Cumulative incidence trends of selected cancer sites in a Philippine population from 1983 to 2002: a joinpoint analysis.

BACKGROUND: Few studies have investigated incidence trends in the Philippines. METHODS: From the databases of the Manila Cancer Registry, cumulative cancer incidence rates were determined for the five most common cancers for both sexes combined. Using joinpoint analysis, incidence trends for 1983-2002 were estimated. RESULTS: Among females, increasing trends were found for breast, 5% annual change, lung (0.5%) and colorectal (1.5%) cancers. Decreasing trends were found for cancers of the liver (-1.2%) and cervix (-1.9%). Among males, increasing trends were found for lung cancer (0.5%), whereas liver cancer rates have been decreasing (-1.0%). Colorectal cancer rates fluctuated. CONCLUSION: Certain sites showed declining incidence trends, but incidence trends for lifestyle-related cancers continue to rise. The prevention of infection-related cancers should also receive priority, particularly by vaccination programmes.

Modulation of enkephalin release by nociceptin (orphanin FQ).

Nociceptin (orphanin FQ) is an endogenous peptide agonist for the newly discovered receptor (opioid receptor-like 1 receptor, ORL1) that bears striking homology to opioid receptors. Initial reports claimed that this peptide had hypoalgesic effects following i.c.v. or i.t. administration. The present study demonstrates that, in the presence of opioid receptor blockade, nociceptin can substantially alter the magnitude of the stimulated release of methionine-enkephalin from the guinea pig myenteric plexus. This effect is concentration dependent. Low doses (1 or 10 nM) inhibit whereas higher concentrations (100 or 1000 nM) enhance evoked enkephalin release. In contrast, in the absence of opioid receptor blockade, a statistically significant inhibition of stimulated enkephalin release is observed in response to 1, 100 or 1000 nM nociceptin. However, the magnitude of this effect did not differ among these concentrations. Furthermore, at 10 nM nociceptin, either an inhibition or enhancement of stimulated enkephalin release is manifest. The ability of naloxone to alter the nociceptin modulation of enkephalin release suggests that a component of the nociceptin modulation of enkephalin release is mediated via opioid receptors. This is consistent with the observation that this peptide has modest affinity for opioid receptors (L > K > 8) which, under appropriate conditions, should be sufficient to permit interactions with multiple opioid receptor types. This complicates dose responsiveness for nociceptin since both the naloxone-resistant (ORL1-mediated) and naloxone-sensitive (opioid receptor-mediated) component exhibit a concentration-dependent bimodality (albeit in opposite directions). Determination of i.c.v. or i.t. nociceptin dose responsiveness over several orders of magnitude is suggested before concluding the physiological effects of this peptide.

Relevance of phosphorylation state to opioid responsiveness in opiate naive and tolerant/dependent tissue.

This laboratory previously reported that the mu-selective opiate receptor agonist, sufentanil, produces a naloxone-reversible, concentration-dependent facilitation or inhibition of the stimulated formation of cAMP in the myenteric plexus. Chronic in vivo exposure to morphine results not only in the loss of inhibitory opioid responsiveness but in the reversal of inhibition to enhancement. The present study demonstrates, in tolerant/dependent as well as opiate naive tissue, that the state of phosphorylation is a critical determinant of the balance between positive and negative opioid modulation of stimulated cAMP formation. In vitro treatment of chronic morphine-treated preparations with inhibitors of protein kinases, abolishes the previously observed reversal of opioid inhibition to enhancement and restores sufentanil inhibitory responsiveness. The established kinase-type selectivity profile of the inhibitors employed suggests the involvement of protein kinase C (PKC) in the tolerant-associated reversal from opioid inhibition to enhancement of cAMP formation. Conversely, treatment of opiate naive tissue with the protein phosphatase inhibitor okadaic acid or a phorbol ester activator of protein kinase C, phorbol 12-myristate 13-acetate (PMA), not only attenuates sufentanil inhibition of evoked cAMP formation but reverses it to a facilitation (as occurs following chronic in vivo morphine exposure). This effect of PMA is abolished by the PKC-selective inhibitor chelerythrine. Moreover, the longitudinal muscle myenteric plexus content of PKC alpha and PKC beta is substantially elevated following chronic morphine treatment. These results underscore the relevance of opioid bimodality to the manifestation of tolerance/dependence and suggest that augmented phosphorylation (mediated at least in part via PKC) is a critical determinant of some of the sequelae of chronic morphine exposure.

Spinal cord dynorphin precursor intermediates decline during late gestation.

This laboratory has previously reported that the maternal opioid analgesia associated with pregnancy and parturition is mediated, at least in part, by a maternal spinal cord dynorphin/kappa opioid system. This analgesia is accompanied by an increase in dynorphin peptides (1-17 and 1-8) in the lumbar spinal cord. Levels of trypsin-generated arginine6-leucine-enkephalin (Leu-Enk-Arg)-immunoreactive determinants were also determined and used to reflect the content of dynorphin precursor intermediates. In spinal tissue, the amount of dynorphin A (1-17) contained in the form of precursor is, at a minimum, 10-fold higher than the content of mature dynorphin A (1-17) or dynorphin (1-8). During gestational day 22, the content of dynorphin precursor is reduced significantly (approximately 50%). The decline in the magnitude of dynorphin precursor intermediates in the spinal cord of pregnant rats vastly exceeds the magnitude of increase in the content of dynorphin peptides (1-17 and 1-8). This difference can best be explained by postulating a corresponding increase in the rate of release of spinal cord dynorphin (1-17). It is suggested that enhanced processing of dynorphin precursor intermediates represents the initial biochemical level of adaptation of spinal dynorphin neurons to increased demands of pregnancy.

Spinal cord dynorphin: positive region-specific modulation during pregnancy and parturition.

In laboratory animals and humans, pregnancy is associated with opioid-mediated elevations in the threshold for responsiveness to aversive stimuli. Previous pharmacological analysis has demonstrated that this analgesia results, at least in part, from the activation of spinal cord kappa opioid receptors utilizing dynorphin as the major opioid substrate. The present report demonstrates that during late pregnancy, the content of spinal dynorphin A(1-17 and 1-8) is altered in a region-specific fashion. As a result, levels of dynorphin peptides are elevated, but only in the lumbar spinal region. In parturient animals, lumbar levels of dynorphin A(1-8) remained elevated but there was an additional increment in the content of dynorphin A(1-17). During late gestation, spinal content of Met-enkephalin and its precursor are also elevated, but, in contrast to dynorphin peptides, there is no interaction between condition and spinal level. Possible analgesic synergy between mu-delta and kappa opioid receptor systems is discussed. It is concluded that some parameter(s) of the pregnant condition triggers the activation of a spinal cord dynorphin system that attenuates the pain associated with late pregnancy and labor.

17 beta-estradiol and progesterone positively modulate spinal cord dynorphin: relevance to the analgesia of pregnancy.

Pregnancy and parturition are associated with opioid-mediated elevations in maternal pain thresholds. This analgesia is subserved by a spinal cord dynorphin/kappa-opiate receptor system. During gestation, elevated pain thresholds are paralleled by a significant increase in the content of dynorphin (1-17 and 1-8) in the lumbar spinal cord. An additional increment in lumbar dynorphin (1-17) concentration, but not that of dynorphin (1-8), occurs in parturient animals. Simulation of the pregnancy blood concentration profile of 17 beta-estradiol and progesterone ('hormone-simulated pregnancy') also results in an opioid analgesia, the magnitude and temporal pattern of which closely approximates that of actual gestation. The current study demonstrates that during hormone-simulated pregnancy, the spinal cord content of dynorphin (1-17) [but not dynorphin (1-8)] is positively modulated. This regulation is time- (or dose-)-dependent and region-specific. Significant elevations in spinal levels of dynorphin (1-17) are observed during steroid dose periods 3 and 4, corresponding to the last week of actual gestation and parturition, respectively. Increased dynorphin (1-17) content is observed in only the lumbar spinal region. These changes are temporally and anatomically identical to those which occur during actual gestation and parturition. It is concluded that changes in circulating 17 beta-estradiol and progesterone, that occur as a natural consequence of gestation, activate a dynorphin system in the lumbar spinal cord. This attenuates the pain associated with late pregnancy and labor. The pattern of circulating sex steroids can be an important determinant of the activity of central opioid analgesic systems.

Antiheparin antibodies: their preparation and use in a heparin immunoassay.

Antibodies that recognize unmodified heparin bound to positively charged macromolecules have been obtained by immunizing rabbits with a methylated bovine serum albumin-heparin precipitate. These antibodies have been used to develop an immunoassay that can quantitate heparin at a concentration of 5 ng/ml in buffer solutions, and at a concentration of 25 ng/ml in plasma without pretreatment of the sample. The specificity of the antibodies is such that they do not recognize other glycosaminoglycans and are able to distinguish among different commercial heparin samples that are otherwise indistinguishable by specific anticoagulant activity or molecular weight distribution.

Preparation and identification of a population of antibodies that recognize carbodiimide-modified heparin.

Protein-heparin complexes, prepared by a water-soluble carbodiimide coupling technique, were used to produce anti-heparin antibodies in rabbits. Antiserums that recognized carbodiimide-treated heparin, but not untreated heparin, were obtained. Carbodiimide-treated heparan sulfate exhibited 10% to 20% cross-reactivity compared with a similarly treated heparin, whereas there was no cross-reactivity with five other carbodiimide-treated mucopolysaccharides. 3H-1-ethyl-3-(3-trimethylammoniumpropyl) carbodiimide iodide was used to demonstrate that carbodiimide forms a stable adduct with heparin and other mucopolysaccharides. Using an antibody fraction that eluted from 1-ethyl-3-(3-trimethylammoniumpropyl) carbodiimide iodide-treated heparin-Sepharose with 2 mol/L KI, it was demonstrated that, for the antibody population studied, the addition of one carbodiimide per heparin molecule resulted in complete epitope expression without loss of anticoagulant activity. The addition of up to eight additional carbodiimide molecules to heparin did not increase the extent of epitope formation, although anticoagulant activity was lost. Except for heparan sulfate, the addition of radiolabeled carbodiimide to other mucopolysaccharides did not result in epitope formation. These data demonstrate that antibodies to an epitope derived from heparin can be formed, that the epitope is fully expressed while anticoagulant activity is present, and that the antibody is specifically directed against an altered portion of the polysaccharide.

Inhibition of human activated Factor X by antithrombin III and alpha 1-proteinase inhibitor in human plasma.

The inhibition of activated human Factor X by human plasma protease inhibitors was investigated in both purified and plasma systems. In the former, antithrombin III, alpha 1-proteinase inhibitor, and alpha 2-macroglobulin, at normal plasma concentrations, markedly inhibited activated Factor X. Significant inhibition by alpha 2-antiplasmin, however, was only achieved when present at 40 times its plasma concentration. The relative rates of inhibition of activated Factor X coagulant activity in normal human plasma, antithrombin III-deficient plasma, and alpha 1-proteinase inhibitor-deficient plasma were 1.0, 0.63, and 0.75, respectively. From these relative rates of inhibition and their measured concentrations in the 3 plasmas, it was calculated that antithrombin III, alpha 1-proteinase inhibitor, and alpha 2-macroglobulin contribute 53, 35, and 12%, respectively, to the inhibition of activated Factor X in normal human plasma. Using 125I-labeled activated Factor X and a combination of sodium dodecyl sulfate disc gel electrophoresis and immunoadsorption, it was then demonstrated that antithrombin III accounted for 45-55%, alpha 1-proteinase inhibitor, 35-40%, and alpha 2-macroglobulin, 10-15% of the inhibition of the labeled protease in normal human plasma. The values obtained with the deficient plasmas are consistent with the distribution of activated Factor X-inhibitor complexes in normal human plasma. These data show by two independent techniques, one measuring coagulant activity and the other 125I-labeled activated Factor X-inhibitor complexes, that both antithrombin III and alpha 1-proteinase inhibitor are the major inhibitors of activated Factor X in normal human plasma.

The rabbit as an animal model for the activated factor X-antithrombin III-heparin reaction.

When activated factor X (Xa) inhibitory activity of serially diluted human and rabbit plasma is determined in a low salt assay, a lineare plot is obtained for human, but not for rabbit plasma. When a high salt assay is used, the dilution curves for both human and rabbit plasma are linear, and qualititive as well as quantitative differences are essentially eliminated. On Sephadex G-200 chromatography Xa inhibitory activity of human and rabbit plasma appears in two peaks. With the low salt assay the first and second peaks for human plasma contain respectively 30%, and 70% of the activity; whereas with rabbit plasma these values are greater than 95% and less than 5% of the activity. With the high salt assay the figures for human plasma are less than 5% and greater than 95%, and with rabbit plasma 65 +/- 3% and 35 +/- 3%, respectively. With the high salt system, rabbit plasma shows a continuous increase in Xa inhibitory activity with increasing heparin concentrations, similar to that obtained with human plasma. In the high salt system the relative contributions of antithrombin III to Xa neutralization in human and rabbit plasma are different. However, in experiments in which Xa inhibitory activity of antithrombin III is altered by heparin, a simple formula, Total activity (%) = 65% + 0.35 x human plasma (%), permits translation of rabbit data on the Xa-antithrombin III-heparin reaction to man. On the basis of these findings, the rabbit model can effectively be used to study the Xa-antithrombin III reaction.