2000

Associative and non-associative fentanyl tolerance in the rat: evaluation of cross tolerance with mu-and kappa-specific opioids.

RATIONALE: Associative tolerance to the analgesic effects of morphine is most pronounced when morphine is paired with a distinctive context at a long interdose interval (IDI). In contrast, morphine administered at a short IDI promotes the development of non-associative tolerance and disrupts the acquisition of associative tolerance. The impact of IDI on the development of associative tolerance to opioids other than morphine has not been investigated previously. OBJECTIVES: This research examined associative and non-associative tolerance to the analgesic effects of fentanyl in rats. Cross tolerance for these two forms of tolerance with morphine (mureceptor agonist) and U50,488H (kappa-receptor agonist) analgesia was also investigated. METHODS: Animals were given eight fentanyl injections (0.10 mg/kg) paired or unpaired with a distinctive context at either a 3-h (short) or 96-h (long) IDI. Subjects were then tested for tolerance in the distinctive context using the tail-flick procedure and dose-response curve methodology. RESULTS: At the short IDI, animals developed non-associative tolerance to fentanyl that was receptor specific, i.e., cross tolerant with morphine analgesia but not with U50,488H analgesia. At the long IDI, fentanyl-tested animals displayed tolerance that appeared to be controlled primarily by associative processes. This associative form of tolerance was also receptor specific, displaying cross tolerance with morphine but not with U50,488H. CONCLUSIONS: The impact of IDI on the development of non-associative and associative fentanyl tolerance is consistent with findings obtained with morphine showing that conditions conducive to the development of non-associative tolerance disrupt the acquisition of associative tolerance. The cross-tolerance data, however, did not parallel previous research examining the cross-tolerance profiles of associative and non-associative morphine tolerance.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2001

Association between epidermodysplasia verruciformis-associated human papillomavirus DNA in plucked eyebrow hair and solar keratoses.

Epidermodysplasia-verruciformis-associated human papillomavirus DNA has been demonstrated in squamous cell carcinomas and plucked hair from immunocompetent patients and renal transplant recipients. This study investigated the association between infection with epidermodysplasia-verruciformis-associated human papillomavirus, identified by the detection of viral DNA in plucked eyebrow hairs, and solar keratoses. These lesions are strongly predictive of squamous cell carcinoma. In a cross-sectional study 518 individuals were enrolled from a randomly selected sample of a subtropical Australian community. Epidermodysplasia-verruciformis-associated human papillomavirus DNA in eyebrow hair was detected using a nested polymerase chain reaction specific for epidermodysplasia-verruciformis-associated human papillomavirus types. Epidermo dysplasia-verruciformis-associated human papillomavirus DNA was present in 121 (49%) of 245 men and 116 (44%) of 262 women. There was a strongly significant increase in epidermodysplasia-verruciformis-associated human papillomavirus infection with age (p < 0.00001), with prevalences of 29% in the 25-39 y age group, 42% at 40-59 y and 65% in the 60-79 y age group. Among men there was a strong association between epidermodysplasia-verruciformis-associated human papillomavirus and solar keratoses with an odds ratio, adjusted for age, skin color, and occupational sun exposure, of 3.40 (95% confidence interval, 1.77-6.53). No such association was found among women [odds ratio 1.03 (95% confidence interval 0.59-1.77, after adjustment for the same factors)]. Differences in occupational sun exposure and smoking histories could not explain these apparently different associations between epidermodysplasia-verruciformis-associated human papillomavirus infection and solar keratoses in men and women. In conclusion, epidermodysplasia-verruciformis-associated human papillomavirus infection is associated with solar keratoses in men suggesting that epidermodysplasia-verruciformis-associated human papillomavirus infection, in conjunction with sex specific factors (like androgens), may be involved in neoplastic changes of keratinocytes.

Adult↗
PubMed2004

Difference in pathogenesis between vitiligo vulgaris and halo nevi associated with vitiligo is supported by an HLA association study.

Human leukocyte antigen (HLA) class II associations with two subtypes of vitiligo: vitiligo vulgaris and halo nevi associated with vitiligo were investigated. In previous studies associations between vitiligo and HLA antigens have been reported but these two subtypes have never been taken into account. However from a clinical and histological point of view, a difference in (auto)-immune pathogenesis can be expected. This difference might be reflected in an association with different HLA alleles. Seventy-six unrelated Dutch Caucasians, 40 with vitiligo vulgaris and 36 with halo nevi associated with vitiligo were included. A panel of randomly chosen HLA typed healthy Dutch blood donors (n = 2400) served as control population. HLA-DR and -DQ typing was carried out on blood samples by amplifying genomic DNA using polymerase chain reaction followed by dot blot hybridization with sequence specific oligonucleotides. The main outcome measures were odds ratio (OR), uncorrected P-value (P(u)) and corrected P-value. There were distinct differences in the clinical manifestations between vitiligo vulgaris and halo nevi associated with vitiligo with respect to precipitating factors, extent and progress of the disease and the association with other auto-immune diseases in the two subtypes and their respective first degree family members. Our stratification reveals differences in HLA class II between both subtypes and between subtypes and controls. A case-control association study showed a significant positive association of HLA-DR4 (OR = 2.787, P(u) = 0.0022) and DR53 (OR = 2.249, P(u) = 0.0153) and a negative association of HLA-DR3 (OR = 0.195, P(u) = 0.0024) with vitiligo vulgaris. The group with halo nevi associated with vitiligo did not show these associations, but had a significant negative association with HLA-DR11 (OR = 0.083, P(u) = 0.0067). In conclusion, the differences in HLA association within clinical subtypes of vitiligo support our suggestion that vitiligo vulgaris and halo nevi associated with vitiligo have distinct pathogenic mechanisms.

Adolescent↗
PubMed2006

Injury risk in professional basketball players: a comparison of Women's National Basketball Association and National Basketball Association athletes.

BACKGROUND: Gender-based differences in injury rates have been reported in scholastic and collegiate basketball. The purpose of this study was to retrospectively compare injury rates in women's and men's professional basketball. HYPOTHESIS: Female professional basketball players are injured at a higher rate than are men. STUDY DESIGN: Cohort study (prevalence); Level of evidence, 2. METHODS: Women's National Basketball Association and National Basketball Association injury data were retrospectively reviewed for 6 full seasons. The frequency of all injuries and the rate of game-related injuries were calculated. RESULTS: Complete player profiles were obtained on 702 National Basketball Association athletes and 443 Women's National Basketball Association athletes who competed in their respective leagues during the data collection period. Total game exposures totaled 70,420 (National Basketball Association) and 22,980 (Women's National Basketball Association). Women's National Basketball Association athletes had a higher overall game-related injury rate (24.9 per 1000 athlete exposures; 95% confidence interval, 22.9-26.9; P < .05) when compared with National Basketball Association athletes (19.3 per 1000 athlete exposures; 95% confidence interval, 18.3-20.4) and sustained a higher rate of lower extremity injuries (14.6 per 1000 athlete exposures; 95% confidence interval, 13.1-16.2; P < .05) than seen in the National Basketball Association (11.6 per 1000 athlete exposures; 95% confidence interval, 10.8-12.4). The lower extremity was the most commonly injured body area (65%), and lateral ankle sprain (13.7%) was the most common diagnosis in both leagues. The incidence of game-related knee injury was higher in Women's National Basketball Association players. The incidence of anterior cruciate ligament injury in the National Basketball Association (n = 22, 0.8%) and Women's National Basketball Association (n = 14, 0.9%) accounted for 0.8% of the 4446 injuries reported. CONCLUSION: The lower extremity is the most frequently injured body area in both leagues, and Women's National Basketball Association athletes are more susceptible than are National Basketball Association athletes. There were, however, few statistical differences in the actual injuries occurring between the 2 leagues.

Adult↗
PubMed2026

Source- and Solubility-specific Choline, Gut Microbiota, and Dyslipidemia Risk: Trimethylamine N-oxide-associated and Non-trimethylamine N-oxide-Associated Patterns in a Prospective Cohort Study.

BACKGROUND: Dietary choline, a major precursor of the gut microbial metabolite trimethylamine N-oxide (TMAO), is implicated in dyslipidemia risk; however, source- and form-specific associations and interactions with gut microbiota remain unclear. OBJECTIVES: The aim of this study was to examine longitudinal associations of source- and form-specific dietary choline with plasma TMAO and dyslipidemia and to identify gut microbiota interactions. METHODS: Using data from the China Health and Nutrition Survey (2018-2023), dietary intake was assessed via 3 consecutive 24-h recalls in this prospective cohort study. Two-level generalized linear mixed-effects models were applied in 4828 adults (mean age: 55.9 &#xb1; 12.6 y, 56.6% females) to assess choline-dyslipidemia associations. Choline-TMAO and TMAO-dyslipidemia analyses were conducted in 1091 participants free of dyslipidemia at baseline. Among 7169 adults with gut microbiome data, Least Absolute Selection and Shrinkage Operator and logistic regression identified lipid-associated gut genera; TMAO relationships were examined in a subset of 693 participants. RESULTS: Higher intakes of total [Q4 compared with Q1: odds ratio (OR) = 1.261; 95% confidence interval (CI): 1.007, 1.580], red meat-derived (OR: 1.753; 95% CI: 1.196, 2.568), and lipid-soluble choline (OR: 1.304; 95% CI: 1.047, 1.624) were associated with higher risk of elevated low-density lipoprotein cholesterol (LDL cholesterol), whereas vegetable-derived choline was inversely associated. Egg-derived and lipid-soluble choline were positively associated with plasma TMAO, which was prospectively associated with 5-y incident dyslipidemia (Q4 compared with Q1-OR: 1.620; 95% CI: 1.047, 2.509), elevated LDL cholesterol (Q3 compared with Q1-OR: 2.478; 95% CI: 1.187, 5.174), and hypertriglyceridemia (Q4 compared with Q1-OR: 1.829; 95% CI: 1.028, 3.225). Three TMAO-associated genera were identified: Lachnospiraceae and Phascolarctobacterium as pro-risk taxa and Turicibacter as protective. The adverse LDLcholesterol association of egg-derived choline was observed exclusively in Phascolarctobacterium-enriched individuals. CONCLUSIONS: Dietary choline source and solubility differentially associated with dyslipidemia risk through TMAO-associated and non-TMAO-associated patterns, with gut microbiota as key modulators.

Humans↗
PubMed1993

Comparison of associative and non-associative conditioning procedures in the induction of LTD in CA1 of the hippocampus.

Recent reports have indicated that weak activity in a test input, negatively correlated (out-of-phase) with tetanization of a separate, converging input, produces an NMDA-independent, associative long-term depression (LTD) of the test input synapses, in hippocampal field CA1 (Stanton and Sejnowski, 1989; Stanton et al., 1991). Associative LTD has also been observed in the dentate gyrus, in vivo, but only following "priming" of the test path with 5 Hz stimulation prior to associative conditioning (Christie and Abraham, 1992b). We have used these stimulus protocols, in vitro, in order to compare the induction of non-associative and associative LTD in field CA1 of the adult rat hippocampus. Stimulation in normal solution evoked a small non-associative LTD, but no associative LTD. Addition of picrotoxin to the medium facilitated the induction of NMDA-dependent non-associative LTD, but not associative LTD. Previously potentiated pathways were not different from naive pathways in expression of LTD of either kind. Finally, 'priming' stimulation (5 Hz) of the test pathway produced a weak, selective enhancement of associative LTD that was, however, not significantly greater than non-associative LTD. These results indicate that, for our experimental conditions, negatively correlated co-activity during afferent tetanization does not induce a substantial associative LTD in area CA1.

2-Amino-5-phosphonovalerate↗
PubMed1997

Sensitization phenomena after repeated administration of cocaine or D-amphetamine in rats: associative and non-associative mechanisms and the role of dopamine in the striatum.

In parallel studies, the contribution of non-associative and associative mechanisms to the development of sensitization to the effects of cocaine and D-amphetamine on locomotor activity and stereotyped behaviour were tested. Rats were pretreated with cocaine, 10 mg/kg s.c. twice, D-amphetamine 1.5 mg/kg s.c. once or with saline. During the pretreatment period, one group of rats was administered the drug in positive temporal association with conditional stimuli (CS) ('associative'), another group in negative temporal association with the CS ('non-associative'), a saline pretreated control group was exposed to the CS but administered the drug only during the test ('naive'). On the test day, 7 days after the last drug administration, in the cocaine-sensitized group, cocaine produced the largest locomotor stimulation and the highest scores of stereotypies (mainly sniffing) in the 'associative' group, significantly smaller effects in the 'non-associative' group, and the smallest effects in the 'naive' group. The stereoypies (mainly licking) produced by D-amphetamine in the amphetamine-sensitized group on the test day, 7 days after the last drug administration, were also most pronounced in the 'associative' group, less pronounced in the 'non-associative' group and least in the 'naive' group, whereas the opposite sequences of intensities were found with regard to locomotor activation. The observations in D-amphetamine-treated groups suggest that there is a negative correlation between locomotor activity and stereotyped licking. Estimation of the extracellular dopamine using microdialysis in the striatum showed no significant differences between the three cocaine groups in the moderate increases. In contrast, after D-amphetamine treatment, the strong increases in dopamine were most pronounced in the 'associative' group, significantly less in the 'non-associative' group and even less in the 'naive' group. The biochemical findings in the D-amphetamine-pretreated animals are apparently related to the pronounced stereotyped licking observed in these animals which is probably induced in the striatum, whereas locomotor activation and sniffing are probably mediated elsewhere and therefore are not reflected biochemically in the striatum.

Animals↗
PubMed1975

Association of ribosomal subunits. IV. Polyamines as active components of the association factor from Bacillus stearothermophilus.

The association of ribosomal subparticles induced by several associating agents has been studied under different conditions. The following observations were made: 1. Spermidine was able to produce the association of subunits, and the concentration and temperature curves of this reaction were similar to those obtained with association factor. The product formed in the latter case was more stable. 2. The association at low Mg2+ concentration was higher with association factor than with polyamines. 3. The temperature-dependent binding of spermidine to 30-S subunits formed an active complex, which was converted into the 30S-50S couples by the addition of 50-S subparticles at low temperature. A similar behaviour has been previously shown for the complete association factor and its low molecular weight fraction. 4. The same unstable form of 30S-50S couples has been obtained either with spermidine or with the low molecular weight component (AFII) of the association factor. In both cases the protein fraction AFI was able to complete the reaction by stabilizing the subunit couple. 5. After glutaraldehyde fixation the products of the reactions with spermidine or association factor behaved in a similar way when they were submitted to long sucrose-gradient centrifugations. 6. The analysis of association factor preparations has shown that they contain spermidine as well as spermine. The polyamine levels in association factor could account for part of the total associating activity.

Bacterial Proteins↗
PubMed2000

A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia.

Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DbetaH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.

Alleles↗
PubMed2003

Immunoblastic lymphoma in persons with AIDS-associated Kaposi's sarcoma: a role for Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus, the viral agent of Kaposi's sarcoma, is associated with two lymphoproliferative disorders: primary effusion lymphoma and multicentric Castleman's disease. To identify other lymphoproliferative conditions linked with Kaposi's sarcoma-associated herpesvirus, we studied non-Hodgkin's lymphomas arising in individuals with AIDS-associated Kaposi's sarcoma. Formalin-fixed tissues from 24 such lymphomas were examined. As expected, two primary effusion lymphomas were Kaposi's sarcoma-associated herpesvirus-positive, with immunohistochemistry demonstrating the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen in the nuclei of all neoplastic cells. Additionally, three of seven evaluable cases of the immunoblastic variant of diffuse large B-cell lymphoma (immunoblastic lymphoma) showed similar latency-associated nuclear antigen staining. These Kaposi's sarcoma-associated herpesvirus-positive immunoblastic lymphomas resembled primary effusion lymphoma histologically but were not known to involve body cavities (sites included lymph nodes, soft tissues of the neck, and spleen). Notably, 5-20% of the neoplastic cells in the Kaposi's sarcoma-associated herpesvirus-positive immunoblastic lymphomas also showed cytoplasmic staining for viral interleukin-6, a biologically active cytokine homologue found in primary effusion lymphoma. We conclude that Kaposi's sarcoma-associated herpesvirus is present in some immunoblastic lymphomas in persons with AIDS-associated Kaposi's sarcoma.

AIDS-Related Opportunistic Infections↗
PubMed1993

Linkage analysis versus association analysis: distinguishing between two models that explain disease-marker associations.

Human genetics researchers have been intrigued for many years by weak-to-moderate associations between markers and diseases. However, in most cases of association, the cause of this phenomenon is still not known. Recently, interest has grown in pursuing association studies for complex diseases, either instead of or in addition to linkage studies. Hence, it is timely to reconsider what a disease-marker association, particularly in the weak-to-moderate range (relative risk < 10), can tell us about disease etiology. To this end, this study accomplishes three aims: (1) It formulates two different models explaining weak-to-moderate associations and derives the relationship between them. One is a linkage disequilibrium model, and the other is a "susceptibility," or pure association, model. The importance of drawing the distinction between these two models and the implications for our understanding of the genetics of human disease will also be discussed. It will be argued that the linkage disequilibrium model represents true linkage but that the susceptibility model does not. (2) It examines two family-based association tests proposed recently by Parsian et al. and Spielman et al. and derives formulas for their behavior under the two models described above. It demonstrates that these tests yield almost identical results under these two models. It shows that, whereas these tests can confirm an association, they cannot determine whether the association is caused by the linkage disequilibrium model or the susceptibility model. The study also characterizes the probabilities yielded by the family association tests in the presence of weak-to-moderate associations, which will aid researchers using these tests. (3) It proposes two approaches, both based on linkage analysis, which can distinguish between the two models described above. One approach involves a straightforward linkage analysis of the data; the other involves a partitioned association-linkage (PAL) test, as suggested by Greenberg. Formulas are derived for testing identity by descent in affected sib pairs by using both approaches. (4) Finally, the formulas and arguments are illustrated with two examples from the literature and one computer-simulated data set.

Alleles↗
PubMed1997

Cytoskeletal association of epidermal growth factor receptor and associated signaling proteins is regulated by cell density in IEC-6 intestinal cells.

Epidermal growth factor (EGF) mediates a variety of physiologic responses in rat intestine. EGF receptor (EGFR) responsiveness to EGF is mediated by the surface expression of high affinity EGFR, which is associated with the cytoskeleton (CSK). EGFR signal transduction appears to be mediated by the CSK association of EGFR and related signaling proteins. In the nontransformed intestinal cell line IEC-6, expression of EGFR, Src homology and collagen protein (SHC), phospholipase C gamma 1 (PLC gamma), and their tyrosine phosphorylation in response to EGF was assayed by immunoblot. The distribution of EGFR and tyrosine-phosphorylated EGFR was regulated by cell density. At confluence, EGFR and tyrosine-phosphorylated EGFR were predominantly associated with the Triton X-100-insoluble CSK at confluence, while predominantly Triton X-100-soluble at subconfluence. PLC gamma was predominantly soluble at both states of confluence. Confluent but not subconfluent IEC-6 cells demonstrated a cascade of EGF-mediated events consisting of a transient CSK association of PLC gamma with EGFR, a brief expression of tyrosine-phosphorylated PLC gamma, a brief increase in PLC gamma CSK association, and a prolonged soluble association of PLC gamma with the EGFR. EGF led to an increase in the CSK association of SHC at both states of confluence and was greater at confluence. EGFR association with SHC was primarily soluble at subconfluence, while at confluence EGFR association was markedly increased and predominantly in the CSK. Thus, cell density regulates the CSK association of the EGFR and its ability to associate and activate signaling pathways in intestinal cells.

Adaptor Proteins, Signal Transducing↗