Lactoferrin causes IgA and IgG2b isotype switching through betaglycan binding and activation of canonical TGF-ß signaling.

Lactoferrin (LF), a pleiotropic iron-binding glycoprotein, is known to modulate the humoral immune response. However, its exact role in Ig synthesis has yet to be elucidated. In this study, we investigated the effect of LF on Ig production by mouse B cells and its underlying mechanisms. LF, like transforming growth factor (TGF)-ß1, stimulated B cells to produce IgA and IgG2b, while downregulating other isotypes. Using limiting dilution analysis, LF was shown to increase the frequency of IgA-secreting B-cell clones. This was paralleled by an increase in Ig germ-line α (GLα) transcripts, indicating that LF plays a role as an IgA switch factor. Interestingly, LF directly interacted with betaglycan (TGF-ß receptor III, TßRIII) and in turn induced phosphorylation of TßRI and Smad3 through formation of the TßRIII/TßRII/TßRI complex, leading to IgA isotype switching. Peroral administration of LF increased intestinal/serum IgA production as well as number of IgA plasma cells in lamina propria. Finally, we found that LF has an adjuvant activity when nontoxigenic Salmonella typhimurium was inoculated perorally, conferring protection against intragastrical infection of toxigenic S. typhimurium. These results suggest that LF has an important effect on the mucosal/systemic IgA response and can contribute to protection against intestinal pathogens.

Incomplete discoid glenoid labrum combined with a ganglion cyst of the spinoglenoid notch.

In a 41-year-old man, right-sided infraspinatus muscle weakness was associated with compression of the suprascapular nerve caused by a spinoglenoid ganglion cyst. The lesion was confirmed using electromyography and MRI. In addition, arthroscopy showed an incomplete discoid labrum. The free inner edge of the labrum was removed as in a meniscectomy of a discoid meniscus in the knee joint. Arthroscopic decompression of the cyst was performed through a juxtaglenoid capsulotomy which was left open. Neurological function recovered completely.

Intestinal microflora and diversification of the rabbit antibody repertoire.

The rabbit establishes its primary Ab repertoire by somatically diversifying an initial repertoire that is limited by restricted VH gene segment usage during VDJ gene rearrangement. Somatic diversification occurs in gut-associated lymphoid tissue (GALT), and by about 1-2 mo of age nearly all Ig VDJ genes are somatically diversified. In other species that are known to establish their primary Ab repertoire by somatic diversification, such as chicken, sheep, and cattle, diversification appears to be developmentally regulated: it begins before birth and occurs independent of exogenous factors. Because somatic diversification in rabbit occurs well after birth in GALT, the diversification process may not be developmentally regulated, but may require interaction with exogenous factors derived from the gut. To test this hypothesis, we examined Ab repertoire diversification in rabbits in which the appendix was ligated shortly after birth to prevent microbial colonization and all other organized GALT was surgically removed. We found that by 12 wk of age nearly 90% of the Ig VDJ genes in PBL were undiversified, indicating that intestinal microflora are required for somatically diversifying the Ab repertoire. We also examined repertoire diversification in sterilely derived remote colony rabbits that were hand raised away from contact with conventional rabbits and thereby acquired a different gut microflora. In these remote colony rabbits, GALT was underdeveloped, and 70% of the Ig VDJ genes in PBL were undiversified. We conclude that specific, currently unidentified intestinal microflora are required for Ab repertoire diversification.

Fragment E derived from both fibrin and fibrinogen stimulates interleukin-6 production in rat peritoneal macrophages.

Fibrin derived from fibrinogen after thrombin cleavage plays an essential role in forming blood clots. Fibrin as well as fibrinogen is also involved in the induction of platelet aggregation, leukocyte cell adhesion and phagocytosis. An additional biological role of fibrin and fibrinogen is presented in this study. One of the proteolytic peptides of fibrin/fibrinogen, fragment E, and not fragment D, was able to stimulate rat peritoneal macrophages to express interleukin-6 (IL-6). The stimulation of fibrin/fibrinogen fragment E on macrophages appeared to work in a dose- and time-dependent manner. Adherent fibrin fragment E was able to stimulate IL-6 expression as well as IL-6 protein production. The effect of fibrin fragment E was inhibited by the addition of an excess amount of GPRP tetrapeptide, but not by GHRP, which are the amino acids derived from the amino terminus of fibrin alpha and beta chains, respectively. These results suggest that fibrin as well as fibrinogen function as a stimulator to macrophages, and leukocyte integrin p150,95 (CD11c/ CD18), not Mac-I (CD11b/CD18), is involved in mediating fibrin stimulatory activity in macrophages.

Double-blind, multicenter trial to compare the efficacy of intramuscular dihydroergotamine plus hydroxyzine versus intramuscular meperidine plus hydroxyzine for the emergency department treatment of acute migraine headache.

STUDY OBJECTIVE: To evaluate intramuscular dihydroergotamine in direct comparison with opioid analgesia in the treatment of acute migraine headache. METHODS: This was a prospective, multicenter, double-blind trial performed in the emergency departments of 11 general hospitals in the United States. One hundred seventy-one patients between the ages of 18 and 60 years who presented to the ED with acute migraine headache were enrolled. Patients were randomly assigned to receive either 1 mg dihydroergotamine (DHE) or 1.5 mg/kg meperidine (MEP) by intramuscular injection. The anti-nauseant hydroxyzine (H) was coadministered in both treatment groups. RESULTS: One hundred fifty-six patients were evaluable. Treatment groups were comparable in sample size, demographics, and baseline measurements of headache pain. Reduction of headache pain as measured on a 100-mm visual analog scale was 41+/-33 mm (53.5% reduction) for the DHE group, and 45+/-30 mm (55.7% reduction) for the MEP group at 60 minutes after treatment (difference=2.2%; 95% confidence interval [CI] -10%, 14.5%; P=.81). Reduction in the severity of nausea and improvement in functional ability were similar between treatment groups. Central nervous system adverse events were less common in the DHE group (DHE 23.5% versus MEP 37.6%, difference-14.1%: 95% CI -28%, 0%). In particular, dizziness was reported less commonly with DHE than MEP (2% versus 15%, difference=-13%: 95% CI -21%, -5%). CONCLUSION: In this prospective, double-blind trial of a convenience sample of ED patients randomly assigned to one of two treatment regimens, DHE and MEP were comparable therapies for acute migraine. The use of DHE avoids several problems associated with opioid analgesia, including dizziness.

Gas exchange and lung mechanics during percutaneous transtracheal ventilation in an unparalyzed canine model.

OBJECTIVE: To compare the efficacy of percutaneous transtracheal ventilation (PTV) in the unparalyzed state with that in the paralyzed state using a sedated nonobstructed canine model. METHODS: Eight mongrel dogs (16.8-32 kg) were anesthetized, instrumented, and placed in a volume plethysmograph. Anesthesia was achieved with pentobarbital sodium (up to 30 mg/kg). The spontaneous respiratory drive was kept intact. PTV was performed using a 13-ga transtracheal catheter and compressed air at 45 psi at an I:E ratio of 1:3 (15 breaths/min). Each dog was sequentially ventilated in both the paralyzed and unparalyzed states. The paralyzed/unparalyzed sequence was alternated among the animals to avoid sequence bias. Paralysis was achieved with succinylcholine (0.1 mg/kg bolus and 0.01 mg/kg/min drip). Reversal of paralysis was achieved by discontinuing the succinylcholine infusion. Key variables, including arterial blood gas, tidal volume, and pulmonary mechanics, were measured and compared for the paralyzed and unparalyzed states. RESULTS: Gas exchanges and lung mechanics were similar between the unparalyzed and paralyzed states. There was no significant difference in mean pH, pCO2, pO2, tidal volume, or peak inspiratory transpulmonary pressure. There was also no significant difference in pulmonary resistance or pulmonary compliance. CONCLUSION: In a sedated nonobstructed canine model, PTV is as efficacious in the unparalyzed state as it is in the paralyzed state. The lung mechanics are also similar in the 2 states. These data suggest that it may be unnecessary to induce paralysis when using PTV for emergency ventilation in the heavily sedated state.

Response to dopamine vs norepinephrine in tricyclic antidepressant-induced hypotension.

OBJECTIVE: To compare the efficacy of dopamine (DA) with that of norepinephrine (NE) in the treatment of refractory hypotension caused by tricyclic antidepressants (TCAs). METHODS: A retrospective analysis was used to compare blood pressure responses in concurrent case series of patients treated with vasopressors for TCA-associated hypotension. The patients were adults (aged > or = 16 years) treated at 2 urban teaching hospitals from 1983 to 1994. All patients were diagnosed as having TCA ingestion (positive serum toxicologic assay), were hypotensive [systolic blood pressures (SBPs) < or = 90 mm Hg], and required vasopressor therapy. The patients were grouped by initial vasopressor treatment (i.e., NE vs DA). RESULTS: There were 26 hypotensive adult patients who met study criteria. All 26 patients remained hypotensive after initial treatment of their TCA-associated hypotension with crystalloid infusion and alkalinization. The NE and DA groups were similar in age, sex, and proportion of patients with single and co-drug ingestion. The NE group, however, had a significantly lower average SBP at study entry (56 vs 74 mm Hg, p = 0.04). Nine of 15 (60%) patients responded to DA (5-10 micrograms/kg/min) and 11/11 (100%) patients responded to NE (5-53 micrograms/min). The difference in response rates was statistically significant (p = 0.02). Six patients in whom DA (max rate 10-50 micrograms/min/kg) failed to raise the SBP subsequently responded to NE (max rate 5-74 micrograms/ min) when this drug was later used. One patient receiving NE (12 micrograms/min) developed ventricular ectopy, successfully treated with lidocaine. There were no ischemic complications from either NE or DA. Patients who failed DA therapy tended to be older (39 vs 30 years, p = 0.08), to be more hypotensive at study entry (64 vs 81 mm Hg, p = 0.008), and to remain hypotensive even at higher doses of DA (24 vs 7 micrograms/min/kg, p = 0.002). CONCLUSION: While this was not a prospective randomized study, NE appears advantageous over DA as the first-line vasopressor agent for those patients who require vasopressor support in the setting of TCA-induced hypotension that is refractory to IV fluid and serum alkalinization.

Open thoracotomy procedural competency: validity study of teaching and assessment modalities.

STUDY OBJECTIVES: To determine (1) reliability and validity estimates of three modalities used to assess open thoracotomy procedural competency and (2) the effect of computer practice on procedural performance as measured by the three assessment modalities. METHODS: An experimental, sequential assessment design with volunteer examinees completing all three assessment modalities (paper, computer, pig model) was implemented at the animal support facilities of a university medical school with an affiliated emergency medicine residency program. Level of physician training (student, resident, faculty) and type of computer practice (thoracotomy, cricothyrotomy) were independent variables. Procedural competency scores were determined for each modality; scores were defined in terms of performance time and performance accuracy for three thoracotomy procedures (opening the chest, pericardiotomy, and aortic cross-clamping). RESULTS: Thoracotomy performance on the pig reliably discriminated among examinees known to differ in level of training. However, computer simulation performance did not significantly differ among examinees with different levels of training. Computer simulation practice significantly improved later performance on the computer assessment (P < .05) but not on the pig assessment. The greatest predictor of procedural competency (time and accuracy) on the pig assessment was the ability to sequentially order procedural steps. CONCLUSION: This study establishes the pig model as superior to the paper and computer models as the criterion standard for open thoracotomy assessment. Psychometric properties support the pig model as the most reliable and valid model yet described for assessing thoracotomy procedural competency. Computer simulation practice using visual images (complex anatomy) and the sequential ordering of procedural steps through paper modeling show promise for teaching and assessment of prerequisite skills required to develop psychomotor procedural competency.

Perceptions and satisfaction with emergency department care.

A telephone questionnaire examining perceived quality of and satisfaction with Emergency Department (ED) care was administered to randomly selected patients within 60 days of their visit to a university hospital ED over a 13-month period. Patients, or the persons who accompanied them to the ED, rated overall service, nursing technical performance, physician technical performance, nursing bedside manner, physician bedside manner, and registration clerk service on a 5-point rating scale (5 = excellent, 4 = very good, 3 = good, 2 = fair, 1 = poor). Patients were also asked if they felt the care was delivered in a timely manner. A total of 618 interviews were conducted (1333 attempts to contact, 12 people declined to be interviewed). The results suggest that patient perceptions of the technical quality of care are more important than perceived timeliness of care or bedside manner in determining patient satisfaction with ED care.