Serendipity and strategy in rapid innovation.

Innovation is to organizations what evolution is to organisms: it is how organizations adapt to environmental change and improve. Yet despite advances in our understanding of evolution, what drives innovation remains elusive. On the one hand, organizations invest heavily in systematic strategies to accelerate innovation. On the other, historical analysis and individual experience suggest that serendipity plays a significant role. To unify these perspectives, we analysed the mathematics of innovation as a search for designs across a universe of component building blocks. We tested our insights using data from language, gastronomy and technology. By measuring the number of makeable designs as we acquire components, we observed that the relative usefulness of different components can cross over time. When these crossovers are unanticipated, they appear to be the result of serendipity. But when we can predict crossovers in advance, they offer opportunities to strategically increase the growth of the product space.

Estimate for the fractal dimension of the Apollonian gasket in d dimensions.

We adapt a recent theory for the random close packing of polydisperse spheres in three dimensions [R. S. Farr and R. D. Groot, J. Chem. Phys. 131, 244104 (2009)] in order to predict the Hausdorff dimension dA of the Apollonian gasket in dimensions 2 and above. Our approximate results agree with published values in two and three dimensions to within 0.05% and 0.6%, respectively, and we provide predictions for dimensions 4-8.

Coping styles in asthma.

Some patients with asthma cope with their disease in ways that are deleterious to them. The coping styles used by these patients often were used by them before the onset of the asthma, but the asthma amplifies these styles, and the coping styles can amplify the asthma. There are striking similarities between these coping styles and those described in cancer victims. Like the latter, they may reflect denial, anger, bargaining, and depression. Recognition that patients are using these coping styles and appropriate intervention will prevent them from continuing to act in these self-destructive manners.

Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommendations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria.

The acquired cold urticaria (ACU) syndromes consists of nonfamilial heterogeneous disorders characterized by urticaria, angioedema, and occasionally symptoms of hypotension after cold exposure. In a study of 50 consecutive patients with ACU syndromes, it was observed that 70% experienced cold-induced systemic reactions, most frequently with aquatic activities. Patients with ACU syndromes were categorized by their response to an experimental cold-stimulation time test (CSTT) i.e., minimum time threshold of cold stimulation required to induce a coalescent wheal. One subpopulation of patients with ACU syndromes with positive CSTTs of 3 minutes or less experienced the highest incidence (68%; 13/19) of severe systemic reactions with hypotensive symptoms after natural cold exposure. However, 32% of patients with ACU syndromes (6/19) who experienced cold-induced systemic reactions with hypotension had a negative CSTT or a positive test of greater than 3 minutes. These observations indicate that all patients with ACU with active histories of cold urticaria are at risk to develop systemic reactions to cold and should therefore refrain from participating in aquatic activities. In addition, high-risk patients should receive prophylactic medications (i.e., cyproheptadine or doxepin) that are effective in suppressing this disorder. A diagnostic classification of cold urticaria is presented. This classification permits a more specific definition of the various cold urticaria disorders that comprise the ACU syndromes.

An improved protocol for the use of troleandomycin (TAO) in the treatment of steroid-requiring asthma.

An improved protocol was developed for the use of troleandomycin (TAO) in severe, steroid-requiring subjects with asthma. Compared to previous reports, this protocol uses a lower starting dose of TAO and a rapid steroid taper. Fifteen patients were treated with TAO following the new guidelines. Steroid requirements in the 15 patients dropped by 68% within 2 weeks, and 13 of the 15 patients were able to be maintained on alternate day steroids. In spite of rapid steroid taper, both FEV1 and mean FVC increased significantly (p less than 0.001). There was a low incidence of side effects and, in contrast to previous reports on TAO, no patient had even a transient increase in cushingoid appearance. Glucose intolerance was observed initially in three patients but resolved with continued steroid taper. Transient liver-enzyme elevation was noted in four patients and in each case reversed with a reduction in TAO dosage. The revised protocol is associated with an improved risk-benefit ratio. New guidelines are presented for the use of TAO in severe steroid-requiring subjects with asthma.

Substrate specificity and partial characterization of the PAF-acylhydrolase in human serum that rapidly inactivates platelet-activating factor.

The structure of the potent inflammatory mediator, platelet-activating factor, is 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (AGEPC, PAF-acether). Human sera contain an acid labile factor (ALF) that is a Ca+2-independent 2-acylhydrolase-specific for AGEPC and AGEPC-like molecules. The enzyme functions by catalytically removing the sn-2 acetyl moiety from AGEPC, producing the biologically inactive sn-2 hydroxy form or 2-lyso-GEPC. Incubation of ALF with sn-2 acyl PAF analogs indicated that the enzyme hydrolyzes the sn-2 fatty acid only if the chain length is five carbons or less, the sn-1 position fatty acid length is greater than 10 carbon units, and at least one methyl group is present on the terminal amine of the choline group. The enzyme was active with either an ether or ester linkage at the sn-1 position. ALF is inactivated by heating to 65 degrees C for 30 min. It is pronase and trypsin sensitive but resistant to papain and papain with dithiothreitol. Further characteristics of human ALF indicated a broad pH range of activity with an optimum of pH 6.2 and an isoelectric point of 6.2 to 6.7. The specificity and Ca+2 independence of human ALF sets it apart from phospholipase A2. It is proposed that human ALF be called human serum PAF-acylhydrolase to distinguish it from other hydrolases currently known to exist.

Association of platelet-activating factor with primary acquired cold urticaria.

We investigated the possibility that the inflammatory reaction in primary acquired cold urticaria might be associated with the release of platelet-activating factor. Six patients with the disease and five normal controls were subjected to cold-water challenges during which blood samples were obtained for measurement of the release of possible mediators: i.e., histamine, neutrophilic chemotactic activity, and platelet-activating factor-like lipid (PAF-LL). Four of the patients had pronounced experimentally induced cold urticaria with angioedema and release of mediators. Levels of the three mediators were not elevated in five normal controls or in two patients in whom cold challenges induced only mild urticaria and angioedema. The effective suppression of cold-induced urticaria in three patients treated with doxepin correlated with inhibition of PAF-LL release but not inhibition of histamine or neutrophilic chemotactic activity release. These data suggest a positive correlation between PAF-LL release and cold urticaria, although the exact relation between PAF-LL and cutaneous lesions of primary acquired cold urticaria has not yet been established.

Allergy-important advances in clinical medicine: platelet-activating factor.

The Scientific Board of the California Medical Association presents the following inventory of items of progress in allergy. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, research workers or scholars to stay abreast of these items of progress in allergy that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another.The items of progress listed below were selected by the Advisory Panel to the Section on Allergy of the California Medical Association and the summaries were prepared under its direction.

Human serum acid-labile factor is an acylhydrolase that inactivates platelet-activating factor.

Platelet-activating factor (PAF) is a phospholipid that activates platelets, induces inflammation, and causes profound alteration in the cardiopulmonary system. PAF from rabbit basophils and hog leukocytes is 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (AGEPC). Human and other mammalian serums contain an acid-labile factor (ALF) that rapidly inactivates AGEPC. ALF is associated with low-density lipoproteins but can be dissociated from the lipoproteins with detergent followed by ultracentrifugation. Delipidated ALF has an isoelectric point of approximately 7.1, its molecular weight is unknown, and it will not react with goat anti-whole human serum, antialbumin, anti-alpha- or anti-beta-lipoproteins, or antiapolipoproteins A or B. ALF has the following characteristics: 1) is acid labile; 2) is Ca2+ independent; 3) has a pH optimum of 6.2; 4) can hydrolyze a four-carbon but not a six-carbon or longer chain fatty acid at the sn-2 position; 5) is independent of an ester or ether linkage at the sn-1 position; 6) is incapable of hydrolyzing sn-2-acetylphosphatidylethanolamine, which indicates the need for at least one methyl group on the choline moiety of AGEPC; 7) requires between 5 and 16 carbons at the sn-1 position to remove a three- or four-carbon fatty acid on the sn-2 position; 8) is inactivated by heating to 65 C for 30 min; 9) is pronase and trypsin sensitive but papain resistant; and 10) is a hydrophobic molecule and thus behaves like a membrane-associated enzyme. Thus, ALF is a specific phosphatide 2-acylhydrolase.

A solid-phase radioimmunoassay to detect antibodies produced by hybridomas to antigens derived from human melanoma cells.

A solid-phase radioimmunoassay to detect antibodies that react with antigens derived from human melanoma cells is described. A soluble preparation derived from Nonidet P-40 lysates of tissue-cultured melanoma cells was dried on the surfaces of wells of polyvinyl chloride microtiter plates and fixed with 0.02% glutaraldehyde. Antibody preparations were added and incubated for 18 h at 4 degrees C. The wells were washed and bound antibodies were detected using radioactive Staphyloccoccal protein A (125I-SpA). Optimal conditions are described for all the steps employed. Concentrations of antigen selected, the amount of 125I-SpA employed and the duration of incubation of antibodies with antigen were found to be critical. The assay was sensitive and reproducible, and lent itself to the simultaneous evaluation of many individual antibody samples in a short period of time. The assay was particularly valuable for rapid screening of hybridoma supernatants for antibodies to antigens derived from melanoma cells and from a panel of other tumor and normal cells.

The presence of platelet-activating factor (PAF) in normal human mixed saliva.

This report describes PAF activity in normal human mixed saliva from each of 24 randomly selected donors. The human salivary PAF (HS-PAF) was similar to rabbit basophil PAF (acetyl glyceryl ether phosphorylcholine or AGEPC) with respect to the following characteristics: 1. HS-PAF co-chromatographed with the standard rabbit basophil AGEPC and with synthetic AGEPC. 2. HS-PAF and AGEPC were unaffected by hirudin, indomethacin, and creatine phosphate/creatine phosphokinase, the respective inhibitors of platelet activation induced by thrombin, arachidonic acid, and ADP. 3. HS-PAF and AGEPC were inactivated by a 5-min incubation with ALF, the acid-labile factor in normal human serum that rapidly destroys AGEPC. 4. HS-PAF was demonstrated to be functionally similar to AGEPC by cross-desensitization experiments. In the absence of Ca++, HS-PAF and AGEPC cross-desensitized washed rabbit platelets to subsequent stimulation by either HS-PAF or AGEPC after recalcification. 5. HS-PAF was demonstrated to be structurally similar to AGEPC by several simple chemical tests for functional groups.

Aspirin and concomitant idiosyncrasies in adult asthmatic patients.

The nasal and respiratory symptoms observed after oral challenge to aspirin (ASA), tartrazine, and other nonsteroidal anti-inflammatory substances are best described as idiosyncratic reactions. A positive response to oral challenge, defined as a 20% fall in forced expiratory volume in 1 sec (FEV1) from baseline for up to 4 hr, occurred in 44 of 230 patients with ASA, 11 of 277 with tartrazine, 2 of 93 with sodium salicylate, and 2 of 69 with acetaminophen. No one had a positive response to tartrazine, sodium salicylate, or acetaminophen who was not also positive to ASA. The dose of ASA causing a positive response was less than 5 grains in 95% of the patients. Of 50 patients with a suspicious history studied in detail, 96% of those with ASA idiosyncrasy had sinusitis and 71% had nasal polyps. Methacholine challenges and random circulating and sputum eosinophils did not differentiate patients with a negative challenge from those with a positive challenge. However, patients with a positive history and positive challenge had significantly more random nasal eosinophils than those with negative aspirin challenges. The term "aspirin triad" has outlived its usefulness since ASA idiosyncrasy can exist in patients lacking certain components of the triad. ASA idiosyncrasy is unsuspected in many patients and possibly overdiagnosed in others.