Mediated priming in younger and older adults

This paper reports the result of a lexical decision experiment in which the primes were either directly related to their targets, mediated, or unrelated. Mediated primes are indirectly related to their targets through a single connecting link (e.g., PASTURE-COW-MILK). Older and younger adult subjects responded to each letter string in a continuous lexical decision task, deciding whether each string was a word or a nonword. The results indicated that both younger and older subjects benefited from the mediated primes, as well as from the directly related primes. The results are discussed in relation to issues of age changes in processing speed.     

A prospective study of the use of a dobutamine stress test to identify outcome in patients with sepsis, severe sepsis, or septic shock

OBJECTIVE: To more clearly define the relationship between an oxygen flux test, oxygen supply dependency, and outcome in patients with sepsis, severe sepsis, or septic shock. DESIGN: Prospective, interventional clinical trial. SETTING: A teaching hospital general intensive care unit in London, UK. PATIENTS: A total of 36 patients with sepsis, severe sepsis, or septic shock were studied during a 10-month period. INTERVENTIONS: After resuscitation, patients were given an intravenous infusion of dobutamine at 10 microg/kg/min for 1 hr. Cardiac and respiratory variables were measured before the infusion and then while the infusion was in progress. Any patient who was able to increase his or her oxygen consumption by >15% was designated a responder to the test. MEASUREMENTS AND MAIN RESULTS: Hemodynamic, oxygen transport, and lactate measurements were made at baseline and after 1 hr of the dobutamine infusion. All patients were then followed up until hospital discharge. Responders to this test had a hospital mortality of 14%, whereas nonresponders had a mortality of 91% (p<.01). The responders were characterized by being younger (p<.05), having higher Acute Physiology and Chronic Health Evaluation III scores (p<.05), and having a greater requirement for inotropic support (p<.05). After the test, the responders had significantly higher oxygen delivery (p<.01) and oxygen consumption (p<.05) than the nonresponders, as well as a significantly greater temperature increase as a result of the infusion (p<.05). The nonresponders were unable to increase either oxygen delivery or oxygen consumption to the dobutamine. This test was highly predictive of outcome (p<.0001). The identification of an increase in both oxygen delivery and oxygen consumption (oxygen supply dependency) was not associated with a poor outcome. CONCLUSION: A dobutamine oxygen flux test provides evidence of the intrinsic function of cells. The inability of these cells to increase oxidative metabolism during sepsis, as indicated by the dobutamine test, is associated with a high mortality.     

Pain management of junctional epidermolysis bullosa in an 11-year-Old boy

Epidermolysis bullosa is a group of hereditary blistering disorders for which there is no definitive therapy. Wound care is an important component of management. Regular dressing changes are required to protect blistered and eroded skin, and to prevent secondary infection and sepsis. These dressing changes can be very painful for patients with extensive erosions. We report our experience of pain management in an 11-year-old boy with severe junctional epidermolysis bullosa. Amitryptiline and cognitive behavioral techniques were effective in relieving chronic pain and discomfort. Oral midazolam 0.33 mg/kg administered 20 minutes prior to baths and dressing changes substantially improved his tolerance of wound care.     

Studies of molecular pharmacophore/receptor models for GABAA/benzodiazepine receptor subtypes: binding affinities of substituted beta-carbolines at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis.

Binding affinities of a series of 44 beta-carbolines with various substituents at the 3-, 4-, 6- and 7-positions are reported at 5 distinct recombinant GABAA/benzodiazepine receptor (BzR) subtypes [alpha x beta 3 gamma 2 (x = 1-3, 5, 6)]. Many of these ligands displayed better selectivity for the alpha 1 containing GABAA isoform. The most selective BCCT 2 and SPH 195 (17) displayed potent affinity (Ki = 0.72 and 7.2 nM for the alpha 1 beta 3 gamma 2 receptor subtype, respectively) and an overall selectivity of 20 and 23 fold, respectively, for the alpha 1 beta 3 gamma 2 receptor subtype. These are the most selective ligands in vitro for the alpha 1 containing GABAA/Bz receptor isoform reported to date to our knowledge. QSAR studies of these ligands for each receptor subtype have been carried out via a Comparative Molecular Field Analysis (CoMFA) and an included volume analysis. Geometries and charge distributions of these ligands have been optimized using ab initio methods (J. Med. Chem., 1992, 35, 4001-4010). Active conformations of flexible 3-alkoxylated beta-carbolines have been examined via a CoMFA approach. QSAR studies via CoMFA support the previous hypothesis that beta-carbolines with different intrinsic activities may follow an alternative alignment rule when they bind into the pharmacophore/receptor site of the BzR. Examination of binding affinities of beta-carbolines by this modeling strategy has established some of the differences, in particular, topologic differences between the lipophilic pockets in the alpha 1 beta 3 gamma 2, alpha 2 beta 3 gamma 2, alpha 3 beta 3 gamma 2, alpha 5 beta 3 gamma 2 and alpha 6 beta 3 gamma 2 subtypes as well as some of the similarities among the pharmacophore/receptor models of these five distinct GABAA/Bz receptor subtypes.     

Mutation testing in melanoma families: INK4A, CDK4 and INK4D.

The INK4A gene which codes for the cyclin-dependent kinase (CDK) inhibitor INK4A or p16 underlies susceptibility to melanoma in some families. Germline mutations in the gene that codes for the target protein of p16, CDK4, underlie susceptibility in very rare families. We report mutation screening of the INK4A and CDK4 genes in 42 UK families. A total of nine families were identified with INK4A mutations and none with CDK4 exon 2 mutations. These mutations were in 8/22 (35%) families with three or more cases of melanoma and 1/20 (5%) families with only two cases. In one of these nine families a novel single base pair substitution was identified, Gly67Arg. In an attempt to identify another melanoma susceptibility gene, a member of the INK4 family, the p19 INK4D gene has been studied. The p19 gene was sequenced in DNA from the 42 UK families and six additional US families. No mutations were identified.     

Cost-effectiveness analysis of pegylated-liposomal doxorubicin and liposomal daunorubicin treatments in patients with Kaposi's sarcoma

Economic evaluations of new AIDS treatment drugs are important. For physicians treating patients with Kaposi's sarcoma, these issues are especially meaningful since cancer treatment costs for this group of patients are high. Kaposi's sarcoma is the most frequently occurring neoplasm in AIDS patients, affecting about 15% of this population. In our study, a retrospective economic evaluation has been made based on data from two randomized phase III clinical studies of severely immune-compromised HIV-infected individuals and which compares liposomal doxorubicin with liposomal daunorubicin. We have estimated the cost and cost effectiveness of the two drugs. The costs per complete or partial response are USS 18340 for daunorubicin and USS 8871 for doxorubicin. The incremental cost per additional responder by using liposomal doxorubicin instead of liposomal daunorubicin is USS 1910. Sensitivity analysis shows that these results hold over a wide range of assumptions.     

Up-regulation of ephrin-A1 during melanoma progression.

Ephrin-A1, formerly called B61, is a new melanoma growth factor; it is angiogenic and chemoattractant for endothelial cells. EPH-A2, or ECK (a receptor for ephrin-A1), is ectopically expressed in most melanoma cell lines; the pathology where this expression is first manifested and the possible role of the receptor in tumor progression are unknown. To determine these, we studied the expression of this ligand and receptor in biopsies of benign and malignant melanocytic lesions. EPH-A2 was not detected in normal melanocytes, benign compound nevi or advanced melanomas, though it was found in 2 of 9 biopsies of malignant melanoma in situ. Ephrin-A1 was present in occasional early lesions and in advanced primary melanomas (43%) and metastatic melanomas (67%). Expression of ephrin-A1 was induced in melanoma cells by pro-inflammatory cytokines. Our findings are consistent with 2 possible roles for ephrin-A1 in melanoma development: it may promote melanocytic cell growth or survival and induce vascularization in advanced melanomas. Both effects may be potentiated by inflammatory responses. Our data are consistent with earlier observations that an inflammatory infiltrate is associated with poor prognosis in thin primary melanomas.     

Requirement for focal adhesion kinase in tumor cell adhesion

Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase and a major phosphotyrosine-containing protein. FAK is found in cell-matrix attachment sites (focal adhesions), and is activated on integrin-ligand binding and by other signaling pathways. Several roles have been proposed for FAK; here we report a novel function. We observed abundant FAK protein in all human melanoma cell lines tested except COLO839, a line that grows predominantly in suspension and was derived from peripheral blood. Five adherent lines, isolated from solid metastases in the same patient as COLO839, did express FAK. We derived four adherent sublines from COLO839. These did express FAK, even when plated on bacteriological plastic, to which they did not adhere. Thus, substrate attachment was not required for FAK expression. Three of the adherent sublines were then grown in the presence of antisense oligonucleotides to the initial FAK coding sequence. All showed substantially reduced FAK expression and, interestingly, the cells largely detached from the substrate while continuing to grow. Similar results were obtained with an independent melanoma line, DX3. Thus, FAK expression appears to be required by melanoma cells for substrate adhesion.