Synaptic activity controls autophagic vacuole motility and function in dendrites.

Macroautophagy (hereafter "autophagy") is a lysosomal degradation pathway that is important for learning and memory, suggesting critical roles for autophagy at the neuronal synapse. Little is known, however, about the molecular details of how autophagy is regulated with synaptic activity. Here, we used live-cell confocal microscopy to define the autophagy pathway in primary hippocampal neurons under various paradigms of synaptic activity. We found that synaptic activity regulates the motility of autophagic vacuoles (AVs) in dendrites. Stimulation of synaptic activity dampens AV motility, whereas silencing synaptic activity induces AV motility. Activity-dependent effects on dendritic AV motility are local and reversible. Importantly, these effects are compartment specific, occurring in dendrites and not in axons. Most strikingly, synaptic activity increases the presence of degradative autolysosomes in dendrites and not in axons. On the basis of our findings, we propose a model whereby synaptic activity locally controls AV dynamics and function within dendrites that may regulate the synaptic proteome.

Role of genetic and environmental factors in the increased blood pressures of Bolivian blacks.

The tendency toward hypertension or higher blood pressure is more common in blacks than whites. The factors that account for these differences are attributed to both environmental and genetic factors. To clarify this issue, an anthropological study of black and nonblack populations in the lowland village of Chicaloma, northeastern Bolivia at a midaltitude of 1,800 m was conducted. The study included 159 subjects, of which 79 were black and 80 were nonblack, 17-78 years. The study suggests the following: (1) the socioeconomic status of blacks as measured by an ownership index is greater than that of nonblacks, (2) blacks had higher average systolic and diastolic blood pressures than nonblacks and showed an age-associated increase in blood pressures, (3) the prevalence of hypertension was higher for blacks (7-6%) than nonblacks (1.3%), but three times lower than among blacks in the United States, (4) skin reflectance is inversely related to blood pressures so that contrary to what has been suggested the darker the skin color, the higher the blood pressures even at comparable levels of affluence. These findings together suggest that genetic factors predispose black individuals to increased blood pressures, but the expression of clinical hypertension is influenced by adverse unaccounted environmental factors. Am. J. Hum. Biol. 11:489-498, 1999. Copyright 1999 Wiley-Liss, Inc.

Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation.

BACKGROUND: Asthma is a heterogeneous process, yet little is understood regarding phenotypes. OBJECTIVE: To determine whether phenotypic differences exist between early-onset, severe asthma as compared with late-onset disease and whether the presence or absence of eosinophilia influences the phenotypes. METHODS: Cross-sectional analysis of integrated clinical, physiologic, and pathologic data collected from 80 subjects with severe asthma. Subjects were divided into those with asthma onset before age 12 years (n = 50) versus after age 12 (n = 30) and by the presence or absence of lung eosinophils. RESULTS: Subjects with early-onset, severe asthma had significantly more allergen sensitivity (skin test positivity, 98% vs 76%, P <.007) and more allergic symptoms (P values all

Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids.

BACKGROUND: Matrix metalloproteinase (MMP)-9 levels are increased in bronchoalveolar lavage (BAL) fluid from patients with severe asthma on high doses of glucocorticoids (GCs). OBJECTIVE: We sought to identify neutrophils as the source of increased BAL fluid MMP-9 in severe asthma and to evaluate the effects of GCs on this MMP-9. METHODS: MMP-9 protein, activity, and mRNA were measured in BAL fluid and cells at baseline, and after in vitro GCs in patients with severe asthma and controls using enzyme immunoassays, zymography, Western blotting, and real-time PCR. RESULTS: The high molecular weight (HMW) form of MMP-9 was significantly increased in severe asthma (P =.02). Western blotting confirmed a heterodimer of MMP-9 and neutrophil gelatinase-associated lipocalin. The HMW MMP-9 correlated with BAL neutrophils (r =.65, P <.0001). BAL cell supernatant MMP-9 protein levels also tended to be higher in patients with severe asthma (overall, P =.09), whereas the HMW activity form was increased (P =.03). MMP-9 protein (and HMW activity) correlated with neutrophils in the cell pellet (r =.75, P <.0001). In contrast to protein and activity, BAL cell mRNA levels were marginally lower in patients with severe asthma than in control subjects (overall, P =.06). Although GCs decreased BAL cell MMP-9 protein and mRNA in vitro, the effect was significantly smaller in severe asthma (P <.01 for both). GCs decreased the pro-MMP-9 activity in patients with severe asthma and normal control subjects, while having no effects on the HMW form (P =.22). Peripheral blood neutrophil MMP-9 protein was not affected by GCs. CONCLUSIONS: BAL neutrophils contribute to BAL fluid MMP-9 protein and activity and are poorly inhibited by GCs.