Cellular life histories and bow tie biology.

Considering the life-long influences of fetal growth biology, it is of interest to further elucidate the nature of the fetal growth process itself. Previous analyses of longitudinal fetal ultrasound data led to the hypothesis that hypoxia signals were important aspects of normal growth biology and directed attention to the place of oxygen as a basic nutrient. From the perspective of the cell, both hypoxia and lack of energy substrate trigger a common adaptive pathway through their effects on ATP availability. Comparative data from animal studies and cell culture provide evidence for an integrated energy/oxygen signaling system that acts redundantly and hierarchically with cellular differentiation programs, providing opportunities for developmental flexibility in response to variable ecologic or environmental challenge. The multinodal and interactive design of the fetal growth process suggests that it follows what has been described as the "bow tie" model of metabolism, with implications for robust and inventive approaches to cell, organ, and whole organism construction.     

Solid tumor screening recommendations in trisomy 18

The purpose of this study was to determine whether trisomy 18 patients are at an increased risk of tumor development and require formal tumor screening recommendations. A literature search of trisomy 18 patients with reports of tumors or malignancies, and compilation of all previously reported as well as new unreported cases was performed. 67 patients with trisomy 18 were found to have documented malignancies. 44 patients had hepatoblastomas, 21 patients had Wilms tumors, one patient had a functional neurogenic neoplasia, and one patient had Hodgkins lymphoma. The increasing numbers of reported malignancies in patients with trisomy 18 supports the indication for an early screening process. Specific screening recommendations are outlined consisting of imaging exams and laboratory values performed at specific intervals.     

Expression of a NOS transgene in dystrophin-deficient muscle reduces muscle membrane damage without increasing the expression of membrane-associated cytoskeletal proteins

Muscular dystrophy that is caused by mutation of the membrane-associated, cytoskeletal protein called dystrophin, is accompanied by loss of a dystrophin-associated protein complex (DPC) that includes neuronal nitric oxide synthase (nNOS). Previous work showed that expression of a nNOS transgene in the dystrophin-deficient, mdx mouse greatly reduces muscle membrane damage. In this investigation, we test whether expression of a nNOS transgene in wild-type or mdx muscle increases expression of DPC proteins, or functionally related proteins in the integrin complex that are upregulated in dystrophin-deficiency, or affects expression of the dystrophin homolog, utrophin. Many members of the DPC are enriched in Western blots of cell membranes isolated from NOS transgenic muscle, compared to wild-type. Similarly, alpha7-integrin and the associated cytoskeletal proteins talin and vinculin are increased in NOS transgenic, non-dystrophic muscle. However, utrophin expression is unaffected by elevated NOS expression in healthy muscle. A similar trend in mRNA levels for these proteins was observed by expression profiling. Analysis of membrane preparations from mdx mice and NOS transgenic mdx mice shows that expression of the NOS transgene causes significant reductions in utrophin, talin, and vinculin. Expression profiling of mRNA from mdx and NOS transgenic mdx muscles also shows reduced expression of talin. Immunohistochemistry of mdx and NOS transgenic mdx muscle indicates that reduction in utrophin in NOS transgenic mdx muscle results from a decrease in regenerative fibers that express high levels of utrophin. Together, these findings indicate that the NOS transgene does not reduce dystrophinopathy by increasing the expression of compensatory, structural proteins.     

Differences Between Treatment Seekers in an Obese Population: Medical Intervention vs. Dietary Restriction

This study examined two groups of people who were pursuing treatment for obesity: either medical intervention (a hospital group; N = 20) or support for dietary restriction (a community group; N = 18). This study addressed four questions: (1) Were there differences between the two groups in terms of their psychological distress (as measured by the Symptom Checklist)? (2) Does binge eating moderate psychological distress? (3) Do feelings of ineffectiveness moderate psychological distress? and (4) Which variables best accounted for group membership (i.e., type of treatment sought)? Results suggested that the hospital group was significantly more distressed than the community group. However, there were no differences between the two groups with respect to binge eating or feelings of ineffectiveness. These findings suggest that it is the effects of morbid obesity that are most likely to moderate psychological distress.     

Latent inhibition of conditioned odor potentiation of startle: a developmental analysis

We conducted a two-part study of age and latent inhibition in the rat. In the first part of the study, rats given odor-shock pairings at 23 or 75 days of age exhibited a potentiated startle response in the presence of the odor the following day. This effect did not occur in rats trained at 16 or 20 days of age. Odor pre-exposure on the day prior to conditioning markedly reduced the odor potentiation of startle effect in 23- and 75-day-old rats but had no effect in 16 and 20-day-olds. In the second part of the study, rats were pre-exposed to the odor at 16 or 20 days of age and then conditioned at 23 days of age. When tested the day after conditioning, these pre-exposed rats exhibited a disruption in the odor potentiation of startle effect. We compare our results with other studies of latent inhibition, and with recent studies on whether conditioned responses are appropriate to the animal's age at training or their age at test.     

The interaction of conflicting retinal motion stimuli in oculomotor control

Summary Oculomotor response has been assessed in humans during the presentation of conflicting retinal motion stimuli. In the majority of experiments a background stimulus was made to move with a constant velocity ramp in one direction followed by rapid resets at regular intervals. In the absence of an adequate fixation target this ramp-reset stimulus induced a nystagmus with a slow-phase velocity and saccadic frequency which remained almost constant as reset frequency was increased from 2 to 5 Hz. Moreover, the induced eye velocity could be considerably increased if the subject attempted active matching of display velocity. During both active and passive responses eye velocity gain reached a peak when display velocity was between 2°/s and 5°/s. The presence of small stationary targets induced a suppression of the passive ramp-reset response which was modified by target eccentricity and by tachistoscopic target illumination. When subjects pursued a sinusoidally oscillating target against a stationary structured background, eye velocity gain was significantly less than for pursuit against a blank background. The degree of interaction between conflicting stimuli was found to be dependent on their relative size, peripheral location and velocity. However, it appears that the human observer is able selectively to enhance feedback gain from one particular source in order to dominate stimuli from other unwanted sources.     

Histopathologic analysis of atypical lesions in image-guided core breast biopsies.

Appropriate follow-up of patients with needle core breast biopsies (NCBB) showing atypical hyperplasia remains unclear because previous studies show that subsequent open biopsies in variable proportions of these patients reveal ductal carcinoma in situ (DCIS) or even invasive carcinoma, indicating significant sampling artifact. NCBB with diagnoses of atypia were morphologically classified into groups as follows: I, ALH (n = 24); II, ADH with minimal cytologic atypism (n = 90); III, atypia, other (9 columnar, 2 apocrine, 11 atypical papillary); IV, severe ADH/borderline DCIS (n = 31). Mammographic and histologic features, including the number of foci of atypia in the NCBB and the calcification span, were then correlated with presence of DCIS or invasive tumor in subsequent open excisions. Open excisional biopsies showed more severe lesions in 12% of Group I-III cases (8% in Group I, 9% in Group II, and 27% in Group III), of which 15 were DCIS and one was an invasive tubular carcinoma (0.3 cm). Of the DCIS, 60% (n = 9) were < or =5 mm, and 13 of 15 (87%) were low grade. The NCBB cavity was immediately adjacent to the more severe lesions in 88% (n = 14) of cases, in keeping with sampling error. The subset showing severe ADH with borderline nuclear features in contrast was associated with a high likelihood (63%) of DCIS in follow-up excisions. NCBB with atypical papillary features also showed a high frequency of DCIS (4/11, 36%) in subsequent open excisions. Other factors associated with more severe lesions on open biopsy included the number of atypical foci in the NCBB (>4, P <.05) and the mammographic calcification span (>2.0 cm, P <.0001). Atypical lesions diagnosed in NCBB samples are radiographically and morphologically heterogeneous, accounting for the variable frequency of DCIS or invasive neoplasm identified in subsequent open excisions, which are usually focal, low grade, and a consequence of sampling artifact (i.e., adjacent to the NCBB cavity). DCIS is more likely if microcalcifications are mammographically extensive or if atypia is multifocal or is associated with borderline cytologic features.     

Anticipatory control of hand and eye movements in humans during oculo-manual tracking

Anticipatory activity of hand and eye has been examined during oculo-manual tracking of a constant velocity visual target with a hand cursor. Both target and cursor were presented briefly (< 480 ms), but repeatedly, at regular inter-stimulus intervals (ISI). In Expt 1, the build-up of hand and eye responses was examined for target velocities varying from 10–40 deg s⁻¹ with an ISI of 2.4 s. The velocity 100 ms after target onset (i.e. prior to visual feedback) for both hand and eye ( V ₁₀₀) progressively increased over the first four presentations but then attained a steady state (SS). SS V ₁₀₀ values for eye and hand increased in proportion to target velocity and were thus predictive of forthcoming movement. Hand velocity exceeded eye velocity but both exhibited similar anticipatory trajectories. In Expt 2, target velocity was constant (40 deg s⁻¹) but ISI varied from 0.48–3.74 s. Subjects made anticipatory eye movements for all ISIs but hand movements were often reactive at the longest ISI. If the target failed to appear as expected, subjects initiated predictive hand and eye responses with timing appropriate for the prevailing ISI. In Expt 3, predictive responses were compared with responses to randomised presentation. Peak hand velocity was greater in the randomised mode than in the predictive condition, whereas the converse was true for peak eye velocity. This difference is discussed in terms of the mechanisms of positional error correction in hand and eye. Results provide evidence of similar anticipatory mechanisms in hand and eye, using storage of velocity and timing to achieve rapid prediction of target motion.     

Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease

BACKGROUND: Reactive nitrogen species, formed via the reaction of nitric oxide (NO) with superoxide anion and via (myelo)peroxidase-dependent oxidation of NO(2)(-), have potent proinflammatory and oxidizing actions. Reactive nitrogen species formation and nitrosative stress are potentially involved in chronic obstructive pulmonary disease (COPD) pathogenesis. OBJECTIVES: To investigate the expression of markers of nitrosative stress, including nitrotyrosine (NT), inducible NO synthase (iNOS), endothelial NO synthase (eNOS), myeloperoxidase (MPO), and xanthine oxidase (XO) in bronchial biopsies and bronchoalveolar lavage from patients with mild to severe stable COPD compared with control groups (smokers with normal lung function and nonsmokers). METHODS: The expression of NT, iNOS, eNOS, MPO and XO in the bronchial mucosa and bronchoalveolar lavage of patients was measured by using immunohistochemistry, Western blotting, and ELISA and correlated with the inflammatory cell profile. RESULTS: Patients with severe COPD in stable phase had higher numbers of NT(+) and MPO(+) cells in their bronchial submucosa compared with mild/moderate COPD, smokers with normal lung function, and nonsmokers (P < .01). iNOS(+) and eNOS(+) but not XO(+) cells were significantly increased in smokers with COPD or normal lung function compared with nonsmokers (P < .05 and P < .01, respectively). In patients with COPD, the number of MPO(+) cells was significantly correlated with the number of neutrophils (r = +0.61; P < .0025) in the bronchial submucosa. Furthermore, the number of NT(+) and MPO(+) cells was negatively correlated with postbronchodilator FEV(1). CONCLUSION: These data suggest that nitrosative stress, mainly mediated by MPO and neutrophilic inflammation, may contribute to the pathogenesis of severe COPD.