Retinal vascular changes in congenital hypertrophy of the retinal pigment epithelium

The overlying retinal blood vessels were abnormal in five cases of congenital hypertrophy of the retinal pigment epithelium. This illustrated the well-recognized association between outer retinal degeneration and obliteration of the overlying retinal vasculature. The proposed pathophysiological mechanisms, however, seem inadequate to explain completely the morphological changes of the retinal blood vessels in the presence of atrophy of the outer retina.     

Differential regulation of early phase and late phase responses in human neutrophils by cAMP

The elevation of intracellular levels of cyclic AMP by forskolin stimulation of adenylate cyclase regulates early and late phase neutrophil responses differentially. Early phase neutrophil responses as measured by shape change in response to chemotactic factors, transmigration across a polycarbonate membrane and priming were unaffected by forskolin-induced elevation of intracellular cAMP. Late phase neutrophil responses such as release of superoxide anions, activation of phospholipase A2 and platelet activating factor (PAF) synthesis were inhibited by increasing intracellular cAMP through the addition of 10 microM forskolin for 10 min prior to stimulation. N-Formyl-methionyl-leucyl-phenylalanine-stimulated arachidonic acid release fell from 9.3% (untreated cells) to 4.6% in forskolin-treated cells. PAF generation was also inhibited from 430 pg/10(6) cells in untreated cells to background levels in forskolin-treated cells (110 pg/10(6) cells). Also, the reduction of cytochrome c by superoxide anions fell from 4.2 nmol/10(6) cells in the absence of forskolin to 2.0 nmol/10(6) cells following forskolin treatment. These results indicate that in neutrophils the elevation of cAMP acts differentially on cellular responses, not affecting early activation events, but markedly inhibiting late events such as the release of inflammatory mediators.     

A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes

Using a polymerase chain reaction strategy we identified a serine proteinase inhibitor (serpin) in human bone marrow that is related to the cellular serpin proteinase inhibitor 6 (PI-6) and the viral serpin cytokine response modifier A (CrmA). This serpin, proteinase inhibitor 9 (PI-9), has an unusual reactive center P1(Glu)-P1'(Cys), which suggests that it inhibits serine proteinases that cleave after acidic residues. The only known serine proteinase with this specificity is granzyme B, a granule cytotoxin produced by cytotoxic lymphocytes. To test the interaction of PI-9 with granzyme B we prepared recombinant hexa-histidine tagged PI-9 in a yeast expression system. Addition of the recombinant protein to native granzyme B resulted in an SDS-resistant complex typical of serpin-serine proteinase interactions. Further analysis showed that complex formation followed bimolecular kinetics with a second order rate constant of 1.7 +/- 0.3 x 10(6) M-1 s-1, which is in the range for a physiologically significant serpin-proteinase interaction. Recombinant PI-9 also completely abrogated granzyme B and perforin-mediated cytotoxicity in vitro. Examination of PI-9 mRNA distribution demonstrated that it is expressed in immune tissue, primarily in lymphocytes. The highest levels of PI-9 mRNA and protein were observed in natural killer cell leukemia cell lines and in interleukin-2 stimulated peripheral blood mononuclear cells, which also produce granzyme B. Like PI-6, PI-9 was shown to be a cytosolic protein that is not secreted. Fractionation of natural killer cells and stimulated peripheral blood mononuclear cells demonstrated that PI-9 is in a separate subcellular compartment to granzyme B. These results suggest that PI-9 serves to inactivate misdirected granzyme B following cytotoxic cell degranulation. This may explain why cytotoxic cells are not damaged by their own granzyme B during destruction of abnormal cells.     

Isoprene cancer risk and the time pattern of dose administration

Most statistical risk assessment models assume that equal, measured on scale such as mg/kg/day, create equal tumor risks. This equivalent dose metric (EDM) hypothesis allows risks to be extrapolated from high concentrations to low-concentrations and from and species, sex, and strain to another, since it implies that all administered dose histories corresponding to the same total dose create the same risk. This paper tests the EDM hypothesis using data on tumor rates in B6C3F mice administered isoprene via inhalation. Its major conclusion is that the EDM hypothesis does not hold for isoprene. For example, it appears that exposure concentration has a greater impact on tumor rates than weeks of exposure. To predict tumor probabilities, the time pattern of dose administration must be considered. The asymmetric effects of concentration, hours-per-day, and number of days of exposure on tumor risks imply that complex dynamic risk models may be needed to accurately describe dose-time-response relations. The traditional concept of a dose-response relation as a static curve relating a numerical summary of dose to a numerical summary of response probability is probably not predictively useful for chemicals such as isoprene, and extrapolations of risk based on the EDM hypothesis could be misleading for such chemicals.     

Measurement artifacts in the assessment of counterproductive work behavior and organizational citizenship behavior: Do we know what we think we know?

An experiment investigated whether measurement features affected observed relationships between counterproductive work behavior (CWB) and organizational citizenship behavior (OCB) and their relationships with other variables. As expected, correlations between CWB and OCB were significantly higher with ratings of agreement rather than frequency of behavior, when OCB scale content overlapped with CWB than when it did not, and with supervisor rather than self-ratings. Relationships with job satisfaction and job stressors were inconsistent across conditions. We concluded that CWB and OCB are likely unrelated and not necessarily oppositely related to other variables. Researchers should avoid overlapping content in CWB and OCB scales and should use frequency formats to assess how often individuals engage in each form of behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of anxiety arousal and mental stress on the vestibulo-ocular reflex

Although the subjective reports of patients suggest that anxiety may aggravate vertigo and imbalance, there has been little research into how anxiety might directly affect balance system functioning. We conducted two studies to examine the effect of anxiety and arousal on the vestibulo-ocular reflex (VOR). In the first study, pre-lest fear ratings were obtained from 20 normal subjects and 36 anxious subjects immediately prior to rotation and caloric testing. Fear ratings were significantly correlated with the maximum slow-phase velocity (SPV) of nystagmus induced by caloric testing. In the second study, we assessed the VOR response to rotation of 36 normal subjects under 3 task conditions: a) minimal alerting (counting backwards during rotation), b) physical arousal (induced by exertion prior to rotation); c) mental arousal (induced by performance of stressful mental tasks during rotation). Both the physical and mental tasks induced a significant increase in heart rate compared with the alerting condition. The maximum SPV of the nystagmus induced by rotation was significantly greater during performance of the mental task than in the other two conditions. These combined results indicate that anxiety may influence the gain of the VOR.     

Miniature packaged actively mode-locked semiconductor laser with tunable 20 ps transform limited pulses

Miniature, fibre tailed and packaged, wavelength tunable actively mode locked semiconductor lasers have been developed for use as sources of approximately 20 ps transform limited pulses. Continuous stable operation with >40 nm tuning ranges centred either at 1.3 mu m or 1.55 mu m have been demonstrated. The package has an adjustable cavity length enabling the repetition frequency to be selected between 2 GHz and 8 GHz. Mean output powers in the monomode fibre tail are in the range -10 dBm to -5 dBm.<>     

Theory as a source of software and system requirements

Requirements Engineering - Today, when undertaking requirements elicitation, engineers attend to the needs and wants of the user groups considered relevant for the software system. However, answers...     

Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway

Cytotoxic lymphocytes (CLs) induce caspase activation and apoptosis of target cells either through Fas activation or through release of granule cytotoxins, particularly granzyme B. CLs themselves resist granule-mediated apoptosis but are eventually cleared via Fas-mediated apoptosis. Here we show that the CL cytoplasmic serpin proteinase inhibitor 9 (PI-9) can protect transfected cells against apoptosis induced by either purified granzyme B and perforin or intact CLs. A PI-9 P1 mutant (Glu to Asp) is a 100-fold-less-efficient granzyme B inhibitor that no longer protects against granzyme B-mediated apoptosis. PI-9 is highly specific for granzyme B because it does not inhibit eight of the nine caspases tested or protect transfected cells against Fas-mediated apoptosis. In contrast, the P1(Asp) mutant is an effective caspase inhibitor that protects against Fas-mediated apoptosis. We propose that PI-9 shields CLs specifically against misdirected granzyme B to prevent autolysis or fratricide, but it does not interfere with homeostatic deletion via Fas-mediated apoptosis.