Photoaging and topical tretinoin: therapy, pathogenesis, and prevention

Repeated exposure to UV radiation from the sun causes premature skin aging. This photoaging is characterized by wrinkles, mottled pigmentations, dry and rough skin, and loss of skin tone. Since the clinical demonstration that the use of topical tretinoin can improve photoaged skin, a great deal of knowledge that may explain wrinkle effacement has been acquired. Central to this pursuit has been dermal collagen. In this article, we summarize evidence (mainly from humans) that implicates a deficiency of superficial dermal collagen as the cause of the dermal aspects of photoaging. In addition, a mechanism through which UV radiation can lead to reduced collagen is presented. Through our understanding of the pathophysiological mechanism of photoaging, our ability to treat and possibly prevent this skin condition is enhanced.     

Cloning and characterization of a novel murine beta chemokine receptor, D6. Comparison to three other related macrophage inflammatory protein-1alpha receptors, CCR-1, CCR-3, and CCR-5

The beta-chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) is chemotactic for many hemopoietic cell types and can inhibit hemopoietic stem cell (HSC) proliferation, effects mediated through G-protein coupled heptahelical receptors. We have isolated cDNAs for seven chemokine receptors, CCR-1 to -5, MIP-1alphaRL1, and a novel cDNA, D6. Chinese hamster ovary cells expressing CCR-1, -3, -5, and D6 bound 125I-murine MIP-1alpha: the order of affinity was D6 > CCR-5 > CCR-1 > CCR-3. Each bound a distinct subset of other beta-chemokines: the order of competition for 125I-murine MIP-1alpha on D6 was murine MIP-1alpha > human and murine MIP-1beta > human RANTES approximately JE > human MCP-3 > human MCP-1. Human MIP-1alpha and the alpha-chemokines did not compete. Like other chemokine receptors, D6 induced transient increases in [Ca2+] in HEK 293 cells upon ligand binding. D6 mRNA was abundant in lung and detectable in many other tissues. Bone marrow cell fractionation demonstrated T-cell and macrophage/monocyte expression of D6, and CCR-1, -3, and -5. Moreover, we could detect expression of CCR-3, CCR-5, and to a greater extent D6 in a cell population enriched for HSCs. Thus, we have characterized four murine beta chemokine receptors that are likely involved in mediating the pro-inflammatory functions of MIP-1alpha and other chemokines, and we present D6, CCR-3, and CCR-5 as candidate receptors in MIP-1alpha-induced HSC inhibition.     

The complications of trauma and their associated costs in a level I trauma center

OBJECTIVES: To estimate the expected costs for acute trauma care, to quantify the costs associated with the development of complications in injury victims, and to determine the deficit incurred by patients in whom complications develop. DESIGN: A retrospective, cohort design. SETTING: A referral trauma center. PATIENTS: A total of 12,088 patients admitted to a single regional trauma center during a period of 5 years. INTERVENTIONS: This is an observational study, and no interventions specific to this study are included in the design. MAIN OUTCOME MEASURES: (1) The expected costs for injury victims based on readily available clinical data. (2) The costs associated with the most important complications of trauma. (3) The effect of complications on inadequate reimbursement for trauma care. RESULTS: The expected costs were estimated using a linear model incorporating demographic variables and measures of injury severity. The expected costs averaged $14,567, and the observed costs averaged $15,032. Six complications were important predictors of cost. These included adult respiratory distress syndrome, acute kidney failure, sepsis, pneumonia, decubitus ulceration, and wound infections. For 1201 individuals with these complications, the predicted costs averaged $23,266 and the observed costs averaged $47,457. The mean excess costs for a single complication ranged from $6669 to $18,052. Multiple complications led to greater increases in excess cost, averaging $110,007 for the 62 patients with 3 or more complications. Costs exceeded reimbursement to a much greater degree in those in whom any of the 6 complications developed. CONCLUSION: Expected hospital costs can be estimated using admission clinical data. Each of 6 complications was associated with enormous increases in costs, indicating their importance as a cause of avoidable expenditures in injury victims and identifying situations in which reimbursement may not be adequate.     

Disruption of syntaxin-mediated protein interactions blocks neurotransmitter secretion

The membrane protein syntaxin participates in several protein-protein interactions that have been implicated in neurotransmitter release. To probe the physiological importance of these interactions, we microinjected into the squid giant presynaptic terminal botulinum toxin C1, which cleaves syntaxin, and the H3 domain of syntaxin, which mediates binding to other proteins. Both reagents inhibited synaptic transmission yet did not affect the number or distribution of synaptic vesicles at the presynaptic active zone. Recombinant H3 domain inhibited the interactions between syntaxin and SNAP-25 that underlie the formation of stable SNARE complexes in vitro. These data support the notion that syntaxin-mediated SNARE complexes are necessary for docked synaptic vesicles to fuse.