Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo

Cyclin D1 is part of a cell cycle control node consistently deregulated in most human cancers. However, studies with cyclin D1-null mice indicate that it is dispensable for normal mouse development as well as cell growth in culture. Here, we provide evidence that ras-mediated tumorigenesis depends on signaling pathways that act preferentially through cyclin D1. Cyclin D1 expression and the activity of its associated kinase are up-regulated in keratinocytes in response to oncogenic ras. Furthermore, cyclin D1 deficiency results in up to an 80% decrease in the development of squamous tumors generated through either grafting of retroviral ras-transduced keratinocytes, phorbol ester treatment of ras transgenic mice, or two-stage carcinogenesis.     

Observer agreement on interpreting colposcopic images of CIN

The purpose of this work was to study intraobserver and interobserver variation in the interpretation of colposcopic images of cervical intraepithelial neoplasia (CIN). Twenty-three experienced colposcopists were asked to assess colposcopic images presented on slides and to select the biopsy site. Eleven cases were independently interpreted twice with an interval of 2-3 months by all observers. No information about the cytological classification was available. In each case the "majority assessment" was considered as the standard, being "no CIN" in 2 cases, CIN I in 4 cases, CIN II in 3 cases, and CIN III in 2 cases. Intraobserver concordance was 66.7%, the kappa value was 0.54. Interobserver agreement was found to be 52.4 and 51.0% in the first and second sessions, respectively, while the mean kappa values were 0.41 and 0.33, respectively. In selecting the site for biopsy, 77.4% of all observers agreed while the same site was selected in 85.3% of cases by the individual colposcopist in the two sessions. Overall, CIN I and II interpretations revealed lower levels of agreement than no CIN or CIN III interpretations. It is concluded that observer variability in interpreting colposcopic images and selecting the site for biopsy is in the same range as observer variation in other subjective diagnostic tests such as cytology and histopathology. This variation should be taken into account in the colposcopical management of patients with abnormal cytology.     

Fuzzy-trace theory and false memory: new frontiers

We describe the origins of fuzzy-trace theory, including Piagetian, interference, information-processing, and judgment and decision-making influences. The contrasting properties of gist and verbatim memory serve as its foundation and, in recent models of spontaneous and implanted false memories, explain seemingly contradictory developmental trends, such as reverse developmental findings, differential time courses for true and false memories, and conflicting effects of trace strength. However, approaches that integrate fuzzy-trace theory with neurological, social, emotional, and motivational perspectives are needed. A method for accomplishing this integration, using the recent models, is introduced and new research that spans these perspectives is discussed. Relations to other contemporary theories, especially source-monitoring and dual-process theories, are also explained. We conclude by rejecting the notion that spontaneous false memories are actually "true" and distinguish gist and verbatim senses of the term "true" that have different consequences in real life.     

Temporal processing of the pitch of complex tones

The effect of tone duration on fundamental frequency (F0) discrimination is greater for complexes containing unresolved harmonics than for those containing resolved harmonics [Plack and Carlyon, J. Acoust. Soc. Am. 98, 1355-1364 (1995)]. Three experiments explored this effect further. The first experiment measured sensitivity (as d') to fundamental frequency (F0) differences for two complexes, both with an F0 of 250 Hz. The first complex was low-pass filtered at 1875 Hz to create a resolved complex and the second was bandpass filtered between 5500 and 7500 Hz to create an unresolved complex. The harmonics for the resolved complex were selected so that no two harmonics were the same between the two observation intervals. Performance for both complexes was measured for tone durations of 20, 40, 80, and 160 ms. For the unresolved complex, the effect of duration was greater than that for the resolved complex and greater than the predictions of a "multiple-looks" model assuming either peripheral (before sampling) or central (after combining samples) sources of variance. The second experiment replicated these results using an F0 of 62.5 Hz with the cutoff frequencies of the bandpass filters divided by four, confirming that the effect is related to resolvability and not to spectral region. In the final experiment, F0 discrimination for pairs of complexes separated by a temporal gap was measured relative to that for one complex. Performance for the resolved and unresolved complexes was similar: Very little effect of gap duration was observed and the results were consistent with the predictions of the peripheral-variance multiple-looks model. Taken together, the results suggest that the pitch mechanism for resolved harmonics uses a relatively short sampling window of around 20 ms, while the mechanism for unresolved harmonics may use a more complex strategy for optimizing the combination of information over time, perhaps involving a flexible integration time.     

The lactulose breath hydrogen test and small intestinal bacterial overgrowth

OBJECTIVES: To i) document the sensitivity and specificity of a combined scintigraphic/lactulose breath hydrogen test for small intestinal bacterial overgrowth and ii) investigate the validity of currently accepted definitions of an abnormal lactulose breath hydrogen test based on "double peaks" in breath hydrogen concentrations. METHODS: Twenty-eight subjects were investigated with culture of proximal small intestinal aspirate and a 10-g lactulose breath hydrogen test combined with scintigraphy. Gastroduodenal pH, the presence or absence of gastric bacterial overgrowth, and the in vitro capability of overgrowth flora to ferment lactulose were determined. RESULTS: Sensitivity (16.7%) and specificity (70.0%) of the lactulose breath hydrogen test alone for small intestinal bacterial overgrowth were poor. Combination with scintigraphy resulted in 100% specificity, because double peaks in serial breath hydrogen concentrations may occur as a result of lactulose fermentation by cecal bacteria. Sensitivity increased to 38.9% with scintigraphy, because a single rise in breath hydrogen concentrations, commencing before the test meal reaches the cecum, may occur in this disorder. Sensitivity remained suboptimal irrespective of the definition of small intestinal bacterial overgrowth used, the nature of the overgrowth flora, favorable luminal pH, the presence of concurrent gastric bacterial overgrowth, or the in vitro ability of the overgrowth flora to ferment lactulose. CONCLUSIONS: Definitions of an abnormal lactulose breath hydrogen test based on the occurrence of double peaks in breath hydrogen concentrations are inappropriate. Not even the addition of scintigraphy renders this test a clinically useful alternative to culture of aspirate for diagnosing small intestinal bacterial overgrowth.     

Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn's disease define a clinical subgroup

BACKGROUND & AIMS: Antineutrophil cytoplasmic antibodies (ANCA) have been consistently detected in a subgroup of patients with Crohn's disease (CD). This study was designed to determine whether serum ANCA expression in patients with CD characterizes an identifiable clinical subgroup. METHODS: The study population consisted of 69 consecutive patients with an established diagnosis of CD as determined by a combination of characteristic clinical, radiographic, endoscopic, and histopathologic criteria. Sera from the patients were analyzed for the presence of ANCAs using the fixed neutrophil enzyme-linked immunosorbent assay (ELISA) assay. Perinuclear ANCA (pANCA)-positive and cytoplasmic ANCA (cANCA)-positive results by ELISA were confirmed by indirect immunofluorescence staining. Clinical profiles of the ANCA-positive patients with CD were compared with those of patients with CD not expressing ANCA (ANCA-negative). RESULTS: pANCA-positive patients with CD have endoscopically and/or histopathologically documented left-sided colitis and symptoms of left-sided colonic inflammation, clinically reflected by rectal bleeding and mucus discharge, urgency, and treatment with topical agents. One hundred percent of patients with CD expressing pANCA had "UC-like" features. CONCLUSIONS: In patients with CD, serum pANCA expression characterizes a UC-like clinical phenotype. Stratification of CD by serum pANCA provides evidence of heterogeneity within CD and suggests a common intestinal mucosal inflammatory process among a definable subgroup of patients with CD and UC expressing this marker.     

Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans

Defining a behavior that requires the function of specific neurons in the free-living nematode Caenorhabditis elegans can allow one to screen for mutations that disrupt the specification or function of those neurons. We identified serotonin-immunoreactive neurons required for tail curling or "turning" behavior exhibited by C. elegans males during mating. Males mutant in three different genes that reduce serotonin expression, cat-1, cat-4, and bas-1, exhibited defects in turning behavior similar to those of wild-type males in which these neurons were ablated. The turning defect of cat-4 males was rescued by exogenous serotonin, consistent with the idea that their behavioral defect is caused by a lack of serotonin. While the serotonin-deficient mutants we analyzed shared certain behavioral traits, they were blocked for serotonin synthesis at different steps. Analysis of these and additional serotonin-deficient mutants may help us understand how a neuron controls the expression of a serotonergic phenotype.     

The synthesis of elastin, collagen, and glycosaminoglycans by high density primary cultures of neonatal rat aortic smooth muscle. An ultrastructural and biochemical study

Primary cultures of neonatal rat aortic smooth muscle cells inoculated at high densities (1 X 10(6) cells/25 cm2 Falcon flask) with adequate nutrient media and pH control grow rapidly and form multilayers of cells with typical "hill and valley" organization. After 10 days growth insoluble elastin formation could be visualized by phase contrast microscopy as small particles which grew rapidly to become larger irregular refractile aggregates and later coalesced to form larger aggregates and small fibres. With light and electronmicroscopy, elastin was the predominant matrix protein formed, with the "hill regions" of cultures containing abundant elastin aggregates and some collagen. In 2-week-old cultures differentiation could be observed within the cell multilayer. The older deeper cells contained more protein synthesis organelles and myofilaments and were in close association with large often coalescing elastin aggregates; compared to younger more superficial cells which contained more free polyribosomes less myofilaments, and were associated with fewer and small elastin aggregates. In older cultures this differentiation was not apparent; the cells contained many myofilaments, dense bodies, and lysosomes. Elastin aggregates and newly formed elastic fibres were abundant in the matrix. Quantitative analysis of insoluble elastin formation in the cell layer during the 4-week culture period indicated continuous biosynthesis and deposition which paralleled that of desmosine formation. Amino-acid analysis of a hot alkali insoluble residue (regarded as elastin) from 30-day-old cultures gave a profile identical with neonatal rat aortic elastin in vivo. Insoluble collagen formation in the cell layer tended to plateau after the log phase of growth was completed (10 days). Proteoglycans were found predominantly in the supernatant media. Glycosaminoglycan analysis revealed a profile of dermatan sulphate (32%), chondroitin 4-sulphate (43%), keratan and heparan sulphate (30%), with only a trace of hyaluronic acid. This study indicates that primary cultures of neonatal rat aortic smooth muscle cells remain differentiated in culture and have the unique capacity to continue to synthesize and deposit large amounts (mg) of insoluble elastin which aggregate and from elastic fibres in vitro.     

The influence of taking uterine biopsies on the concentration of some steroids in the blood and in the uterus, on the ovarian activity, and on the sexual behaviour of the mare

It has been shown that stimulation of the uterus of mares by the daily taking of biopsies can result in the occurrence of oestrous symptoms. This is accompanied by some follicular growth and a progesterone content in the blood often higher than 1 ng/ml. The following observations suggest that this progesterone originates in the uterus and not in the ovaries: (1) no active corpora lutea appeared to be present in the ovaries after ovariectomy, (2) ovariectomized mares showed the same oestrous symptoms in similar experiments and even mating took place, (3) in the uterine biopsies the concentration of the compound referred to as "5.4", which is assumed to be easily convertible into progesterone, had already increased considerably in the second biopsy, (4) administration of stilboestrol reduced the rise of the progesterone level in the uterine biopsies as well as in the blood. The absence of oestradiol-17 beta in the ovarian follicles and the fact that ovariectomized mares also come into heat suggest that oestrogens cannot be held responsible for the oestrous symptoms in these mares. Our experiments demonstrate that the uterus can be involved in sexual behaviour and the formation of steroids.