Social capital: a novel platform for understanding social determinants of health in systemic lupus erythematosus.

OBJECTIVE: The objective of this paper is to introduce the concept of social capital as a unique and distinct entity from the traditional psychosocial factors of social support, depressive symptoms, and self-efficacy in systemic lupus erythematosus (SLE) patients, and to evaluate how social capital varies in an SLE sample according to demographic, clinical, and psychosocial variables. METHODS: In a cross-sectional study, SLE patients completed the Adapted Social Capital Assessment Tool (A-SCAT), which measures cognitive and structural social capital. Patients also completed measures of social support, depressive symptoms, and SLE self-efficacy. Correlations were evaluated between social capital scores and demographic, clinical, and psychosocial variables. RESULTS: We recruited 89 patients (mean age: 39 ± 15 years old, 83 (93): female; mean SLEDAI: 4; mean SLICC 1). The mean A-SCAT score was 34 ± 15 (normal: 0-71); higher scores were associated with female sex, older age, higher education, Caucasian race, and non-Medicaid insurance (p ≤ 0.03 for all); associations were attributable to structural social capital. Social capital was not associated with depressive symptoms, self-efficacy, or affectionate and interaction social support, but was associated with informational and tangible social support (r = 0.39, r = 0.26, respectively, p ≤ 0.02). There were no associations between SLEDAI and SLICC and social capital, social support, and depressive symptoms. CONCLUSIONS: Social capital is a novel construct that, like other traditional psychosocial measures, addresses aspects of SLE not reflected by markers of disease activity. Social capital, however, is distinct from traditional psychosocial measures and offers a new platform on which ideas of social connectedness can broaden our understanding of health and chronic illness.

The heme oxygenase/biliverdin reductase system in skin cancers.

The heme oxygenase/biliverdin reductase (HO/BVR) pathway enhances cell stress response by degrading excess heme or producing antioxidant and cytoprotective molecules. Recently, members of the HO/BVR system have been proposed as biomarkers for the early diagnosis of free radical-related diseases. In this study, the presence of both the inducible and constitutive HO isoforms (HO-1 and HO-2, respectively) and BVR was evaluated by immunohistochemistry in human skin cancer samples. Moderate/strong immunoreactivities against HO-1, HO-2 and BVR were detected in 100% of the nodular malignant melanoma samples, whereas in basal cell carcinoma specimens these figures were 62%, 88% and 60%, respectively, with a faint/moderate degree of expression. Faint/moderate HO-1, HO-2 and BVR immunoreactivities were detected in 33%, 66% and 100% of melanocytic nevi samples, respectively. In conclusion, HO-1 and HO-2 and BVR were expressed in the cytosols of skin cancer cells, whereas perilesional normal epidermis showed only faint staining, thus leading to the hypothesis that the HO/BVR system is activated in skin cancers.

Electron shell ionization of atoms with classical, relativistic scattering.

We investigate forward scattering of ionization from neon, argon, and xenon in ultrahigh intensities of 2 × 10(19) W/cm(2). Comparisons between the gases reveal the energy of the outgoing photoelectron determines its momentum, which can be scattered as far forward as 45° from the laser wave vector k(laser) for energies greater than 1 MeV. The shell structure in the atom manifests itself as modulations in the photoelectron yield and the width of the angular distributions. We arrive at an agreement with theory by using an independent electron model for the atom, a dipole approximation for the bound state interaction, and a relativistic, three-dimensional, classical radiation field including the laser magnetic field. The studies provide the atomic physics within plasmas, radiation, and particle acceleration in ultrastrong fields.

The heme oxygenase/biliverdin reductase system: a potential drug target in Alzheimer’s disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of cognitive function, the inability to perform the activities of daily living and psychiatric symptoms. The formation of toxic aggregates of amyloid-beta-peptide (Abeta), through the activities of beta - and gamma- secretases, is considered as the earlier event in the pathogenesis of the disease. The deposition of both Abeta and the following hyperphosphorylation of tau protein, trigger an exaggerate immune-inflammatory response culminating with the production of excess reactive oxygen and nitrogen species responsible for damage on cellular nucleic acids, proteins and lipids. One of the mechanisms used by neural cells to counteract oxidative/nitrosative damage in AD is the enhancement of the cell stress response. Among the main components of the cell stress response is the heme oxygenase/biliverdin reductase (HO/BVR) axis, which catalyzes the degradation of heme which is toxic if produced in excess or under redox unbalanced conditions. However, the HO/BVR system and its by-products, carbon monoxide and bilirubin, have also been shown to be neuroprotective by activating pro-survival pathways and scavenging free radicals. Nevertheless, recent research demonstrated as both the inducible isoform of HO, known as HO-1, and BVR undergo oxidative/nitrosative/phosphorylative post-translational modifications in AD brain which alter the ability of HO-1 and BVR to activate the cell stress response. In this light, naturally occurring substances or drugs (e.g. statins) that prevent the post-translational modifications leading to a controlled up-regulation of the HO/BVR system have been proposed as potential new tools for the treatment of AD.

A pilot study of office-based spirometry in patients with systemic lupus erythematosus.

BACKGROUND: Although pulmonary involvement is common in systemic lupus erythematosus (SLE), its effects on healthy lifestyle physical activity and its association with fatigue have not been well characterized. The goals of this study were to describe pulmonary function measured by office-based spirometry in patients with SLE and to compare spirometry with physical activity and systemic fatigue. METHODS: During an office visit, 49 patients with SLE completed spirometry assessing: a) forced expiratory volume in 1 s (FEV(1), a measure of airway patency and responsiveness); b) forced vital capacity (FVC, a measure of lung volume); and c) maximum voluntary ventilation (MVV, a measure of volume of air moved during rapid breathing) which has been hypothesized to be decreased in SLE due to muscle fatigue. Patients also performed a 2-min corridor walking test and completed self-reported questionnaires measuring weekly physical activity and systemic fatigue. RESULTS: Mean age was 45 years, 45 (92%) were women, mean SLEDAI and SLICC scores were 2.8 and 1.0, respectively. Some 24 patients had a smoking history, and 15 had a history of SLE-related pleuritis, which was not active at enrollment. FEV(1) and FVC were 96% of predicted, but MVV was only 55% of predicted. The distance walked during the corridor test was similar to that of patients with other chronic diseases; however, self-reported physical activity was less than recommended by national guidelines. There were no associations between spirometry values and history of pleuritis, other pulmonary diagnoses, or smoking (p > .10 for all comparisons), however, better FEV(1) (p = .04) and better FVC (p = .04) were associated with more self-reported activity and better FEV(1) (p = .03) was associated with longer distance walked during the corridor test. Most patients reported marked systemic fatigue; however, there were no associations between spirometry values and fatigue scores (p > .10 for all comparisons). CONCLUSIONS: MVV was markedly diminished, which supports the hypothesis that SLE may be associated with respiratory muscle fatigue during rapid breathing. MVV was not associated with mild-to-moderate patient-directed physical activity; however, lower FEV(1) and FVC were associated with less self-reported and performance-based physical activity.

Perceptions and measurements of physical activity in patients with systemic lupus erythematosus.

Promoting physical activity should be a priority for patients with systemic lupus erythematosus (SLE) because a sedentary lifestyle compounds patients' already disproportionately high risk for cardiovascular events and other adverse health outcomes. The objectives of this pilot study were to assess physical activity in 50 patients with SLE and to compare activity levels with clinical and psychosocial variables, such as fatigue, depressive symptoms, and social support and stress. Patients were asked open-ended questions about physical activity, and responses were coded according to Grounded Theory. Patients then completed the Paffenbarger Physical Activity and Exercise Index, a survey of lifestyle energy expenditure reported in kilocalories/week, performed a 2-minute walk test according to a standard protocol, and completed questionnaires measuring fatigue, depressive symptoms and social support and stress. Most patients (92%) were women, had a mean age of 45 years, and did not have extensive SLE. In response to open-ended questions, patients reported they avoided physical activity because they did not want to exacerbate SLE in the short term. However, if they could overcome initial hurdles, 46 patients (92%) thought physical activity ultimately would improve SLE symptoms. Walking was the preferred activity and 45 (90%) thought they could walk more. According to the Paffenbarger Index, mean energy expenditure was 1466 ± 1366 kilocalories/week and mean time spent in moderate-intensity activity was 132 ± 222 min/week. In total, 18 patients (36%) and 14 patients (28%) met physical activity goals for these values, respectively. Mean distance walked during the 2-minute test was 149 ± 28 m, equivalent to two blocks, which is similar to reports for stable patients with other chronic diseases. Patients with more social stress and more fatigue reported less physical activity. We conclude that the proportion of patients meeting physical activity goals was low; however, patients performed well on a standard walking test. Most patients believed physical activity provided long-term benefits for SLE and that they could be more physically active.

Paradoxical inhibition of cardiac lipid peroxidation in cancer patients treated with doxorubicin. Pharmacologic and molecular reappraisal of anthracycline cardiotoxicity.

Anticancer therapy with doxorubicin (DOX) and other quinone anthracyclines is limited by severe cardiotoxicity, reportedly because semiquinone metabolites delocalize Fe(II) from ferritin and generate hydrogen peroxide, thereby promoting hydroxyl radical formation and lipid peroxidation. Cardioprotective interventions with antioxidants or chelators have nevertheless produced conflicting results. To investigate the role and mechanism(s) of cardiac lipid peroxidation in a clinical setting, we measured lipid conjugated dienes (CD) and hydroperoxides in blood plasma samples from the coronary sinus and femoral artery of nine cancer patients undergoing intravenous treatments with DOX. Before treatment, CD were unexpectedly higher in coronary sinus than in femoral artery (342 +/- 131 vs 112 +/- 44 nmol/ml, mean +/- SD; P < 0.01), showing that cardiac tissues were spontaneously involved in lipid peroxidation. This was not observed in ten patients undergoing cardiac catheterization for the diagnosis of arrhythmias or valvular dysfunctions, indicating that myocardial lipid peroxidation was specifically increased by the presence of cancer. The infusion of a standard dose of 60 mg DOX/m(2) rapidly ( approximately 5 min) abolished the difference in CD levels between coronary sinus and femoral artery (134 +/- 95 vs 112 +/- 37 nmol/ml); moreover, dose fractionation studies showed that cardiac release of CD and hydroperoxides decreased by approximately 80% in response to the infusion of as little as 13 mg DOX/m(2). Thus, DOX appeared to inhibit cardiac lipid peroxidation in a rather potent manner. Corollary in vitro experiments were performed using myocardial biopsies from patients undergoing aortocoronary bypass grafting. These experiments suggested that the spontaneous exacerbation of lipid peroxidation probably involved preexisting Fe(II) complexes, which could not be sequestered adequately by cardiac isoferritins and became redox inactive when hydrogen peroxide was included to simulate DOX metabolism and hydroxyl radical formation. Collectively, these in vitro and in vivo studies provide novel evidence for a possible inhibition of cardiac lipid peroxidation in DOX-treated patients. Other processes might therefore contribute to the cardiotoxicity of DOX.

Protective role of MnSOD and redox regulation of neuronal cell survival.

Reactive oxygen species (ROS) play a central role in neuronal pathophysiology and in neurodegenerative disorders. However, recent evidence indicates that these molecules also operate as signaling intermediates in a variety of physiological settings, including cell protection from apoptosis. Data presented here strongly support such a dual role for oxidants in neuronal cell homeostasis. In rat pheocromocytoma cells, cell rescue by the nerve growth factor (NGF) is accompanied by a transient burst of ROS generated in the cytosol by a GTPase-dependent mechanism. Within the NGF signaling cascade, ROS lie upstream and are necessary for activation/phosphorylation of AKT/PKB and of the antiapoptotic transcription factor cAMP-responsive element-binding protein (CREB). Conversely, an increase in mitochondrial oxygen species heralds apoptosis of serum-deprived cells, and these events can be prevented by cell exposure to NGF or by treatment with the mitochondrially targeted antioxidant MitoQ. Importantly, NGF-mediated decrease of mitochondrial ROS is dependent on the transcriptional up-regulation of the manganese superoxide dismutase (MnSOD) by active CREB. These observations therefore outline a circuitry whereby cytosolic redox signaling promotes neuronal cell survival by increasing the mitochondrial antioxidant defenses.

A model for physicians' therapeutic decision making.

We explored physician's cognitive processes when making therapeutic decisions in a complex situation in which more than one treatment option is acceptable. Eighteen internists were presented with three hypothetical cases of patients with coronary artery disease and were asked to explain their treatment decisions. Based on process tracing, we characterized their method of therapeutic decision making. We found that physicians use a three-stage process that we call focal composite analysis: (1) selection of a few facts (focal points) and evaluation of each fact individually with respect to treatment options; (2) reassessment of the value of the focal points with respect to each other and unification of the case; and (3) summation of the values of the focal points to make the final decision. Using this model, we predicted physicians' actual treatment decisions in 96% of the hypothetical cases. Further analysis revealed a wide variety of focal points chosen overall, with most physicians choosing different focal points in each case. Of a total of 32 focal points chosen in three cases, only two focal points were predictors of the physicians' actual treatment choices. We conclude that in the complex problem considered here physicians use a staged process of choosing and evaluating information to make therapeutic choices.

Rosmarinic acid up-regulates the noise-activated Nrf2/HO-1 pathway and protects against noise-induced injury in rat cochlea.

Noise-induced hearing loss depends on progressive increase of reactive oxygen species and lipoperoxidative damage in conjunction with the imbalance of antioxidant defenses. The redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in the regulation of cellular defenses against oxidative stress, including heme oxygenase-1 (HO-1) activation. In this work we describe a link between cochlear oxidative stress damage, induced by noise exposure, and the activation of the Nrf2/HO-1 pathway. In our model, noise induces superoxide production and overexpression of the lipid peroxidation marker 4-hydroxy-nonenals (4-HNE). To face the oxidative stress, the endogenous defense system is activated as well, as shown by the slight activation of superoxide dismutases (SODs). In addition, we observed the activation of the Nrf2/HO-1 pathway after noise exposure. Nrf2 appears to promote the maintenance of cellular homeostasis under stress conditions. However, in this model the endogenous antioxidant system fails to counteract noise-induced cell damage and its activation is not effective enough in preventing cochlear damage. The herb-derived phenol rosmarinic acid (RA) attenuates noise-induced hearing loss, reducing threshold shift, and promotes hair cell survival. In fact, RA enhances the endogenous antioxidant defenses, as shown by decreased superoxide production, reduced expression of 4-HNE, and up-regulation of SODs. Interestingly, RA potentiates the Nrf2/HO-1 signaling pathway, as shown by immunohistochemical and Western blot analyses. Thus, protective effects of RA are associated with the induction/activation of the Nrf2-ARE signaling pathway in addition to RA direct scavenging capability.

The generation of nitric oxide and carbon monoxide produces opposite effects on the release of immunoreactive interleukin-1beta from the rat hypothalamus in vitro: evidence for the involvement of different signaling pathways.

Both the cytokine, interleukin-1 (IL-1), and the gaseous neurotransmitters, nitric oxide (NO) and carbon monoxide (CO), have been implicated in the control of neuroendocrine functions, such as the release of CRH and luteotropic hormone-releasing hormone from the hypothalamus. Though increased levels of IL-1 in this brain region are unambiguously associated with enhanced CRH and reduced luteotropic hormone-releasing hormone release, the net effects of the two gases are still unclear, but in vivo and in vitro evidence suggests that the generation of NO and CO within the hypothalamus might counteract the stimulatory effects of IL-1 and bacterial lipopolysaccharide on the neuroendocrine stress axis. In this study, we have investigated the effects of NO and CO on the release of immunoreactive (ir)-IL-1beta from the rat hypothalamus in vitro. It was observed that the NO donor, sodium nitroprusside (SNP), stimulates ir-IL-1beta release under basal conditions, whereas the increase in CO levels obtained with hemin, the CO precursor through the heme oxygenase pathway, has no effect on basal ir-IL-1beta release but inhibits release stimulated by high K+ concentrations. The opposite effects of the two gases on cytokine release seemed to be caused by the activation of different signaling pathways, because: 1) SNP, but not CO-saturated solutions, is able to increase cyclic GMP levels in hypothalamic tissue; 2) CO-saturated solutions increase PGE2 production and release from the hypothalamic explants, whereas SNP has no effect; 3) SNP-stimulated ir-IL-1beta release is counteracted by a selective inhibitor of soluble guanylyl cyclase, LY 83583, but not by a cyclooxygenase inhibitor, indomethacin; and 4) conversely, indomethacin, but not LY 83583, reverses the inhibitory effect of hemin on K+-stimulated ir-IL-1beta release. It is concluded that NO and CO signal in the rat hypothalamus via the activation of soluble guanylyl cyclase and cyclooxygenase, respectively.

Carbon monoxide as a novel neuroendocrine modulator: inhibition of stimulated corticotropin-releasing hormone release from acute rat hypothalamic explants.

Although recent evidence suggests that the gas nitric oxide (NO) can modulate the secretion of corticotropin-releasing hormone (CRH) from acute rat hypothalamic explants, another gas, carbon monoxide (CO), has been suggested to play a role in neural signaling in the brain; CO may complement the activity of NO in long term potentiation. In this study, we have investigated whether CO shares with NO the ability to modify the release of CRH from the rat hypothalamus. Hemin, a specific CO precursor through the enzyme heme oxygenase (the enzymatic pathway synthesizing endogenous CO), was found to inhibit in a dose-dependent manner KCl-stimulated CRH release, with a maximal effect at 1 microM, while showing no effect on basal CRH secretion. The stimulation of CRH by interleukin-1 beta (100 ng/ml) was also significantly antagonized by hemin (1 microM). An inhibitor of heme oxygenase, zinc-protoporphyrin-9, had no effect on basal or stimulated CRH release up to a maximal dose of 10 microM. When hemin and zinc-protoporphyrin-9 were given together, the hemin-induced inhibition of CRH release was completely antagonized by the enzyme inhibitor. These findings provide evidence that endogenous CO may play a role in the control of CRH release; by analogy with NO, CO may represent a major new neuroendocrine modulator.

Signaling pathways involved in lipopolysaccharide stimulation of prostaglandin production by rat hypothalamic astroglial cells.

The aim of this study was to investigate the mechanisms through which bacterial lipopolysaccharide (LPS) stimulates prostaglandin (PG) production in rat hypothalamic astroglial cells in vitro. The latter were treated with LPS alone or LPS plus antagonists of the interleukin-1 (IL-1) and nitric oxide (NO) pathways, and the subsequent changes in cyclooxygenase (COX) activity were monitored by measuring a COX end-product, prostaglandin E2 (PGE2), released into the incubation medium. LPS produced a concentration-dependent increase in PGE2 release from astroglia after 24 h incubation; experiments with selective antagonists showed that the increase in PGE2 release induced by LPS may be, at least in part, mediated by IL-1 and NO.

Inhibition of heme oxygenase in the central nervous system potentiates endotoxin-induced vasopressin release in the rat.

Previous in vitro studies have shown that increases in endogenous carbon monoxide (CO) generation via activation of the enzyme heme oxygenase (HO) within the rat hypothalamus are associated with the reduced release of the neuropeptides, vasopressin (AVP) and oxytocin, while evidence concerning corticotrophin-releasing hormone (CRH) is controversial. The present study investigated whether there is also a functional relationship between the HO-CO pathway and AVP and corticosterone (Cort) in vivo. Male Wistar rats were challenged with bacterial lipopolysaccharide (LPS) at doses producing significant activation of the hypothalamo-pituitary-adrenal (HPA) axis. LPS was given alone or after pretreatment with the HO inhibitor Sn-protoporphyrin-9 (SnPP9). The latter was injected either intraperitoneally (i.p.) or by intracerebroventricular (i.c.v.) route. SnPP9 given i.p. failed to modify either basal or LPS-stimulated levels of AVP and Cort. On the contrary, i.c.v. SnPP9 strongly potentiated LPS-induced AVP release and significantly enhanced basal serum Cort levels, although it failed to potentiate stimulation by LPS. The LPS + i.c.v. SnPP9 also significantly reduced the hypothalamic stores of AVP compared to controls, correlating with increased circulating levels of AVP. Taken collectively, these data are in concordance with previous in vitro observations showing that the HO-CO pathway acts centrally to attenuate endotoxin-stimulated AVP release, while having less effects on the pituitary-adrenal axis.

Comparing discriminative validity between a disease-specific and a general health scale in patients with moderate asthma.

Health-related quality of life scales such as the Asthma Quality of Life Questionnaire and the Medical Outcomes Study Short-form General Health Survey SF-36 have become important measures of health status in clinical asthma trials. The discriminative properties of these scales, however, have not been extensively evaluated and compared. The purposes of this study were to assess and compare scale and discriminative properties of the Asthma Quality of Life Questionnaire (AQLQ) and the SF-36 in a group of patients with moderate asthma using a patient-rated global measure of disease activity as the criterion variable. Patients were interviewed in-person with a series of questionnaires including the AQLQ and the SF-36, and were also asked the global question "How active is your asthma now?" with possible responses of "extremely," "very," "moderately," "mildly" or "not active." Discriminative properties were determined using receiver operating characteristic (ROC) curves with responses to the global question as the criterion variable and mean domain scale scores as the independent variables. Relative validities for the AQLQ and SF-36 domains were also compared. A total of 230 patients, mean age of 41 years, were enrolled. Scores were lower and ranges were narrower for the AQLQ compared to the SF-36. In general, the AQLQ and the SF-36 were highly correlated, with r = 0.69 for the AQLQ overall score and the SF-36 Physical Component Summary (PCS) score. According to ROC analyses, both scales had excellent discriminative properties; however the area under the ROC curve was higher for the AQLQ overall score (0.81) than for the PCS (0.75). When ranked according to ROC area, the symptoms domain (0.83) had the greatest area under the ROC curve, followed by the emotional (0.76) and activities (0.76) domains of the AQLQ. However, in some cases, the area under the curve was less for an AQLQ domain (for example, 0.71 for the environmental domain) than for SF-36 domains (for example, 0.75 for the role physical, and 0.75 for the social domain). Similarly, the AQLQ overall had a higher relative validity (5.2) compared to the PCS (2.2), and the symptoms domain of the AQLQ had the highest relative validity (6.0). Thus, both the Asthma Quality of Life Questionnaire and the SF-36 were able to characterize patients with moderate asthma in our cross-sectional study. In addition, both scales had strong discriminative properties when assessed with a global patient rating of current disease activity.

Evidence that carbon monoxide stimulates prostaglandin endoperoxide synthase activity in rat hypothalamic explants and in primary cultures of rat hypothalamic astrocytes.

Carbon monoxide (CO) shares with nitric oxide (NO) the ability to modulate the release of hypophysiotropic peptides from rat hypothalamic explants. While both gases are believed to act as neural messengers in the brain via the activation of soluble guanylyl cyclase, the latter is almost undetectable in the rat hypothalamus. NO has been shown to exert some of its biological actions through the modulation of prostaglandin endoperoxide synthase (PGHS) activity. We have, therefore, investigated whether CO also can use PGHS as a signaling pathway in the hypothalamus. Endogenous CO is produced in equimolar amounts with biliverdin (BV) by the catabolism of hemin through heme oxygenase (HO). Hemin, two inhibitors of HO, zinc-protoporphyrin-9 (ZnPP9) and tin-mesoporphyrin-9 (SnMP9), ferrous hemoglobin (Hb), indomethacin and dexamethasone (DEX) were used as pharmacological tools. Prostaglandin E2 (PGE2) released from rat hypothalamic explants or primary cultures of hypothalamic astrocytes was taken as a marker of PGHS activity. It was found that: (1) hemin evokes an increase in PGE2 release from hypothalamic explants; (2) this effect is counteracted by ZnPP9, SnMP9, Hb and indomethacin; (3) the metallo-porphyrins and indomethacin, but not Hb, are also able to inhibit basal PGE2 release from hypothalamic explants; and (4) dexamethasone does not inhibit, and even potentiates, the stimulatory effect of hemin on PGE2 release from hypothalamic astrocytes. The evidence presented here suggests that the catabolism of endogenous or exogenously added hemin is associated with an increase in PGE2 production in the rat hypothalamus. This effect can be attributed to the formation of CO, since the other end-product of HO, BV, does not enhance PGE2 release. Thus, at least some of the biological effects of CO at the hypothalamic level might be mediated by the activation of the PGHS pathway.

Activation of heme oxygenase and consequent carbon monoxide formation inhibits the release of arginine vasopressin from rat hypothalamic explants. Molecular linkage between heme catabolism and neuroendocrine function.

Heme oxygenase (HO)-catalyzed degradation of cellular heme moieties generates biliverdin and equimolar amounts of carbon monoxide (CO), which has been implicated as a possible modulator of neural function. Technical difficulties preclude direct measurements of CO within intact nervous tissues; hence, alternative procedures are needed to monitor the formation and possible biologic functions of this gas. In the present study rat hypothalamic explants were found to generate 114 +/- 5 or 127 +/- 11 pmol biliverdin/hypothalamus/1 h (n = 3) upon incubation with 1 or 10 microM hemin, respectively. Ten micromolar zinc-protoporphyrin IX (Zn-PP-IX), a known inhibitor of HO, significantly decreased the degradation of 10 microM hemin from 127 +/- 11 to 26 +/- 11 pmol biliverdin/hypothalamus/1 h (n = 3; P < 0.01). Biliverdin was the principal product of HO-dependent heme degradation, as its possible conversion into bilirubin was precluded by hemin-dependent inhibition of biliverdin reductase. Basal or hemin-supplemented hypothalamic incubations were also shown to generate sizable amounts of propentdyopents (PDPs), reflecting HO-independent degradation pathways which do not liberate CO and cannot be inhibited by Zn-PP-IX. Plotting the ratio of biliverdin to PDPs thus provided an index of the efficiency with which hemin was degraded through biochemical pathways involving CO. Under the experimental conditions of our study, the biliverdin/PDPs ratio varied from 0 to 32 or 15%, depending on the absence or presence of 1 or 10 microM hemin respectively: this suggested that the formation of CO was most efficient at 1 microM hemin. Under these defined conditions, 1 microM hemin was also found to inhibit the release of arginine vasopressin (AVP) evoked by depolarizing solutions of KCl. A series of experiments showed that the effect of hemin was counteracted by Zn-PP-IX, and also by tin-mesoporphyrin IX, which is even more selective in inhibiting HO; it was also attenuated in the presence of the gaseous scavenger ferrous hemoglobin. Furthermore, the inhibition of AVP release could be reproduced by omitting hemin and by incubating hypothalami under CO, whereas treatment with biliverdin had no effect. This suggested that the release of AVP was suppressed by HO degradation of hemin, yielding CO as a modulator of hypothalamic function. These observations may be relevant to diseases characterized by inappropriate secretion of AVP and enzymatic disturbances affecting the synthesis of heme and the formation of CO through the HO pathway (e.g., acute intermittent porphyria or lead intoxication).

Gaseous neuromodulators in the control of neuroendocrine stress axis.

The gaseous neuromodulator carbon monoxide has been shown to reduce the stimulated release of stress neuropeptides, such as vasopressin and oxytocin, from the rat hypothalamus in vitro, while evidence concerning corticotropin-releasing hormone is controversial. In vivo studies have been conducted in the rat, inhibiting heme oxygenase activity--and hence carbon monoxide biosynthesis--in the central nervous system by means of specific heme oxygenase blockers; these studies showed that basal heme oxygenase activity tends to oppose exaggerated increases in vasopressin secretion following immune-inflammatory challenges, whereas it favors the normal rise in circulating ACTH which follows footshock. Another gas normally produced in mammalian brains under basal conditions, hydrogen sulfide, also appears to play a role in the control of the hypothalamo-pituitary-adrenal axis. Indeed, increases in hydrogen sulfide levels within the hypothalamus, either obtained with hydrogen sulfide-enriched media or by the addition of the hydrogen sulfide precursor S-adenosyl-methionine, are associated with the inhibition of the stimulated release of corticotropin-releasing hormone from rat hypothalamic explants. Parellel in vivo experiments in the rat under resting conditions and after stress-induced adrenocortical activation show that S-adenosyl-methionine significantly reduces the rise in serum corticosterone levels caused by 1-h exposure to cold. These results demonstrate the pathophysiological importance of both carbon monoxide and hydrogen sulfide in the regulation of neuroendocrine function.

Adaptations made by rheumatoid arthritis patients to continue working: a pilot study of workplace challenges and successful adaptations.

OBJECTIVES: The goals of this pilot study were to use qualitative research techniques in a group of currently employed patients with rheumatoid arthritis (RA) to develop categories of challenges encountered in maintaining employment and categories of successful adaptations made to continue working; and to identify obstacles considered to be persistent threats to continued employment. METHODS: Patients were interviewed by telephone with a questionnaire composed of structured-response format and open-ended response format questions focusing on specific challenges and adaptations in the workplace. RESULTS: Of the 22 patients interviewed, 96% were women, mean age was 50 years, 84% were college graduates, and the majority had light physical job demands and high autonomy over their work and hours worked. Patients encountered diverse challenges, such as fatigue, pain, typing, writing, physical requirements, maintaining a pleasant disposition, working overtime, traveling for business, commuting, being on time, not being able to choose rest periods, and environmental issues. Patients also made multiple adaptations to continue working, the most helpful being changing job or altering career path (36%), altering work hours (32%), using more disease-modifying antirheumatic drugs (27%), using car service (23%), sleeping more (18%), and working at home (14%). Patients were not at all confident in their ability to continue working because of RA, and perceived the following persistent threats to continued employment: fatigue (45%), not being able to use hands (45%), not being able to choose rest periods (27%), and commuting problems (18%). In addition, patients confronted psychological stresses, such as dealing with coworkers and supervisors and balancing job and personal roles. These challenges and adaptations included unfavorable work-related occurrences, or "negative work-role events." CONCLUSIONS: Seemingly successfully employed patients with RA faced multiple challenges and made major adaptations to maintain employment and still perceived their employment to be in jeopardy because of RA. The findings of this study have important implications for screening patients at risk for negative work-role events and for possible work-related and social support interventions aimed at preserving employment.

Evidence for the neuronal origin of immunoreactive interleukin-1 beta released by rat hypothalamic explants.

In this study, we have investigated the release of immunoreactive interleukin-1 beta (irIL-1 beta) from the rat hypothalamus in vitro. It was found that (1) tissue explants release sizable amounts of irIL-1 beta (ranging from 0.43 to 0.52 pg/mg of wet tissue) in 20 min incubations; (2) basal release in significantly increased by depolarization induced with 56 mM KCl; (3) K(+)-induced irIL-1 beta release is inhibited by the specific blocker of N-type calcium channels, omega-conotoxin, and by verapamil, but not by nifedipine; (4) K(+)-induced release is also inhibited by the Na+ channel blockers tetrodotoxin and lidocaine; (5) irIL-1 beta release is significantly increased by noradrenalin; such increase is antagonized by verapamil and the beta-blocker propranolol, but not by the alpha-blocker phentolamine. The present evidence suggests that irIL-1 beta released by rat hypothalamic explants following KCl depolarization is neuronal in origin.