Temporal summation of repetitive click stimuli

Monaural loudness balances were performed by eight normal-hearing subjects to determine the effect of click repetition rate on loudness sensation. Click trains of 500 msec duration were matched in loudness to a standard 500 msec 1000 Hz tone burst presented at three reference loudness levels (70, 80, and 90 phons). Click trains were presented at repetition rates of 11, 31, 51, and 91 clicks per sec. It was found that click trains at faster repetition rates required lower intensities for judgments of equal loudness sensation. This finding was attributed to the process of temporal loudness summation. The magnitude and nature of the temporal summation process as well as the influence of the reference loudness level are discussed.     

Canadian Association of General Surgeons Evidence Based Reviews in Surgery. 6. "GERD" as a risk factor for esophageal cancer. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.

Question: Is gastroesophageal reflux a risk factor for the development of esophageal adenocarcinoma? Design: A case control study. Setting: A population-based study in Sweden between 1994 and 1997. Participants: Cases included all patients with gastric or esophageal adenocarcinoma and half of all patients with esophageal squamous cell cancer, under the age of 80 years and living in Sweden between Dec. 1, 1994, and Dec. 31, 1997. Controls were selected randomly from among persons matched for age (within 10 yr) and sex in the entire Swedish population, through the use of a population register, which is computerized and updated continuously. Assessment of risk factors: Symptomatic reflux was assessed according to the severity of the symptoms (heartburn only, regurgitation only, heartburn and regurgitation combined, nightly symptoms), frequency and duration. Adjustment was made for age, sex, body mass index, smoking history, alcohol ingestion, socioeconomic status, intake of fruit and vegetables, overall energy intake, posture and the degree of physical activity both at work and during leisure. Main outcome measures: Gastric and esophageal adenocarcinoma and esophageal squamous cell cancer. Main results: Among participants with recurrent symptoms of reflux, as compared with those without such symptoms, the odds ratios were 7.7 (95% CI, 5.3–11.4) for development of esophageal adenocarcinoma and 2.0 (95% CI, 1.4–2.9) for adenocarcinoma of the cardia. The more frequent, more severe and longer duration the symptoms of reflux were, the greater was the risk. Among persons with long-standing, severe symptoms of reflux, the odds ratios were 43.5 (95% CI, 18.3–103.5) for development of esophageal adenocarcinoma and 4.4 (95% CI, 1.7–11.0) for adenocarcinoma of the cardia. The risk of esophageal squamous cell carcinoma was not increased with reflux (odds ratio, 1.1; 95% CI, 0.7–1.9). Conclusion: The study identified a strong and probably causal relation between symptomatic reflux as a strong risk factor for esophageal adenocarcinoma and a relatively weak risk factor for adenocarcinoma of the gastric cardia.     

The MTT assay for chemosensitivity testing of human tumors of the central nervous system

In this study we assessed the influence of patient- and drug-specific parameters in the short-term MTT-chemosensitivity assay in 150 primary cell cultures derived from human brain tumors. In 45 patients the MTT assay was directly compared with the CFA (Colony Forming Assay). Resistance was 10-20% higher in the MTT assay than in the CFA, but there was a good agreement in both assays, that more malignant gliomas had a higher in vitro chemosensitivity against ACNU and BCNU. Overall the results demonstrate, that there is no uniform correlation between the in vitro chemosensitivity and the histopathological classification of the tumors, which corresponds well to the clinical situation. On the basis of this study we suggest prospective clinical trials with the MTT assay in human brain tumors.     

Altered responsiveness to stress and NMDA following prenatal exposure to cocaine

Pregnant Sprague--Dawley rats were treated once daily with 40-mg/kg cocaine or saline from gestation days (GD) 12 to 21. A third group of pregnant dams was used as a pairfed control. Male and female offspring were examined for stress endurance response as determined by the cold-water swim test on postnatal days (PND) 21, 30, 40, and 60. Male and female offspring exposed to cocaine in utero were found to have diminished tolerance and altered hormonal response to stress. Moreover, prenatal cocaine exposure has been associated with significant increases in severity of N-methyl-D-aspartate (NMDA; 35 mg/kg) behavioral responses (tail twitches, wetdog shaking, and convulsion) as compared to control. Examining the experimental groups for pain sensitivity using the tail-flick and the hot-plate methods indicated that prenatal cocaine exposure altered pain sensitivity. NMDA receptor binding studies showed an increase in receptor density in the hippocampus and hypothalamus of the cocaine-treated group. These results indicate that gestational cocaine exposure is associated with long-term alterations in response to stress, NMDA receptor, and pain sensitivity in the rat offspring.     

A blood-borne antigen induces rapid T-B cell contact: a potential mechanism for tolerance induction

Understanding the difference between the development of a productive T‐cell response and tolerance is central to discerning how the immune system functions. Intravenous injection of soluble protein is thought to mimic the presentation of self‐serum and orally introduced antigens. It is generally toleragenic. The current view is that this outcome reflects the failure of ‘immunogenic’ dendritic cells to relocate to the T‐cell zone of the secondary lymphoid tissues. Here, using a peptide/I‐E^k tetramer and antibodies to stain splenic sections, we showed that antigen‐specific T cells were activated in the spleen within hours of injection or feeding of protein. The activated T cells were found to be located at the T–B junction, the bridging zone and the B‐cell area, interacting directly with B cells. In addition, B cells gain the ability to present antigen. Our results suggest a way for T cells to be stimulated by blood‐borne antigen presented by naïve B cells, a potential mechanism of tolerance induction.     

Some early events in the primary mitogenic stimulation of lymphocytes differ from later interleukin stimulation and other quiescence to growth activation systems.

The requirement for activity of the enzyme ADP-ribosyl transferase (ADPRT) and changes in single-strand DNA breaks were assessed during the initial stimulation of quiescent murine splenic lymphocytes with mitogen alone, the stimulation of activated blasts with IL-2-containing medium and, for comparison, the serum stimulation of quiescent fibroblasts and the induction of haemoglobin synthesis in an erythromyeloid cell line K562. Inhibitors of ADPRT, at concentrations previously found to have no effect on the proliferation of lymphoblastoid cell lines, blocked the stimulation of spleen cells by Con A or LPS; non-inhibitory analogues had much less effect. No early increase in ADPRT activity after mitogenic stimulation was detectable. The rejoining of single-strand breaks was observed after stimulation of splenic lymphocytes with Con A, but not consistently with LPS. Conversely, ADPRT inhibitors had only little effect on the IL-2-induced stimulation of Con A blasts, and no effect on the stimulation of fibroblasts or K562. Neither were any changes in strand breaks associated with these systems. These findings implicate ADPRT activity and the rejoining of strand breaks in the early mitogenic response as being distinct from later IL-2 activation and changes from quiescence to growth in other cell types.     

The human Y chromosome.

Despite its central role in sex determination, genetic analysis of the Y chromosome has been slow. This poor progress has been due to the paucity of available genetic markers. Whereas the X chromosome is known to include at least 100 functional genetic loci, only three or four loci have been ascribed to the Y chromosome and even the existence of several of these loci is controversial. Other factors limiting genetic analysis are the small size of the Y chromosome, which makes cytogenetic definition difficult, and the absence of extensive recombination. Based on cytogenetic observation and speculation, a working model of the Y chromosome has been proposed. In this classical model the Y chromosome is defined into subregions; an X-Y homologous meiotic pairing region encompassing most of the Y chromosome short arm and, perhaps, including a pseudoautosomal region of sex chromosome exchange; a pericentric region containing the sex determining gene or genes; and a long arm heterochromatic genetically inert region. The classical model has been supported by studies on the MIC2 loci, which encode a cell surface antigen defined by the monoclonal antibody 12E7. The X linked locus MIC2X, which escapes X inactivation, maps to the tip of the X chromosome short arm and the homologous locus MIC2Y maps to the Y chromosome short arm; in both cases, these loci are within the proposed meiotic pairing region. MIC2Y is the first biochemically defined, expressed locus to be found on the human Y chromosome. The proposed simplicity of the classical model has been challenged by recent molecular analysis of the Y chromosome. Using cloned probes, several groups have shown that a major part of the Y chromosome short arm is unlikely to be homologous to the X chromosome short arm. A substantial block of sequences of the short arm are homologous to sequences of the X chromosome long arm but well outside the pairing region. In addition, the short arm contains sequences shared with the Y chromosome long arm and sequences shared with autosomes. About two-thirds of XX males contain detectable Y derived sequences. As the amount of Y sequences present varies in different XX males, DNA from these subjects can be used to construct a map of the region around the sex determining gene. Assuming that XX males are usually caused by simple translocation, the sex determining genes cannot be located in the pericentric region. Although conventional genetic analysis of the Y chromosome is difficult, this chromosome is particularly suited to molecular analysis. Paradoxically, the Y chromosome may soon become the best defined human chromosome at the molecular level and may become the model for other chromosomes.     

Gain of 1q and loss of 22 are the most common changes detected by comparative genomic hybridisation in paediatric ependymoma

Ependymomas are the third most common brain tumour in the paediatric population. Although cytogenetic and molecular analyses have pinpointed deletions of chromosomes 6q, 17, and 22 in a subset of tumours, definitive patterns of genetic aberrations have not been determined. In the present study, we analysed 40 ependymomas from paediatric patients for genomic loss or gain using comparative genomic hybridisation (CGH). Eighteen of the tumours (45%) had no detectable regions of imbalance. In the remaining cases, the most common copy number aberrations were loss of 22 (25% of tumours) and gain of 1q (20%). Three regions of high copy number amplification were noted at 1q24-31 (three cases), 8q21-23 (two cases), and 9p (one case). Although there was no association with the loss or gain of any chromosome arm or with benign versus anaplastic histologic characteristics, the incidence of gain of 7q and 9p and loss of 17 and 22 was significantly higher in recurrent versus primary tumours. This study has identified a number of chromosomal regions that may contain candidate genes involved in the development of different subgroups of ependymoma.