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Purpose: There is emerging evidence that radiomics analyses can improve detection of skeletal fragility. In this cross-sectional study, we evaluated radiomics features (RFs) on computed tomography (CT) images of the lumbar spine in subjects with or without fragility vertebral fractures (VFs). Methods: Two-hundred-forty consecutive individuals (mean age 60.4 ± 15.4, 130 males) were evaluated by radiomics analyses on opportunistic lumbar spine CT. VFs were diagnosed in 58 subjects by morphometric approach on CT or XR-ray spine (D4-L4) images. DXA measurement of bone mineral density (BMD) was performed on 17 subjects with VFs. Results: Twenty RFs were used to develop the machine learning model reaching 0.839 and 0.789 of AUROC in the train and test datasets, respectively. After correction for age, VFs were significantly associated with RFs obtained from non-fractured vertebrae indicating altered trabecular microarchitecture, such as low-gray level zone emphasis (LGLZE) [odds ratio (OR) 1.675, 95% confidence interval (CI) 1.215–2.310], gray level non-uniformity (GLN) (OR 1.403, 95% CI 1.023–1.924) and neighboring gray-tone difference matrix (NGTDM) contrast (OR 0.692, 95% CI 0.493–0.971). Noteworthy, no significant differences in LGLZE (p= 0.94), GLN (p= 0.40) and NGDTM contrast (p= 0.54) were found between fractured subjects with BMD Tscore < − 2.5 SD and those in whom VFs developed in absence of densitometric diagnosis of osteoporosis. Conclusions: Artificial intelligence-based analyses on spine CT images identified RFs associated with fragility VFs. Future studies are needed to test the predictive value of RFs on opportunistic CT scans in identifying subjects with primary and secondary osteoporosis at high risk of fracture.

Feelings of gratitude motivate intimates to maintain valuable relationships. However, it is unknown whether expressions of gratitude similarly increase recipients’ relationship commitment. Two experiments tested the idea that expressions of gratitude simultaneously increase and decrease recipients’ commitment via different interpersonal evaluations, and reciprocity of gratitude determines the implications of such expressions. In Study 1, couples exchanged letters that did or did not express gratitude. Study 2 was a high-powered, preregistered experiment that led participants to believe they were or were not grateful for their partners, and their partners were or were not grateful for them. Both studies subsequently assessed automatic partner evaluations, deliberative partner and self-evaluations, and relationship commitment. Results demonstrated that intimates automatically evaluated partners who expressed gratitude more favorably and thus became more committed; however, if intimates did not reciprocate such gratitude, their deliberate self-evaluations became more favorable than their partner evaluations, and thus they became less committed.

Production scheduling is a class of widely studied combinatorial optimization problems. Given the complexity of the most addressed production environments several solution procedures have been proposed. In recent years, operational researcher practitioners have been paying attention to solving production scheduling problems using constraint programming, and growing interest in this research domain has been evidenced. The aim of this study is to report a descriptive bibliometric analysis of applications of constraint programming in production scheduling problems. The scope of the study is limited to reviewing 170 scientific papers published between 1992 and 2023 from the Scopus and Web of Science databases. In our proposed research questions, we could address the main topics studied, the most studied performance measures, and the profile of the analyzed documents. Furthermore, we could identify the main gaps and present suggestions for future research.

Maintaining sexual satisfaction is a critical, yet challenging, aspect of most romantic relationships. Although prior research has established that sexual communal strength (SCS)—i.e., the extent to which people are motivated to be responsive to their partner’s sexual needs—benefits romantic relationships, research has yet to identify factors that promote SCS. We predicted that gratitude would increase SCS because gratitude motivates partners to maintain close relationships. These predictions were supported in three studies with cross-sectional, longitudinal, and experimental methods. Specifically, experiencing and receiving expressions of gratitude were associated with greater SCS. These studies are the first to investigate the benefits of gratitude in the sexual domain and identify factors that promote SCS. Together, these results have important implications for relationship and sexual satisfaction in romantic relationships.

The objective of this study was to determine if sires have a significant effect on methane (CH4) production in a feedlot setting. To reduce the emission of greenhouse gases from cattle, evaluating variables that are easy to manage and change becomes important for a solution. If sires influence methane production, selection can be used to reduce methane production in cattle as sire differences are indicative of a genetic influence. The data used in this study were obtained from Colorado State University (CSU), with animals from John E. Rouse Beef Improvement Center. Animals with methane data were included in this analysis if sire parentage was known. After filtering, there were 68 Angus cattle, with 56 sires and 12 heifers included in the study. A linear model fitting sire and pen to methane was used. RStudio was used for the general linear model, and significance values were generated. Individual CH4 emissions were collected using GreenFeed free-stall systems (C-Lock) in each of the four pens at the CSU Agricultural Research Development and Education Center facility in Fort Collins, CO. Methane emissions were measured over a 52-day period. The average animal age at the start of the period was 241± 15.76 days. After all collections were completed, the mean CH4 mass flow was 180.4 g/day with a median of 181.4 g/day. The minimum was 107.5 g/day with a maximum of 247.0 g/day. There were sex differences (P <0.05) for (CH4) emission rate. Primary to this study, sires had a significant effect on (CH4) emission rates (P <0.05). The range of sire means for methane production was considerable with the 1stand 3rdquartiles of 157.8 g/day and 209.6 g/day. In these data, sires significantly influenced the (CH4) emission rates of their progeny, and we believe selection could be used to reduce overall (CH4) emissions. With these results, however, additional analyses to fully understand if there truly is a genetic component to (CH4) production could be undertaken once additional data has been collected. These future studies need to consider the relationships between methane production and other traits such as average daily gain, dry matter intake, and weight as selection needs to occur while considering a system-wide perspective.

Treatment of experimental data often entails fitting frequency functions, in order to draw inferences on the population underlying the sample at hand, and/or identify plausible mechanistic models. Several families of functions are currently resorted to, providing a broad range of forms; an overview is given in the light of historical developments, and some issues in identification and fitting procedure are considered. But for the case of fairly large, well behaved data sets, empirical identification of underlying distribution among a number of plausible candidates may turn out to be somehow arbitrary, entailing a substantial uncertainty component. A pragmatic approach to estimation of an approximate confidence region is proposed, based upon identification of a representative subset of distributions marginally compatible at a given level with the data at hand. A comprehensive confidence region is defined by the envelope of the subset of distributions considered, and indications are given to allow first order estimation of uncertainty component inherent in empirical distribution fitting.

How do relationship maintenance behaviors affect individual well-being? Given that people who invest time and effort toward achieving important goals see their outcomes as more reflective of their skills and abilities than do people who invest less time and effort, engaging in relationship maintenance behaviors may lead people to experience increased individual well-being when those behaviors appear to be successful but decreased well-being when they appear to be unsuccessful. A diary study of romantic relationships, a diary study of friendships, and a longitudinal study of newlyweds provided support for this prediction. In all three studies, relationship maintenance behaviors were negatively associated with depressive mood when followed by relatively high relationship quality, but positively associated with depressive mood when followed by relatively low relationship quality. Accordingly, relationship maintenance processes are not inherently beneficial or harmful; their intrapersonal implications depend on the context in which they occur.

Identification of distribution underlying experimental data sets, lacking established mechanistic models, calls for an inferential process involving necessarily uncertainty of some sort. While components pertaining to parameter estimation are routinely tak en into account, those related to selection of distribution form often are not; their awkward theoretical evaluation may explain why the issue tends to be conveniently ignored. Such an attitude may however lead to severe underestimation of overall uncertainty, s ince the component accounting for identification of distribution form often exceeds those concerning estimates of parameters. A pragmatic approach is presented, relying upon numerical simulation, allowing realistic evaluation of uncertainty inherent in empirical identification of form in a straightforward way. Application to an actual case is presented, and issues concerning identification procedure for parameters of auxiliary empirical distributions are discussed.

The control of cytosolic calcium is a major determinant not only of cardiac function, but also of the capability of myocardial tissue to survive damage. Increase of diastolic calcium leads rapidly to cell injury, and may be induced by a wide range of causes. In this review we describe the major points of calcium control in cardiac myocytes, mainly in mammalian ventricle, focusing on mechanisms of intracellular calcium influx during excitation, voltage gated channels of the sarcolemma and ryanodine receptors of the sarcoplasmic reticulum (SR), and efflux during relaxation, principally the sodium/calcium exchanger in membrane and the SR calcium complex. Mitochondria also depend on calcium concentration while also participating in its control. Moreover, we will outline receptor check points and their roles in physiology and pathology. We will focus on some new aspects of potential protective mechanisms that have been recently described and that involve peptide ligands and that in the case of the Neuregulin1beta/ErbB pathway are already reaching the clinical trial relevance.

The involvement of Chromogranin A (CgA) in the cardiovascular function regulation is attributed to its function as a prohormone. Several studies indicated that CgA-derived peptides, particularly Vasostatin-1 (VS-1) and Catestatin (CST), exert signaling effects in numerous organs/systems, including the cardiovascular system. This review focuses on the recently described signaling pathways activated by VS-1 and CST, giving insights into the mechanisms at the basis of their cardiac negative inotropic action, their vasodilator effects and their cardioprotective role observed in different experimental conditions. Accumulated evidences provided convincing support for VS-1 and CST as vasoactive peptides indirectly acting on cardiomyocytes through a Ca2-independent/PI3-K-dependent NO release from endothelial cells. This pathway is supposed to be triggered by the interaction of these peptides with the plasma membrane. The premise of these studies grounds on the biochemical features of VS-1 and CST, which are structurally characterized by amphipathic properties and the ability to interact with mammalian and microbial membranes. On the other hand, recent data obtained in both isolated heart and isolated cardiomyocytes suggest that the VS-1 and CSTmediated cardioprotective effects are primarily direct on the myocardium, rather than endothelium-dependent. Anyway, both direct and indirect pathways seem to be characterized by the absence of specific membrane receptors on target cells, highlighting intriguing novelties in the topic of cell signaling, in particular respect to an hypothetical receptor-independent eNOS activation.

Blood platelets maintain vascular integrity and promote primary and secondary hemostasis following interruption of vessel continuity. Biochemical or physical damage to the coronary, carotid or peripheral arteries is followed by excessive platelet activation and recruitment culminating in vascular occlusion and tissue ischemia. Currently inadequate therapeutic approaches to stroke and coronary artery disease are a public health issue. Following our demonstration of neutrophil leukotriene production from arachidonate released from activated aspirin-treated platelets, we studied interactions between platelets and other blood cells, leading to concepts of transcellular metabolism and thromboregulation. Thrombosis has a proinflammatory component whereby biologically active substances are synthesized by interactions between different cell types that could not individually synthesize the product(s). Endothelial cells control platelet reactivity via three biochemical systems—autacoids leading to production of prostacyclin and nitric oxide, and endothelial ecto-ADPase/CD39/NTPDase-1. The autacoids are fluid-phase reactants, not produced by tissues in the basal state. They are only synthesized intracellularly and released upon interactions of cells with an agonist. When released, autacoids exert fleeting actions in the immediate milieu, and are rapidly inactivated. CD39 is an integral component of the endothelial cell surface and is substrate-activated. It maintains vascular fluidity in the complete absence of prostacyclin and nitric oxide, indicating that they are ancillary components of hemostasis. Therapeutic implications for the autacoids have not been compelling because of their transient, local and fleeting action, and limited potency. Conversely, CD39, acting solely on the platelet releasate, is efficacious in three different animal models. It metabolically neutralizes a prothrombotic platelet releasate via deletion of ADP—the major recruiting agent responsible for formation of an occlusive thrombus. In addition, solCD39 reduced ATP- and ischemia-induced norepinephrine release in the heart. This reduction can prevent fatal arrhythmia. Moreover, solCD39 ameliorated the sequelae of stroke in CD39 null mice. CD39 represents the next generation of cardioprotective and cerebroprotective molecules.

The means by which endometrial receptivity influences conception rates in assisted reproductive technology (ART) is poorly understood. As the glycoprotein CA-125 is a product of human endometrium and is measurable in the peripheral circulation, it was investigated whether it might serve as an indicator of endometrial receptivity and predictor of pregnancy. In this prospective study, serum CA-125 concentrations of 75 ART cycles were measured 1 day before and on the day of human chorionic gonadotrophin (HCG) administration, and on the day of oocyte retrieval. These women did not have endometriosis and were induced by long-protocol gonadotrophin-releasing hormone analogue. Pregnancy was achieved in 35 (46.7%) cycles, but not in 40 cycles (53.3%). Serum CA-125 concentrations 1 day before and on the day of HCG administration and on the day of oocyte retrieval were significantly higher in cycles with pregnancy than in those without pregnancy (P < 0.05). It was noted that CA-125 concentrations on the day of oocyte retrieval were the best predictors of pregnancy, with concentrations >10 IU/ml having an accuracy of 86.6% for pregnancy. In conclusion, in intracytoplasmic sperm injection cycles, women with high serum CA-125 concentrations (>10 IU/ml) on the day of oocyte retrieval had very high pregnancy rates.

The introduction of advanced assisted reproduction technologies (ART) has created opportunities for the treatment of infertility among patients with myelomeningocele (MMC). The aim of this study was to assess the possibility of semen retrieval and to analyse the semen quality in men with MMC. Nine men, aged 22 to 39 with MMC participated in the study. Two participants were able to achieve unassisted ejaculation. Vibratory stimulation was unsuccessfully attempted in the remaining seven participants who then underwent electroejaculation under general anaesthesia. In total, enough spermatozoa for intracytoplasmic spermatozoa injection were retrieved from five participants. In four cases, no spermatozoa were observed in the ejaculates. Testicular biopsies, however, revealed spermatogenesis, and thus a reproductive potential, in one of these men. Therefore, in six of the nine men with MMC, fatherhood seemed possible with modern ART, despite the semen quality generally being very poor.

The introduction of advanced assisted reproduction technologies (ART) has created opportunities for the treatment of infertility among patients with myelomeningocele (MMC). The aim of this study was to assess the possibility of semen retrieval and to analyse the semen quality in men with MMC. Nine men, aged 22 to 39 with MMC participated in the study. Two participants were able to achieve unassisted ejaculation. Vibratory stimulation was unsuccessfully attempted in the remaining seven participants who then underwent electroejaculation under general anaesthesia. In total, enough spermatozoa for intracytoplasmic spermatozoa injection were retrieved from five participants. In four cases, no spermatozoa were observed in the ejaculates. Testicular biopsies, however, revealed spermatogenesis, and thus a reproductive potential, in one of these men. Therefore, in six of the nine men with MMC, fatherhood seemed possible with modern ART, despite the semen quality generally being very poor.

The importance of finite-capacity schedulers is increasing, with respect to the widespread MRP packages, due to their ability to model the shop floor more accurately. However, this very advantage may turn into a disadvantage, since it is quite difficult to devise a high-quality general purpose scheduler able to cope with the technological peculiarities of different production environments. Furthermore, a detailed schedule is prone to disruptions due to the uncertainty affecting the shop floor. Hence, we need both a modular approach to devise and assemble local schedulers and a way to link predictive and real time scheduling. To cope with both requirements, we propose a scheduling approach based on a generalization of the well-known shifting bottleneck method. The scheme is based on the coordination of local schedulers by a general scheme, such that the knowledge needed to cope with technological peculiarities is locally confined. The aim of the coordination mechanism is to generate a set of local due dates which can be used as targets to drive real time dispatching.

The genes of the trithorax group (trxG) in Drosophila melanogaster are required to maintain the pattern of homeotic gene expression that is established early in embryogenesis by the transient expression of the segmentation genes. The precise role of each of the diverse trxG members and the functional relationships among them are not well understood. Here, we report on the isolation of the trxG gene moira (mor) and its molecular characterization. mor encodes a fruit fly homolog of the human and yeast chromatin-remodeling factors BAF170, BAF155, and SWI3. mor is widely expressed throughout development, and its 170-kDa protein product is present in many embryonic tissues. In vitro, MOR can bind to itself and it interacts with Brahma (BRM), an SWI2-SNF2 homolog, with which it is associated in embryonic nuclear extracts. The leucine zipper motif of MOR is likely to participate in self-oligomerization; the equally conserved SANT domain, for which no function is known, may be required for optimal binding to BRM. MOR thus joins BRM and Snf5-related 1 (SNR1), two known Drosophila SWI-SNF subunits that act as positive regulators of the homeotic genes. These observations provide a molecular explanation for the phenotypic and genetic relationships among several of the trxG genes by suggesting that they encode evolutionarily conserved components of a chromatin-remodeling complex.

Platelet-activating factor (PAF) is an autacoid whose cardiovascular actions include a potent negative inotropic effect. The mechanism of this decrease in myocardial contractility is still at issue, as both a decrease and an increase in trans-sarcolemmal Ca++ influx have been reported. Because changes in intracellular sodium activity (aiNa) are known to influence myocardial contractility, we investigated whether PAF affects aiNa. Thus, we have measured contractile responses to PAF (1 nM-1 microM) in isolated guinea pig right ventricular papillary muscles paced at constant rate, and recorded transmembrane action potential and aiNa with conventional and sodium-selective microelectrodes, respectively. Our findings suggest that PAF does not affect slow inward Ca++ current, because PAF neither affected nor prevented histamine-induced restoration of contractile responses in K+-depolarized papillary muscles. On the other hand, we found the negative inotropic effect of PAF to be associated with a shortening of the action potential duration and with a decrease in aiNa. The specific PAF antagonist compound CV-3988 inhibited all three electro-mechanical responses. Our findings imply that the decrease in contractile force caused by PAF may depend on the reduction in aiNa; as aiNa falls, intracellular Ca++ may be lost via the Na+/Ca++ exchange and contractility decreases. The shortening of the action potential duration by PAF may reflect a decrease in Na+ influx and the consequent reduction in aiNa.

Because platelet-activating factor (PAF) has prominent depressant effects on cardiac contractility in various mammalian species, we assessed the negative inotropic effect of PAF on non-coronary perfused human right atrial pectinate muscles paced at constant rate. We found that PAF is a potent negative inotropic agent (EC50 approximately equal to 160 pM), whose action is unmodified by atropine, indomethacin and the leukotriene receptor antagonist compound FPL 55712. The negative inotropic effect of PAF was, however, antagonized by drugs known to inhibit PAF-induced platelet aggregation: the order of relative potency was SRI 63-441 greater than CV-3988 greater than alprazolam greater than or equal to triazolam; i.e., the same order in which these compounds antagonize the effects of PAF on platelets. Thus, the potent negative inotropic effect of PAF on human myocardium is independent of coronary flow changes, involves neither cholinergic mechanisms nor arachidonate metabolites and is probably mediated by specific receptors.

Release of cardiac histamine by immunologic and pharmacologic stimuli is known to provoke ventricular arrhythmias. Augmented histamine efflux from ischemic myocardium has been proposed but remains controversial. The purpose of this study was to determine whether cardiac histamine efflux is precipitated by coronary artery occlusion and if so, whether histamine efflux is associated with the development of early ischemic ventricular arrhythmias. The left anterior descending coronary artery was occluded while recording a continuous electrocardiogram and coronary sinus blood was sampled frequently during the first 30 min of coronary artery occlusion in pentobarbital-anesthetized, openchest dogs. Coronary sinus histamine concentration rose from a mean baseline of 0.06±0.10 ng/ml (±SD) before coronary artery occlusion to a mean peak of 0.61±0.40 ng/ml after coronary artery occlusion (p<0.0001;n=14). The median peak coronary sinus histamine concentration was significantly greater in dogs that suffered ventricular fibrillation after coronary artery occlusion (n=4) than in those that did not (n=10) (0.86 ng/ml vs. 0.37 ng/ml;p=0.05). The area under the coronary sinus histamine concentration-vs.-time curve (“total cardiac histamine efflux”) correlated directly with the total number of ventricular premature contractions during the first 30 min after coronary artery occlusion (r=0.81;p<0.005;n=10), and with infarct size (r=0.91;p<0.01;n=6). Thus, during acute myocardial ischemia, the coronary sinus histamine concentration increases simultaneously with the development of early ischemic ventricular arrhythmias and in proportion to their severity.

Paclitaxel (Taxol) is an anticancer agent with clinical activity against various human cancer types. Paclitaxel blocks cell division by stabilizing microtubules, a mechanism that also underlies its major side effects (neutropenia and neurotoxicity). Paclitaxel can also alter cardiac function, and to elucidate the mechanism of this activity, we tested the mechanical and electrical effects of paclitaxel and a series of analogs (docetaxel, taxol B, taxol C and N-methyltaxol C; 5-20 microM) on two different cardiac preparations, the isolated coronary perfused heart and the papillary muscle of the guinea pig. Paclitaxel and N-methyltaxol C induced conduction arrhythmias and reduced coronary flow and left ventricular systolic pressure in the isolated heart, whereas the other taxol derivatives tested had no significant effect. Moreover, paclitaxel blocked the vasodilator effect of bradykinin in the isolated heart. Paclitaxel and N-methyltaxol C produced a positive inotropic effect in papillary muscle, without alterations in the action potential. In the latter preparation, no significant variations were observed after treatment with the other taxol derivatives. The in vitro cardiodepressant and arrhythmogenic activity of paclitaxel is similar to that reported after its clinical administration and might be due to coronary vasoconstriction. The precise role of microtubules as modulators of intracellular calcium in cardiac and smooth muscle cells is at present unclear, because docetaxel and other taxol analogs, though they exhibited similar activity on tubulin, lacked cardiac effects.

Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) is produced by the vascular wall and is a key modulator of vascular tone and blood pressure. NO is also produced by vascular smooth muscle (VSMC) where it can inhibit proliferation. Since cytokine-activated VSMC proliferation is a major event in the development of atherosclerosis, we investigated the influence of cholesterol (CE)-enrichment of VSMC on cytokine-induced NO synthesis. Treatment of VSMC with native LDL for one week did not promote CE-accretion or alter NO production following exposure to endotoxin (LPS). In contrast, CE-enrichment by cationized LDL augmented LPS-induction of NO synthesis 2-5-fold. While TNF-α promoted little NO synthesis in control VSMC, it was very potent after CE-enrichment. Similarly, CE-enrichment augmented IL-lα-induced NO synthesis. However, CE-enrichment did not affect the synergistic induction of NO synthesis by cytokines in combination with IFN-γ. Our findings suggest that CE-enrichment of VSMC upregulates signal transduction pathways which mediate cytokine and LPS induction of NO synthase activity.

To evaluate the incidence of delivery in women after a traumatic spinal cord injury and to describe pregnancy outcome in this group of patients.

1. Physiological and molecular evidence for the presence and functional role of M1 muscarinic cholinergic receptors (mAChRs) in adult guinea‐pig ventricular cells is presented. 2. Whole‐cell clamp measurements of the L‐type calcium current (ICa) in isolated myocytes were performed. Caesium was used to suppress potassium currents. ICa was increased by the muscarinic agonist carbachol in cells pretreated with pertussis toxin which blocked the M2 mAChR‐triggered cascade of intracellular signalling, while it was not changed in untreated cells. 3. If the M2‐mediated regulation of ICa was blocked by directly saturating the cell with cyclic adenosine monophosphate (cAMP) through the patch pipette, application of carbachol induced a further small increase of the current above the level reached after cAMP perfusion. This increase was more pronounced in cells pretreated with pertussis toxin. 4. The carbachol‐induced increase of ICa was blocked by the selective M1 mAChR antagonist pirenzepine. 5. The application of high concentrations of carbachol increased the accumulation of [3H]inositol monophosphate up to 240% above control levels. This increase was reduced by application of pirenzepine. 6. The expression of M1 receptor mRNA in ventricular cardiocytes was shown by reverse transcriptase‐polymerase chain reaction. 7. These results suggest that M1 mAChR regulation of ICa can be a component of the paradoxical positive inotropism induced by high concentrations of muscarinic agonists.

The molecular imprinting technique was used in the synthesis of polymers having a high affinity for testosterone. These polymers thus function as receptor binding mimics for the drug. Various polymerization conditions were examined in order to determine their influence on the binding strength and selectivity of the binding mimics. Using a series of similar steroids, we were able to identify features of the molecules which affect their affinity for the polymer matrix. The efficacy of covalent and noncovalent imprinting methods was also compared. As determined by HPLC, the most selective (noncovalently imprinted) polymer bound testosterone over 4 times more strongly than did a nonimprinted polymer and at least 3 times more selectively than steroids of similar structure.

Tubular-fluid reabsorption by specialized cells of the nephron at the junction of the ascending limb of the loop of Henle and the distal convoluted tubule, termed the macula densa, releases compounds causing vasoconstriction of the adjacent afferent arteriole. Activation of this tubuloglomerular feedback response reduces glomerular capillary pressure of the nephron and, hence, the glomerular filtration rate. The tubuloglomerular feedback response functions in a negative-feedback mode to relate glomerular capillary pressure to tubular-fluid delivery and reabsorption. This system has been implicated in renal autoregulation, renin release, and longterm body fluid and blood-pressure homeostasis. Here we report that arginine-derived nitric oxide, generated in the macula densa, is an additional intercellular signaling molecule that is released during tubular-fluid reabsorption and counters the vasoconstriction of the afferent arteriole. Antibody to rat cerebellar constitutive nitric oxide synthase stained rat macula densa cells specifically. Microperfusion of the macula densa segment of single nephrons with N omega-methyl-L-arginine (an inhibitor of nitric oxide synthase) or with pyocyanin (a lipid-soluble inhibitor of endothelium-derived relaxation factor) showed that generation of nitric oxide can vasodilate the afferent arteriole and increase glomerular capillary pressure; this effect was blocked by drugs that prevent tubular-fluid reabsorption. We conclude that nitric oxide synthase in macula densa cells is activated by tubular-fluid reabsorption and mediates a vasodilating component to the tubuloglomerular feedback response. These findings imply a role for arginine-derived nitric oxide in body fluid-volume and blood-pressure homeostasis, in addition to its established roles in modulation of vascular tone by the endothelium and in neurotransmission.

1Burimamide selectively inhibited the formation of thromboxane A2from prostaglandin endoperoxides by human platelet microsomes in a dose‐dependent manner (IC50= 2.5 × 10−5m). Burimamide was found to be equipotent to imidazole as a thromboxane synthetase inhibitor.2Metiamide, cimetidine and a series of compounds either bearing a structural or pharmacological relationship to histamine caused little or no inhibition of thromboxane A2biosynthesis by human platelet microsomes.3Burimamide (5 × 10−4to 2.3 × 10−3m) did not inhibit either the cyclo‐oxygenase or the prostacyclin synthetase of sheep seminal vesicles or the prostacyclin synthetase of dog aortic microsomes.4Burimamide (2.5 × 10−5to 1.2 × 10−4m) inhibited sodium arachidonate‐induced human platelet aggregation; the degree of inhibition was dependent upon the concentration of arachidonic acid used to aggregate the platelets.

The effects of the sulfidopeptide leukotrienes (LTs) on the contractile response of electrically paced guinea-pig right ventricular papillary muscles in vitro were studied. LTs caused a concentration-dependent (1 nM-20 microM) negative inotropic effect; the order of relative potency was LTC4 greater than or equal to LTD4 greater than LTE4. A maximal 30% decrease in contractility occurred with 1 microM LTC4. The LT-induced decrease in contractile force was not mediated by cyclooxygenase products of the arachidonic acid cascade, as it was not influenced by indomethacin (14 microM). On the other hand, the slow-reacting substance-antagonist compound FPL 55712 (480 nM) caused a marked shift to the right of the LTC4 concentration-response curve. Because the negative inotropic effect of LTD4 was attenuated by increasing [Ca++]o, we next assessed the negative inotropic effect of LTs under conditions in which myocardial contractility depends solely on the slow inward Ca++ current. As a model, we used the isoproterenol- or histamine-induced restoration of contractile response in papillary muscles rendered inexcitable by 22 mMK+. LTC4 (16-480 nM) and LTD4 (20-600nM) inhibited isoproterenol- and histamine-induced restoration of contractility in a dose-dependent manner; a maximal 90% inhibition occurred with 0.48 microM LTC4. This effect of LTs was reversed by an elevation in [Ca++]o from 1.8 to 5.4 mM and prevented by FPL 55712 (480 nM). In muscles maintained at 5.4 mM [K+]o, LTC4 (160 and 480 nM) and LTD4 (1 microM) shifted the force-frequency curve (0.1-2 Hz) downwards in a parallel fashion; a similar alteration was obtained by lowering [Ca++]o to 1 mM.

Adenosine is known to attenuate the positive inotropic and chronotropic effects of norepinephrine and histamine by reducing cyclic AMP accumulation. We assessed whether adenosine, while inhibiting the cardiac responses mediated by beta and H2 receptors, leaves unmodified the responses mediated by alpha and H1 receptors. In isolated cardiac preparations from the guinea pig, adenosine antagonized the positive inotropic effect of histamine more than that of norepinephrine. This most likely occurred because, by attenuating H2 and beta responses, adenosine unmasked the H1-negative and alpha-1-positive components of the inotropic effects of histamine and norepinephrine. Consistent with this hypothesis, the pure H2 agonist impromidine appeared to be antagonized by adenosine less than histamine, and norepinephrine less than isoproterenol. In addition, adenosine antagonized the positive inotropic effect of norepinephrine in the presence of the alpha-1 blocker prazosin, whereas it did not affect the inotropic effect of phenylephrine. In the papillary muscle depolarized by 22 mM K+, adenosine antagonized the restoration of contractile responses induced by histamine or norepinephrine. This action of adenosine was reversed by the phosphodiesterase inhibitor papaverine and by the adenylate cyclase activator forskolin, suggesting that adenosine attenuates beta and H2 responses by suppressing the cyclic AMP-dependent facilitation of Ca++ influx promoted by the two amines. Our data indicate that adenosine selectively attenuates H2 and beta but not alpha and H1 responses. Thus, when catecholamines, histamine and adenosine are released together, as in myocardial ischemia, in addition to their individual effects, negative inotropism, decreased impulse conduction velocity and coronary constriction (i.e., H1- and alpha-mediated responses) may result from the adenosine-histamine-norepinephrine interaction.

The heart has not been regarded as a major target organ of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity notwithstanding that lethal cardiac dysfunction can occur in the absence of histopathological changes. To assess possible TCDD cardiotoxicity, we studied the effect of TCDD five days after treatment (10 micrograms/kg of body weight; single dose given i.p. in corn oil) on the contractility of guinea pig right ventricular papillary muscle. Controls were treated with corn oil. TCDD treatment significantly decreased beta-adrenergic responsiveness. In papillary muscles from TCDD-treated guinea pigs, the positive inotropic effect of isoproterenol (0.03-0.3 microM) was decreased by a mean of 65% (P less than 0.001), and the enhancement in the velocity of relaxation was 60% less than in the controls (P less than 0.05). On the other hand, TCDD treatment did not alter the positive inotropic effect of lower concentrations of isoproterenol (0.1-10 nM). After TCDD, responsiveness to low-frequency stimulation (0.1 and 0.25 Hz) was enhanced, responsiveness to increases in extracellular Ca2+ concentration was attenuated, and isoproterenol-elicited aftercontractions in K+-depolarized preparations were increased in magnitude. Collectively, the latter findings suggest that in addition to decreasing beta-adrenergic responsiveness, TCDD increases the intracellular Ca2+ concentration in papillary muscle. Finally, slow Ca2+ channels were not blocked after TCDD treatment, inasmuch as isoproterenol restored contractility equally effectively in K+-depolarized TCDD-treated and control papillary muscles. Our findings indicate that TCDD causes a specific pattern of cardiac dysfunction in a mammalian species, selectively augmenting or decreasing different cardiac responses. The cardiac changes are consistent with reported membrane effects of TCDD; further, they suggest that the heart may be a major target organ for TCDD toxicity.

Under given conditions, time and feed dependent fracture is the predominant failure mechanism of cutting tools. Assuming as a first approximation a decay in fracture resistance linear with cutting time, a model is developed which describes the overall variation in terms of variation in tool life (at constant feed) and fracture resistance (estimated from increasing feed tests). Validation of the model and quantitative evaluation of parameters are obtained from a set of cutting tests performed on a CNC lathe both at constant and variable feed rate. The effects on the model of single and combined variation of the main parameters are examined, and the main implications of the tradeoff between material removal rate and hazard function are discussed.

We had found previously that complement-derived anaphylatoxins C3a and C5a function as mediators/modulators of cardiac immune hypersensitivity reactions. The purpose of this study was to determine the secondary mediators responsible for the cardiac effects of C5a. Recombinant human C5a (rhC5a) caused dose-dependent tachycardia, slowing of atrioventricular nodal conduction, a short lasting increase followed by a prolonged decrease in left ventricular contractility, and coronary vasoconstriction. These changes were associated with the release of histamine, thromboxane A2 and adenosine into the coronary effluent. Our data indicate that the positive inotropic and chronotropic effects of rhC5a are mediated by histamine release and consequent activation of H2-receptors, the coronary-vasoconstricting effect is due to thromboxane release and the negative dromotropic effect is associated with adenosine release. Furthermore, the decrease in contractility caused by rhC5a is likely to result from the H1-mediated negative inotropic effect of histamine compounded by the ischemic conditions created by the coronary vasoconstricting effects of thromboxane A2 and, perhaps, leukotrienes. Our findings demonstrate that C5a has marked cardiac effects at concentrations approximating those attained in vivo in a multitude of pathophysiological conditions in which complement is activated, including myocardial infarction. Thus, anaphylatoxins may play a role in the development of ischemic cardiac dysfunction.

In a series of articles from the Stockholm Spinal Cord Injury Study (SSCIS), the health status of a near-total regional SCI population comprising 353 subjects has been investigated. The present study describes the psycho-social and financial consequences of SCI in this group. It is based on a level-of-living survey that has been used annually on 8000-14 000 Swedes since 1974. The health-focused version of this survey was used for data collection in the subset of 326 subjects in the SSCIS that were residents of the Greater Stockholm area. The normative material consisted of 1978 interviews of residents of the same area, provided by the Swedish Bureau of Statistics. The results show that SCI subjects, although provided with basic material commodities up to par with the general population, have less financial reserves and more frequently express worry about their finances. Less than half of the subjects are gainfully employed, when part-time jobs are also included. Social activities are more restricted, and more centered on the core social network. Several items in the survey point to a preoccupation with personal rather than public matters.We feel that these factors, at least to some degree, are consequential to separation from the workplace, with resulting disadvantageous financial and social effects. Intensified vocational rehabilitation efforts might thus be justified from both an economic and a psycho-social point of view.

In previous articles on the Stockholm Spinal Cord Injury Study (SSCIS), we have reported the frequent occurrence of medical problems in a near-total regional SCI population comprising 353 subjects. This present study further investigates health-related issues in this SCI population, by a level-of-living survey that has been used annually on 8000–14000 Swedes since 1974. The health-focused version of this survey was used for data collection in those 326 subjects in the SSCIS who were residents of the Greater Stockholm area. Subjects of the SSCIS living on the island of Gotland were excluded because they represented a sociodemographically different (rural) population. The normative material consisted of 1978 interviews of residents of the Greater Stockholm area, provided by the Swedish Bureau of Statistics. Results show a higher utilisation of health care resources among SCI subjects, shown by higher rates of long-term sick leave and sick pension, and more treatment as inpatients, emergency room attendees, and outpatients. Pain, bladder problems, and psychological symptoms are more commonly reported by SCI subjects. Medications such as antibiotics, analgesics, sedatives, hypnotics and laxatives are used more frequently in the SCI group. In contrast, no statistically significant differences were found as regards reported prevalence of diseases other than SCI, including diabetes, hypertension and cardiac disease. The results thus verify the impression from our previous studies of a clearly increased morbidity among these SCI subjects. The increased morbidity seems to be accounted for by the SCI itself, or conditions directly caused by it.