The schistosome oligosaccharide lacto-N-neotetraose expands Gr1(+) cells that secrete anti-inflammatory cytokines and inhibit proliferation of naive CD4(+) cells: a potential mechanism for immune polarization in helminth infections.

Immunomodulatory oligosaccharides found on helminths also are found in human milk, and both helminths and milk have been shown to be immunosuppressive. We have been examining the immunomodulatory capabilities of two oligosaccharides expressed in milk and on helminth parasites, lacto-N-fucopentaose III and lacto-N-neotetraose (LNnT). In an attempt to dissect mechanisms that lead to Th2 polarization and immune suppression, we examined the early response in mice to the glycoconjugate LNnT-Dextran (LNnT-Dex). We found that injection of LNnT-Dex expanded a cell population, phenotypically defined as Gr1(+)/CD11b(+)/F4/80(+), as early as 2 h after injection. Examination of spontaneous cytokine production showed that this Gr1(+)/F4/80(+) population of cells spontaneously produced low levels of proinflammatory cytokines, but higher levels of IL-10 and TGF-beta ex vivo, compared to peritoneal cells from mice injected with Dex. Gr1(+) cells adoptively suppressed naive CD4(+) T cell proliferation in vitro in response to anti-CD3/CD28 Ab stimulation. Suppression of naive CD4(+) cells involved cell contact and was dependent on IFN-gamma and NO, with a discrete role played by IL-10. Coculture of naive CD4(+)T cells with Gr1(+) suppressor cells did not lead to CD4(+) T cell apoptosis, although it did imprint on naive CD4(+) T cells a response characterized by lower levels of IFN-gamma, coincident with increased IL-13 production. Our results suggest that both human milk and helminth parasites may share a ligand-specific mechanism involved in the generation of anti-inflammatory mediators that suppress Th1-type and inflammatory responses.

Mechanomyographic and electromyographic responses during fatigue in humans: influence of muscle length.

Mechanomyography (MMG) provides a measure of muscle mechanical changes during contractions. The purpose of this study was to quantify alterations in MMG signals during fatigue at two muscle lengths. Comparisons with electromyographic (EMG) recordings were made. A group of 13 subjects performed isometric dorsiflexions (50% of maximum for 60 s) at 40 degrees of plantarflexion (long, l(l)) and 5 degrees of dorsiflexion (short, l(s)). The mean power frequency of the EMG (f(EMG)) and MMG (f(MMG)) signals and the mean rectified MMG (rMMG) and EMG (rEMG) were determined over each 1-s period, normalized to the respective maximal value, regressed against time, and the resulting slopes (units = %max. s(-1)) were analyzed. The slopes were larger (P = 0.007) at l(l) compared to l(s) [mean l(l) 0.50 (SD 0.26), mean l(s) 0.27 (SD 0.16)], however there were no differences (P = 0.24) between mean fMMG slopes [l(l) -0.10 (SD 0.16), l(s) -0.16 (SD 0.11)]. Similarly, slopes were larger (P = 0.001) at l(l) versus l(s) [l(l) 0.26 (SD 0.13), l(s) 0.08 (SD 0.15)] and there were no differences (P=0.89) between mean fEMG slopes [l(l) -0.15 (SD 0.14), l(s) -0.14 (SD 0.12)]. At 5 s following the exercise to fatigue mean MVC (units = %max) were not significantly different between l(l) and l(s) [P = 0.08; l(l) 78.8 (SD 9.1), l(s) 85.2 (SD 6. 0)]. These results showed that during fatiguing contractions, MMG and EMG amplitudes increased while frequency characteristics decreased at both muscle lengths. The change in and was greater at l(l) but no differences in fMMG or fEMG slopes occurred between lengths. These results would suggest that larger increases in motor unit recruitment occur with time during fatigue at l(l) compared to l(s).

Donepezil therapy in clinical practice: a randomized crossover study.

OBJECTIVE: To determine the efficacy of donepezil hydrochloride for the treatment of Alzheimer disease in patients drawn from clinical practice. DESIGN: Two-center, randomized, placebo-controlled, double-masked crossover study. SETTING: Memory disorders units at Massachusetts General and Brigham and Women's hospitals, Boston. PATIENTS: Sixty individuals (30 men and 30 women; mean +/- SD age, 75.0+/-9.5 years) with probable Alzheimer disease and scores of 20 or less on the information-memory-concentration subscale of the Blessed Dementia Scale. INTERVENTIONS: Placebo wash-in, followed in randomized sequence by (1) donepezil hydrochloride therapy, 5 mg/d, for 6 weeks, followed by placebo washout for 6 weeks and (2) placebo treatment for 6 weeks. PRIMARY OUTCOME MEASURE: Change in Alzheimer's Disease Assessment Scale cognitive subscale scores from the beginning to the end of the two 6-week treatment periods. RESULTS: Among patients completing treatment and testing for both periods (n = 48), subscale scores improved (mean +/- SEM) 2.17+/-0.98 points (95% confidence interval, 0.20-4.10 points) during donepezil therapy relative to placebo therapy (P = .04). Scores returned toward baseline within 3 weeks of drug washout. There was no associated change in caregiver-rated global impression (donepezil vs placebo: proportion improved, 0.24 vs 0.22; proportion worsened, 0.27 vs 0.35; P = .34) or on specific tests of explicit memory or verbal fluency. Contrary to studies with tacrine, the presence of the apolipoprotein E epsilon4 allele did not predict donepezil treatment failure. Most common adverse events related to donepezil therapy were nausea (5 patients), diarrhea (3 patients), and agitation (3 patients). Serious events possibly related to drug use were seizure, pancreatitis, and syncope (1 patient each). CONCLUSION: This independent confirmation of data from phase 3 trials suggests that donepezil therapy modestly improves cognition in patients with Alzheimer disease who are encountered in clinical practice.

Orchestrating phonosurgery.

A thyroplasty implant (prosthesis) has been designed to accomplish medialization to restore/improve the voice in unilateral vocal cord paralysis. The perioperative nurse plays an essential role in ensuring success of laryngoplasty procedures by communicating with the surgeon and planning for the timely delivery of appropriate sizers, implants, and instrumentation. The surgical team will witness the success of the thyroplasty procedure when the patient phonates as various implant sizers are applied/implanted to achieve improvement of the voice.