Prevention of NKT cell activation accelerates cutaneous wound closure and alters local inflammatory signals

We previously reported that in the absence of NKT cells, wound closure was accelerated in a murine excisional punch wound model. Here, we explored whether purposefully inhibiting NKT cell activation had similar effects on wound closure and the dermal inflammatory response to injury. We found that prevention of NKT cell activation accelerated wound closure in a dose-responsive manner. If anti-CD1d was administered before wounding, NKT cell infiltration into cutaneous wounds was diminished without quantitative changes in cellular infiltrates. Furthermore, prevention of NKT cell activation transiently enhanced the local production of a subset of chemokines, including MIP-2, MCP-1, MIP-1α, and MIP-1β, and altered the relative expression of CD69 and CXCR2 on the surface of both circulating and wound NKT cells. Taken together, these findings suggest that wounding activates NKT cells via CD1d presentation of glycolipid antigen and help further define a role for NKT cells in the regulation of wound inflammation and closure. Many soluble factors have been targeted as potential wound healing therapies, but their clinical success has been limited. Given our findings, the NKT cell may be an attractive target for wound healing therapies.     

Prevention of injury-induced suppression of T-cell immunity by the CD1d/NKT cell-specific ligand alpha-galactosylceramide

Infection, sepsis, and multiple organ failure continue to be significant factors leading to morbidity and mortality after severe injury. Studies by our laboratory and others have identified injury-induced defects in both innate and adaptive components of host defense. We previously reported that CD1d-restricted natural killer T (NKT) cells actively suppress effector T-cell immunity after burn injury via production of excess IL-4 and failure to produce IFN-gamma. alpha-Galactosylceramide (alpha-GalCer) is a synthetic NKT cell-specific ligand presented exclusively to invariant NKT cells and is known to improve immunity against tumors and infection by promoting IFN-gamma production. Here, we confirmed the role of Valpha14-Jalpha281 invariant NKT cells in mouse model of burn injury-induced suppression of T-cell immunity and further asked whether alpha-GalCer can improve immunity after injury via similar mechanisms. We observed that systemic treatment with alpha-GalCer prevented the injury-induced suppression of Ag-specific T-cell responsiveness both in vitro and in vivo and restored the ability of splenic lymphocytes to produce both IL-2 and IFN-gamma. Moreover, burn injury was associated with diminished expression of major histocompatibility complex II and CD40 on antigen presenting cells that were both restored by alpha-GalCer treatment to levels seen in sham-treated mice. Collectively, these data suggest that, via manipulation of the NKT cell population, we may be able to maintain T-cell function and improve host defense after burn injury.     

Perception of the Missing Fundamental by Chinchillas in the Presence of Low-Pass Masking Noise

The pitch of the missing fundamental (F0) is one of the principal psychological attributes of human pitch perception. Behavioral responses to harmonic tone complexes having missing F0s were measured in chinchillas using operant conditioning and stimulus generalization. Animals were trained to discriminate between tone complexes having a 500-Hz F0 and a 125-Hz F0. When animals were tested with tone complexes having the same F0s, but where the F0s were missing, responses were similar to those obtained when the F0s were present, suggesting that missing F0 sounds were perceptually equivalent to F0 present sounds. Behavioral responses to F0 present and missing F0 stimuli were similar in the presence of low-pass masking noise, suggesting that the perception was not due to the reinsertion of the F0 through cochlear nonlinearities. Gradients in behavioral responses were observed when the F0s of test complexes were systematically varied, suggesting the existence of a psychological dimension related to F0. Behavioral responses were related to the F0 rather than to spectral differences among test stimuli when the F0 and spectrum were varied independently. The results indicate that chinchillas possess a pitch-like perception of the missing F0 that is unlikely to arise from cochlear distortion products.     

A prospective analysis of c-myc oncoprotein levels as a prognostic marker in malignant melanoma.

BACKGROUND: Previous studies from our group had identified c-myc oncoprotein expression as an important prognostic parameter in a series of retrospective studies of primary and metastatic melanoma and other variants of this disease. This study set out to prospectively evaluate the prognostic significance of c-myc positivity in a consecutive series of primary melanomas presenting at Mount Vernon Hospital Regional Plastic Surgery and Burns Centre. METHODS: A consecutive series of 117 primary melanomas underwent flow cytometric analysis for c-myc expression at diagnosis. Routine clinical and histological parameters were collected from each patient's clinical records and survival assessed. The mean follow up was 45 months. RESULTS: Kaplan-Meier survival analysis demonstrated that Breslow depth, histogenic subtype, ulceration, age and sex had prognostic significance. Survival analysis revealed high c-myc positivity to be significantly associated with poorer outcome (P<0.043). Each of the main prognostic parameters were assessed for their independent significance using Cox Proportional Hazards; only c-myc retained independent significance (P<0.039). CONCLUSIONS: The strength of this study is that it was performed in a consecutive series of patients followed up in a longitudinal prospective study. c-myc was not the strongest predictor of survival in univariate analysis, but was the only parameter that retained significance in multivariate analysis.     

Discrimination of rippled-spectrum noise from flat-spectrum noise by chinchillas: evidence for a spectral dominance region

Iterated rippled noise having infinite iterations is generated when a flat-spectrum wideband noise is delayed T ms and the delayed version is added to the undelayed noise through positive feedback. The resulting signal has a rippled spectrum, and the perceived pitch of this iterated rippled noise by human listeners corresponds to a frequency of 1/T. We have previously demonstrated that chinchillas can discriminate the rippled-spectrum noise from the flat-spectrum noise. In the present study, chinchillas discriminated a bandpass filtered rippled-spectrum noise from a bandpass flat-spectrum noise in a psychophysical task. The passbands were set to be one octave wide. Psychometric functions were obtained for 5 chinchillas and performance was measured as d′. The best behavioral performance was obtained when the center frequency of the bandpass filter generally corresponded to the 3rd–5th harmonic peak of the rippled noise (i.e., at 3/T to 5/T), but the precise location of the dominant region varied with the delay of the rippled noise such that the dominance region tended to shift to lower harmonics as 1/T increased. These results indicate that not all spectral regions are weighted equally in the discrimination task. The spectral dominance region found in chinchillas is similar to that described for human pitch perception.     

Effects of experimentally induced mild hyperthyroidism on growth hormone and insulin secretion and sex steroid levels in healthy young men

Although triiodothyronine (T₃) exerts major regulatory actions in both animals and humans, most clinical studies of T₃ administration have been relatively short-term. The present study examined the effects of more than 2 months (63 days) of low-dose T₃ treatment on overnight pulsatile growth hormone (GH) secretion, short-term insulin secretion, and of sex steroid levels in seven healthy, lean men studied at an inpatient metabolic unit. At baseline, there were strong correlations between sex hormone—binding globulin (SHBG) and several measures of GH production, including total GH production (r = .99), GH interburst interval (r = −.75, and GH mass (r = .82). SHGB was also inversely correlated with basal insulin secretion (r = −.74). There was a 42% increase in serum levels of total testosterone (18.5 ± 1.3 to 26.3 ± 1.8 nmol/L, P = .005) and a 150% increase in SHBG (18.0 ± 2.2 to 44.9 ± 7.0 nmol/L, P = .008) following T₃ treatment. Estradiol and free testosterone levels were unchanged by treatment, although free testosterone decreased from 142.8 ± 18.4 to 137.3 ± 19.5 pmol/L. T₃ treatment significantly reduced the GH interburst interval (P < .05) and produced slight increases in the measures of GH secretion. There were no statistically significant effects of T₃ treatment on insulin secretion, although insulin peak amplitude, mass secreted per burst, and total production all decreased. We conclude that experimentally induced T₃ excess in healthy men produces significant and sustained changes in sex hormone levels and GH secretion. Furthermore, there are strong associations between SHBG and both GH and insulin secretion independent of thyroid hormone excess that require additional study.     

Influence of a carbohydrate-electrolyte beverage on performance and blood homeostasis during recovery from football.

This study compared the efficacy of a 7% glucose polymer beverage containing electrolytes (GP) versus a nonnutrient, nonelectrolyte placebo (P) in maintaining blood homeostasis during recovery from football and determined whether consumption of the GP beverage improved anaerobic performance immediately after football competition when compared with the placebo. Forty-four high school football players participated in a 50-play scrimmage designed to simulate game conditions. At each of six periods before and during the scrimmage, players consumed 170 ml of the GP or P beverage. Eight maximal-effort 40-yd sprints (40-sec rest intervals) were performed before and after the scrimmage to assess the decrement in anaerobic performance from the scrimmage. Venous blood samples were drawn before and after the scrimmage and analyzed. The pre- to postscrimmage differences in mean and peak sprint velocities did not differ between treatments, nor did body weight and plasma. In contrast, the percent decrease in plasma volume was significantly greater in the P group. Postscrimmage increases in glucose and insulin were greater in the GP group. These data suggest that CHO-electrolyte drinks do not prevent a decline in anaerobic performance when compared to water, but a CHO-electrolyte drink is more effective in maintaining PV than water during recovery from anaerobic exercise.     

Effects of caffeine,sleep loss,and stress on cognitive performance and mood during U.S. Navy SEAL training

Abstract Rationale. When humans are acutely exposed to multiple stressors, cognitive performance is substantially degraded. Few practical strategies are available to sustain performance under such conditions. Objective. This study examined whether moderate doses of caffeine would reduce adverse effects of sleep deprivation and exposure to severe environmental and operational stress on cognitive performance. Methods. Volunteers were 68 U.S. Navy Sea-Air-Land (SEAL) trainees, randomly assigned to receive either 100, 200, or 300 mg caffeine or placebo in capsule form after 72 h of sleep deprivation and continuous exposure to other stressors. Cognitive tests administered included scanning visual vigilance, four-choice visual reaction time, a matching-to-sample working memory task and a repeated acquisition test of motor learning and memory. Mood state, marksmanship, and saliva caffeine were also assessed. Testing was conducted 1 and 8 h after treatment. Results. Sleep deprivation and environmental stress adversely affected performance and mood. Caffeine, in a dose-dependent manner, mitigated many adverse effects of exposure to multiple stressors. Caffeine (200 and 300 mg) significantly improved visual vigilance, choice reaction time, repeated acquisition, self-reported fatigue and sleepiness with the greatest effects on tests of vigilance, reaction time, and alertness. Marksmanship, a task that requires fine motor coordination and steadiness, was not affected by caffeine. The greatest effects of caffeine were present 1 h post-administration, but significant effects persisted for 8 h. Conclusions. Even in the most adverse circumstances, moderate doses of caffeine can improve cognitive function, including vigilance, learning, memory, and mood state. When cognitive performance is critical and must be maintained during exposure to severe stress, administration of caffeine may provide a significant advantage. A dose of 200 mg appears to be optimal under such conditions. Electronic Publication