Modulation of paired-pulse responses in the dentate gyrus: effects of prenatal protein malnutrition

Since our major hypothesis is that prenatal protein malnutrition significantly affects hippocampal neuroplasticity, this study examined the effects of prenatal protein malnutrition on the modulation of dentate granule cell excitability in freely moving rats at 15, 30 and 90 days of age across the vigilance states of quiet waking (QW), slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Using paired-pulse stimulation, the paired-pulse index (PPI), a measure of the type and degree of modulation of dentate granule cell excitability elicited by stimulation of the medial perforant path, was obtained for each vigilance state at each stage of development. Four specific measures of granule cell excitability were computed, namely, PPI using both population spike amplitude (PSA) and EPSP slope measures, absolute values of PSA(1) and EPSP(1) slope. PPI values obtained at 15, 30 and 90 days of age, however, were altered during normal ontogenetic development, but not by vigilance state. At 15 days of age, the malnourished group exhibits greater early inhibition of the PPI using the PSA measure at IPIs between 20 and 30 ms regardless of vigilance state, while at 30 days of age, the malnourished group exhibits greater facilitation at IPIs between 50 and 70 ms during QW and SWS, but not during REM sleep. In the control adult (PND90) and juvenile (PND30) animal, PSA(1) values are significantly higher during SWS than in QW or REM sleep. However, for the younger malnourished animals (PND15 and PND30), PSA(1) values were found to be significantly greater during REM sleep rather than SWS. Therefore, as the animal matures, there appears to be a shift in vigilance state dependent synaptic transmission through the hippocampal trisynaptic circuit from REM sleep to SWS in both control and malnourished animals, with the change occurring later in malnourished animals when compared to control ones. Furthermore, our findings suggests that prenatal protein malnutrition significantly alters modulation of dentate granule cell excitability (i.e., PPI values using the PSA measure) during the earlier stages of development but not in adulthood.     

Dentate granule cell modulation in freely moving rats: vigilance state effects

Dentate granule cell population responses to paired-pulse stimulation applied to the perforant pathway across a range of interpulse intervals (IPIs) were examined during different vigilance states-quiet waking (QW), slow-wave sleep (SWS), and rapid-eye movement (REM) sleep-in freely moving rats at 15, 30 and 90 days of age. Using these evoked field potentials, the paired-pulse index (PPI), a measure of the type and degree of modulation of dentate granule cell excitability, was computed and shown to be altered as a function of age. Animals, 15 days old, showed significantly lower levels of early inhibition (20-40 ms IPIs), i.e., greater PPI values, during all three vigilance states when compared to both the 30- and 90-day old animals. Adult, i.e, 90-day old animals, on the other hand, showed significantly greater levels of late inhibition (300-1000 ms IPIs), i.e., lower PPI values, than the younger animals (15- and 30-day old) during QW and SWS. These results indicate that as the dentate field of the hippocampal formation matures there are significant alterations in the modulation of dentate granule cell activity.     

Sympathetic skin response in hemodialysis patients: correlation with nerve conduction studies and adequacy of dialysis

A sympathetic skin response (SSR) test was performed in diabetic and nondiabetic patients undergoing regular hemodialysis and the results correlated with nerve conduction studies (NCS): sensory conduction velocity (SCV) and motor conduction velocity (MCV). Comparisons were made between diabetic and nondiabetic patients and between cuprophane and polyacrylonitrile membrane dialyzed patients. Six nondiabetic uremic patients (30%) and all diabetic patients had no SSR. Eight nondiabetic uremic patients (40%) had a mildly impaired response. Nondiabetic patients with a normal response were younger (31.1+/-16.4 years) than the patients with abnormal SSR, whether mildly impaired response (58.3+/-20.3 years; p<0.05, Anova) or absent response (65.3+/-13.8 years; p<0.01, Anova). SCV, MCV, and SSR values were reduced (p<0.01) in uremic patients with respect to normal subjects. Severity and frequencies of sensory NCS abnormalities in nondiabetic patients were: normal 20%, mildly impaired 75%, and severely impaired 5%. Severity and frequencies of motor conduction abnormalities were: normal 80%, mildly impaired 20%, severely impaired 0%. The SSR abnormality incidence in patients with a normal NCS was similar to that in patients with either mildly or severely impaired NCS (chi-square test). There was a positive linear correlation between the SSR amplitude and SCV (r = 0.52, p<0.01) and MCV (r = 0.49, p<0.01). The SSR latency was also significantly related to SCV (r = 0.66, p<0.01) and MCV (r = 0.61, p<0.01). A significant negative correlation was found between age and SSR parameters, amplitude (r = -0.56, p<0.01) and latency (r = -0.66, p<0.01). No correlation was found between duration of hemodialysis or Kt/V and SSR. No differences were found in SSR, NCS, or Kt/V values between cuprophane membrane and polyacrylonitrile membrane dialyzed patients (Student's t test). The relationship between NCS and SSR in uremic patients was confirmed. Old age and diabetes mellitus, but not the dialysis membrane used, were confirmed as synergistic factors of neuropathic impairment. It appeared that SSR is more sensitive than NCS in detecting polyneuropathy in uremic patients on hemodialysis.     

Psychosocial stress in Marine Corps officers

Stress research in military populations has largely been devoted to specialized situations "at risk" for high levels of stress, such as combat, recruit training, sea duty, as well as post-traumatic stress in veterans. Though the armed forces continue to train for war during peacetime, military personnel also carry out administrative, executive, and technical job functions not directly related to combat preparations. Little data exists researching stress experienced in military non-combat environments. A study was conducted assessing levels of stress of 900 Marine Corps officers assigned to various headquarters and stations. Randomly selected participants completed the Derogatis Stress Profile (DSP). The study examined stress as a function of rank and the individual officer's perception of stress. Total stress levels of the subjects were compared to those used to norm the DSP.     

Reference Data of Vertebral Morphometry by X-ray Absorptiometry (MXA) in Argentine Women

Anterior, middle, and posterior heights and A/P and M/P ratios were determined from T5 to L4 in 111 normal Caucasian Argentine women from 20 to 70 years of age using dual energy X-ray absorptiometry (DXA) densitometry (Expert XL). Scanning time was less than 1 minute and the semiautomatic analysis requires ∼5 minutes. The precision error for the measurements ranged from 2.2% to 4.6%. The absolute precision error for heights was 0.6 mm. The vertebral bodies tended to be significantly larger in younger women than older women, especially for anterior and middle heights and the A/P and M/P ratios of the mid-thoracic vertebrae (T6–T10). There were no significant differences between pre- and postmenopausal women in the lumbar vertebral heights. It does not appear that this was a cohort effect because stature was identical in both age groups, and there was no age difference in posterior height. The Expert-XL software normalized the vertebral height based on the average height of the L2-L4 segment in order to minimize the influence of interindividual variation of body size. The average Z-scores for vertebral heights and ratios provided by the software were close to zero indicating that the normalization procedure appropriately corrected for smaller stature in Argentine women. Consequently, the reference values for morphometry X-ray absorptiometry (MXA) were appropriate for our population. In summary, we found that (1) in ``normal' women the anterior heights of the thoracic vertebrae (and therefore the A/P ratio) were higher in premenopausal than in postmenopausal women; and (2) the normalization approach corrected for differences of vertebral height and allowed utilization of the manufacturers software in our population. Received: 28 June 1999 / Accepted: 2 November 1999     

Validity and reliability of acoustic analysis of respiratory sounds in infants.

OBJECTIVE: To investigate the validity and reliability of computerised acoustic analysis in the detection of abnormal respiratory noises in infants. METHODS: Blinded, prospective comparison of acoustic analysis with stethoscope examination. Validity and reliability of acoustic analysis were assessed by calculating the degree of observer agreement using the kappa statistic with 95% confidence intervals (CI). RESULTS: 102 infants under 18 months were recruited. Convergent validity for agreement between stethoscope examination and acoustic analysis was poor for wheeze (kappa = 0.07 (95% CI, -0.13 to 0.26)) and rattles (kappa = 0.11 (-0.05 to 0.27)) and fair for crackles (kappa = 0.36 (0.18 to 0.54)). Both the stethoscope and acoustic analysis distinguished well between sounds (discriminant validity). Agreement between observers for the presence of wheeze was poor for both stethoscope examination and acoustic analysis. Agreement for rattles was moderate for the stethoscope but poor for acoustic analysis. Agreement for crackles was moderate using both techniques. Within-observer reliability for all sounds using acoustic analysis was moderate to good. CONCLUSIONS: The stethoscope is unreliable for assessing respiratory sounds in infants. This has important implications for its use as a diagnostic tool for lung disorders in infants, and confirms that it cannot be used as a gold standard. Because of the unreliability of the stethoscope, the validity of acoustic analysis could not be demonstrated, although it could discriminate between sounds well and showed good within-observer reliability. For acoustic analysis, targeted training and the development of computerised pattern recognition systems may improve reliability so that it can be used in clinical practice.     

Discovery of benzo[e]pyridoindolones as kinase inhibitors that disrupt mitosis exit while erasing AMPK-Thr172 phosphorylation on the spindle

Aurora kinases play an essential role in mitotic progression and are attractive targets in cancer therapy. The first generation of benzo[e]pyridoindole exhibited powerful aurora kinase inhibition but their low solubility limited further development. Grafting a pyperidine-ethoxy group gives rise to a hydrosoluble inhibitor: compound C5M.C5M could efficiently inhibit the proliferation of cells from different origins. C5M prevented cell cycling, induced a strong mitotic arrest then, cells became polyploid and finally died. C5M did not impair the spindle checkpoint, the separation of the sister chromatids and the transfer of aurora B on the mid-zone. C5M prevented histone H3 phosphorylation at mitotic entry and erased AMPK-Thr172 phosphorylation in late mitosis. With this unique profile of inhibition, C5M could be useful for understanding the role of phospho-Thr172-AMPK, in abscission and the relationship between the chromosomal complex and the energy sensing machinery.C5M is a multikinase inhibitor with interesting preclinical characteristics: high hydro-solubility and a good stability in plasma. A single dose prevents the expansion of multicellular spheroids. C5M can safely be injected to mice and reduces significantly the development of xenograft. The next step will be to define the protocol of treatment and the cancer therapeutic field of this new anti-proliferative drug.     

Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

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