Co-expression of the P75 neurotrophin receptor and neurotrophin receptor-interacting melanoma antigen homolog in the mature rat brain

The p75 neurotrophin receptor (p75(NTR)) is involved in the regulation of neuronal survival and phenotype, but its signal transduction mechanisms are poorly understood. Recent evidence has implicated the cytoplasmic protein NRAGE (neurotrophin receptor-interacting MAGE (from Melanoma AntiGEn) homolog) in p75(NTR) signaling. To gain further insight into the role of NRAGE, we investigated the co-expression of NRAGE and p75(NTR) in mature rat brain. In all areas examined, NRAGE appeared to be confined to neurons. In the basal forebrain cholinergic complex, NRAGE immunoreactivity was evident in all p75(NTR)-positive neurons. There were many more NRAGE-positive than p75(NTR)-positive neurons in these regions, however. NRAGE was also expressed in areas of the basal forebrain that did not express p75(NTR), including the lateral septal nucleus and the nucleus accumbens. A finding in marked contrast to previous studies was the presence of p75(NTR) immunoreactivity in neuronal cell bodies in the hippocampus. Hippocampal p75(NTR) immunoreactivity was apparent in rats 6 months and older, and was localized to the dentate gyrus and stratum oriens. All p75(NTR)-positive neurons in the dentate gyrus and hippocampal formation were positive for NRAGE. The majority of granular cells of the dentate gyrus and pyramidal cells in the hippocampal formation were positive for NRAGE and negative for p75(NTR). NRAGE was also present in some neuronal populations that express p75(NTR) after injury, including striatal cholinergic interneurons, and motor neurons. A region of marked disparity was the cerebral cortex, in which NRAGE immunoreactivity was widespread whereas p75(NTR) was absent. The results are consistent with an important role for NRAGE in p75(NTR) signaling, as all cells that expressed p75(NTR) also expressed NRAGE. The wider distribution of NRAGE expression suggests that NRAGE may also participate in other signaling processes.     

Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D

BACKGROUND: Anxious depression, defined as Major Depressive Disorder (MDD) with high levels of anxiety symptoms, may represent a relatively common depressive subtype, with distinctive features. OBJECTIVE: The objective of this study was to determine the prevalence of anxious depression and to define its clinical correlates and symptom patterns. METHOD: Baseline clinical and sociodemographic data were collected on 1450 subjects participating in the STAR*D study. A baseline Hamilton Rating Scale for Depression (HAM-D) Anxiety/ Somatization factor score of > or =7 was considered indicative of anxious depression. The types and degree of concurrent psychiatric symptoms were measured using the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items endorsed by study participants for each diagnostic category. MDD symptoms were assessed by clinical telephone interview with the 30-item Inventory of Depressive Symptomatology (IDS-C30). RESULTS: The prevalence of anxious depression in this population was 46 %. Patients with anxious MDD were significantly more likely to be older, unemployed, less educated, more severely depressed, and to have suicidal ideation before and after adjustment for severity of depression. As far as concurrent psychiatric symptoms are concerned, patients with anxious depression were significantly more likely to endorse symptoms related to generalized anxiety, obsessive compulsive, panic, post-traumatic stress, agoraphobia, hypochondriasis, and somatoform disorders before and after adjustment for severity of depression. Anxious-depression individuals were also significantly less likely to endorse IDS-C30 items concerning atypical features, and were significantly more likely to endorse items concerning melancholic/endogenous depression features. CONCLUSION: This study supports specific clinical and sociodemographic correlates of MDD associated with high levels of anxiety (anxious depression).     

Microsatellite instability and alteration of the expression of hMLH1 and hMSH2 in ovarian clear cell carcinoma

Microsatellite instability (MSI) is commonly seen in tumors associated with the hereditary nonpolyposis colorectal cancer syndrome and is caused by defects in the DNA mismatch repair genes. MSI has also been observed in various sporadic cancers, including colorectal, gastric, and endometrial. The role and incidence of MSI in ovarian clear cell carcinoma remain unknown. This study was conducted to evaluate the frequency of MSI in ovarian clear cell carcinomas and to evaluate the sensitivity and specificity of immunohistochemistry in predicting mismatch-repair gene deficiency. A total of 42 ovarian clear cell carcinomas were analyzed for MSI using a panel of 5 microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250). Alterations in the expression of hMLH1 and hMSH2 proteins in these tumors were examined. Of the 42 ovarian clear cell tumors analyzed, 6 demonstrated a high level of MSI (MSI-H), 3 demonstrated a low level of MSI (MSI-L), and the remaining 33 exhibited microsatellite stability (MSS). No correlation was found between MSI level and patient age or tumor stage or size (P >0.05). Loss of expression of either hMLH1 or hMSH2 was observed in 4 of the 6 (67.7%) MSI-H tumors, whereas 34 of the 36 (94.4%) MSI-L or MSS tumors expressed both the hMLH1 and hMSH2 gene products. Our results indicate that MSI-H is involved in the development of a subset of ovarian clear cell carcinomas. A strong correlation exists between alterations in the expression of hMLH1 and hMSH2 and the presence of MSI-H in these tumors. However, immunohistochemical testing alone may miss a small fraction of cases with MSI-H.     

Clonal chromosome abnormalities in human breast carcinomas I. Twenty-eight cases with primary disease

Cytogenetic analysis was performed on a selected series of short-term cultures of primary breast carcinomas from 28 patients. All patients had histopathologically confirmed malignancies, with the majority (25/28 cases) demonstrating infiltrating ductal carcinoma. All 28 cases evidenced clonal chromosome abnormalities, with 10/28 displaying only numeric aberrations, whereas 18/28 displayed clonal structural alterations. In near-diploid tumors the most common numeric changes were — 17 and — 19. However, trisomy 7 was the only numeric change in two near-diploid tumors. Structural chromosome alterations were primarily isochromosomes, apparent terminal deletions, and unbalanced non-reciprocal translocations. Chromosomes 1 (10/18–56%) and 6 (8/18–44%) were most frequently altered in this series. Breakpoints of clonal structural abnormalities were shown to cluster to several chromosome segments, including 1p22-q11, 3p11, 6p11–13, 7p11-q11, 8p11-q11, and 19q13. Analysis of the gain or loss of specific chromosome segments revealed that the most consistent tendency was over-representation of 1q, 3q, and 6p. © 1993 Wiley-Liss, Inc.     

Geneticists' views on science policy formation and public outreach

Though much research about the public's views of scientists, genetic research and its moral, ethical, and social implications exists, little has been done to investigate how scientists view their own role(s) in public discussions and policy formation related to genetic research and technologies. We interviewed 20 academic geneticists in the United States about their perceptions of the roles they and others (e.g., professional societies, the public, ethicists, and elected officials) do and should play in the formation of science policy, the communication of science to the public, and the public discussions of moral and ethical issues raised by scientific advances. The participants in our study thought that scientists should be more actively involved in public outreach and science policy formation, but frequently they felt ill-equipped and unsupported by their peers and institutions to pursue these activities. Furthermore, many were skeptical of or did not trust elected officials--who they consider uninformed about the issues and too driven by political agendas--to formulate sound science policy. They do, however, have faith in the ability of scientific societies to influence policy effectively, and some thought that societies should play a larger role, both in science policy and as a liaison between scientists and the public. Finally, participants offered suggestions for increasing the involvement and influence of scientists in science-policy formation and public discourse.     

Measuring sleep habits without using a diary: the sleep timing questionnaire

STUDY OBJECTIVES: To develop a single-administration instrument yielding equivalent measures of sleep to those obtained from a formal (2-week) sleep diary. DESIGN & SETTING: A single-administration Sleep riming Questionnaire (STQ) is described (and reproduced in the Appendix). Test-retest reliability was examined in 40 subjects who were given the STQ on two occasions separated by less than 1 year. Convergent validity was measured both by comparing STO-derived measures with objective measures derived from wrist actigraphy (n=23) and by comparing STQ-derived measures with other subjective measures derived from a detailed 2-week sleep diary in two nonoverlapping samples (n=101, 93). Correlations of STQ measures with age and momingness-eveningness (chronotype) were also examined. SUBJECTS: The analyses used sample sizes of 40, 23, 101, and 93 (both genders, overall age range 20y-89y). Most subjects were healthy volunteers; some Study 4 subjects were patients (enrolled in research protocols). RESULTS: Test-retest reliability for the STQ was demonstrated for estimates of bedtime (r = 0.705, p < 0.001) and waketime (r = 0.826, p < 0.001). Convergent validity using wrist actigraphy was demonstrated by correlations of 0.592 (p < 0.005) for bedtime, and of 0.769 (p < 0.001) for waketime. Diary studies indicated STQ bedtime and waketime data to be highly correlated (at about 0.8) with those obtained from a formal 2-week sleep diary. The STQ also provided data on estimated sleep latency and wake after sleep onset (WASO), which correlated reliably (at about 0.7) with average nightly ratings of these variables from a 2-week sleep diary. Mean estimated values of sleep latency and WASO from the two instruments were within 1 minute of each other. ST-derived bedtimes and waketimes correlated with both age and chronotype in the expected direction (older subjects earlier, morning types earlier). CONCLUSION: The STQ may be a reliable valid measure of sleep timing that could provide a time-efficient alternative to traditional sleep diaries.     

Regulation of BCR signal transduction in B-1 cells requires the expression of the Src family kinase Lck

Although found predominantly in the peritoneal and pleural cavities, B-1 cells are also present in other peripheral tissues such as spleen and lung. While similar in surface phenotypes, such as CD5, all B-1 cells are not equivalent in their response to stimuli. Here, we report that the src family kinase Lck is required to confer the BCR hyporesponsiveness typical of CD5+ B-1 cells and appears involved in the maintenance of their unique function. Splenic B-1 cells express CD5 but not Lck and are not hyporesponsive; however, within the peritoneum, these B-1 cells are induced to express Lck and acquire a hyporesponsive phenotype. Peritoneal B-1 cells from lck-deficient mice, while CD5+, no longer exhibit attenuated BCR signaling. Interestingly, lck-null mice exhibited increased natural antibody levels characteristic of B-1 cells. Taken together, these results demonstrate a key role for Lck in modulating the signaling and cellular fate of B-1 B cells.     

Impact of suppression of viral replication by highly active antiretroviral therapy on immune function and phenotype in chronic HIV-1 infection

We compared immune phenotypes, lymphocyte proliferation (LP), and delayed type hypersensitivity (DTH) responses in 28 male antiretroviral treatment-naive and experienced HIV-1-infected patients, matched pair-wise according to age and CD4+ T-lymphocyte count. Median CD4+ T-lymphocyte counts were 441 cells/microL and 483 cells/microL and median CD4+ T-lymphocyte nadirs were 435 cells/microL and 150 cells/microL in both groups, respectively. Absolute numbers of circulating T-lymphocyte subpopulations and proportions of naive and memory T-lymphocytes were comparable in the two groups. Untreated patients had greater proportions of activated CD4+ (p <.05) and CD8+ (p <.01) T-cells expressing human leukocyte antigen (HLA)DR and CD38 and fewer CD8+ cells expressing CD28 (p <.05). DTH and LP responses were comparable in both groups except for HIVp24, LP responses, and mumps DTH responses, which were of greater magnitude in the group treated with highly active antiretroviral therapy (HAART) (p <.05). Thus, HIV-1-infected patients who experienced substantial increases in CD4+ T-lymphocyte counts after suppression of viral replication on HAART had fewer activated lymphocytes and similar immune function when compared with findings in untreated patients with similar CD4+ T-cell counts. HIV replication has minimal real-time effect on CD4+ T-cell function in response to non-HIV antigens but helper T-cell responses to HIV-gag antigen are impaired during ongoing viral replication and may be restored by antiretroviral therapy.