IgE-dependent histamine-releasing factors. A brief review.

A cytokine, termed histamine-releasing factor (HRF) and produced by many cell types, has become the focus of research by many investigators due to its potential importance as a stimulus in chronic inflammation. We are producing and characterizing an HRF which causes IgE-mediated histamine release from human basophils. Following extensive purification procedures, the molecule will be sequenced and synthesized. A functional heterogeneity of IgE molecules was revealed by these studies. We are currently producing IgE antibody in vitro and testing the hypothesis that differential glycosylation is the basis for the heterogeneity. Knowledge of the structures and interactions of these molecules should advance our understanding of allergic and more chronic diseases.     

Relationship between saccadic eye movements and cortical activity as measured by fMRI: quantitative and qualitative aspects

We investigated the quantitative relationship between saccadic activity (as reflected in frequency of occurrence and amplitude of saccades) and blood oxygenation level dependent (BOLD) changes in the cerebral cortex using functional magnetic resonance imaging (fMRI). Furthermore, we investigated quantitative changes in cortical activity associated with qualitative changes in the saccade task for comparable levels of saccadic activity. All experiments required the simultaneous acquisition of eye movement and fMRI data. For this purpose we used a new high-resolution limbus-tracking technique for recording eye movements in the magnetic resonance tomograph. In the first two experimental series we varied both frequency and amplitude of saccade stimuli (target jumps). In the third series we varied task difficulty; subjects performed either pro-saccades or anti-saccades. The brain volume investigated comprised the frontal and supplementary eye fields, parietal as well as striate cortex, and the motion sensitive area of the parieto-occipital cortex. All these regions showed saccade-related BOLD responses. The responses in these regions were highly correlated with saccade frequency, indicating that repeated processing of saccades is integrated over time in the BOLD response. In contrast, there was no comparable BOLD change with variation of saccade amplitude. This finding speaks for a topological rather than activity-dependent coding of saccade amplitudes in most cortical regions. In the experiments comparing pro- vs anti-saccades we found higher BOLD activation in the "anti" task than in the "pro" task. A comparison of saccade parameters revealed that saccade frequency and cumulative amplitude were comparable between the two tasks, whereas reaction times were longer in the "anti" task than the pro task. The latter finding is taken to indicate a more demanding cortical processing in the "anti" task than the "pro" task, which could explain the observed difference in BOLD activation. We hold that a quantitative analysis of saccade parameters (especially saccade frequency and latency) is important for the interpretation of the BOLD changes observed with visual stimuli in fMRI.     

Renin inhibitors

Since the early 1980s, an intensive effort has been focused on the development of orally effective and long-acting inhibitors of renin. During this time, in vitro potency has increased greatly, with several transition-state inhibitor designs yielding inhibitors with subnanomolar IC50 values. In the meantime, both the molecular weight and peptide character of the inhibitors has decreased as important binding elements have been focused into smaller and more stable structures. The resulting inhibitors have shown promising activities in several in vivo models and (in two cases) in man. Nevertheless, renin inhibitors reported to date have limited oral bioavailability and short duration of action, and improvements in both will be necessary for them to compete effectively with ACE inhibitors. Renin inhibitors which have entered clinical studies have at least one naturally occurring amino acid and three or more amide bonds. It is reasonable to expect that continued development will produce wholly nonpeptide inhibitors with still lower MW, and it may be these "second-generation" inhibitors which will succeed as therapeutic agents. Development of orally effective and long-acting inhibitors of renin will enable their long-term antihypertensive efficacy and possible advantages over ACE inhibitor to be investigated.     

THE EFFECT OF PROSTAGLANDIN E1 ON PULMONARYBLOOD FLOW AFTER RETROGRADE FLUSH ANDCOLD STORAGE OF LUNGS

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Surgical management of malignant melanoma using dynamic lymphoscintigraphy and gamma probe-guided sentinel lymph node biopsy: the Emory experience

Sentinel lymph node (SLN) biopsy is revolutionizing the surgical management of primary malignant melanoma. It allows accurate nodal staging which targets patients who may benefit from regional lymphadenectomy and systemic therapy. This is a retrospective review of patients treated at Emory University for stage I and II malignant melanoma with gamma probe-guided SLN biopsy from 1/1/94 to 6/30/98. Three hundred sixty patients (males 228, females 132) were identified. Primary melanoma sites included: head and neck 58, trunk 148, and extremities 154 (upper 71, lower 83). Primary tumor staging was T1 9, T2 134, T3 153, and T4 64. SLNs were successfully identified in 99.7 per cent of patients and 98.9 per cent of nodal basins mapped. In 275 (76.6%) cases a single draining nodal basin was identified. In 84 (23.3%) cases there were multiple draining nodal basins. Positive SLNs were identified in 63 patients (17.5%). SLN positivity by tumor staging was T1 0 per cent, T2 9.0 per cent, T3 22.2 per cent, and T4 26.6 per cent. The overall recurrence rate was 11.9 per cent. Recurrences by SLN status were SLN+, 27 per cent, and SLN-, 8.8 per cent. Regional recurrence occurred in 7 (2.4%) of the 297 with negative SLN biopsies and 7 (11.1%) of the 63 with positive SLN biopsies. Dynamic lymphoscintigraphy and gamma probe-guided SLN localization was successful in more than 98 per cent of cases. Patients with negative SLN biopsies have a low risk of recurrence.