FGF23-klotho axis, bone fractures, and arterial stiffness in dialysis: a case-control study.

We performed a case-control study on 130 age- and sex-matched hemodialysis patients. In multivariate analysis, we observed that FGF23 levels were associated with fracture incidence and that soluble α-klotho levels were associated with the aortic-brachial arterial stiffness ratio. INTRODUCTION: New bone markers such as sclerostin, Dickkopf-related protein 1 (DKK1), fibroblast growth factor-23 (FGF23), and α-klotho have been identified as potential key players in bone and vascular abnormalities of chronic kidney disease. Therefore, we aimed to assess whether these markers are associated with fractures, bone metabolism, and vascular stiffness in dialysis patients. METHODS: In a prospective hemodialysis cohort, where plasma samples and vascular assessment were performed at baseline, we matched patients who experienced a fracture during follow-up with sex- and age-matched non-fractured patients on a 1:4 ratio. Sclerostin, DKK1, α-klotho, FGF23, and markers of bone formation (alkaline phosphatase and procollagen type 1-N terminal propeptide [P1NP]) and bone resorption (tartrate-resistant acid phosphatase 5b [TRAP5b]) were measured in baseline plasma samples. Aortic-brachial pulse wave velocity ratio, a blood pressure independent measure of arterial stiffness, was used to assess vascular stiffness at baseline. RESULTS: We included 130 hemodialysis patients (26 fractured, 104 non-fractured) with a median follow-up of 42 months and a median age of 72 years. In multivariate Cox regression models, high FGF23 levels were associated with increased fracture incidence (adjusted HR = 2.97; 95% CI 1.18, 7.43). α-Klotho levels were associated with bone formation but not resorption markers. In both univariate and multivariable adjusted models, α-klotho levels were inversely associated with the aortic-brachial pulse wave velocity ratio (ß = - 0.070; 95% CI - 0.133, - 0.006). CONCLUSIONS: These results suggest a role for FGF23/klotho axis on bone and vascular metabolism in dialysis populations.

[Cardiovascular manifestations in patients with COPD]. / Les manifestations cardiovasculaires chez les patients atteints d'une BPCO.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterized mainly by airway obstruction due to chronic bronchitis and/or emphysema. In addition, COPD is frequently associated with other health problems with serious systemic manifestations. In particular, COPD patients are at increased risk of cardiovascular disease. BACKGROUND: Current knowledge about cardiovascular disease in patients with COPD mainly concerns the high prevalence of cardiac arrhythmias in this population. Systemic hypertension, cardiovascular disease, heart failure and cerebro-vascular disease are also frequently encountered. This review discusses the cardiovascular manifestations associated with COPD, excluding right heart failure due to pulmonary hypertension. VIEWPOINTS AND CONCLUSION: Non pulmonary health problems in patients with COPD, such as cardiovascular disease, are arousing increasing interest in the medical community. More studies are needed to increase our knowledge of cardiovascular disease in COPD and allow better medical management of patients.

Effect of some experimental interviewing techniques on reporting in the health interview survey.

This experimental field study was carried out to test certain questionnaire designs and inter-viewing techniques which might improve the re-porting of health events in a modified Health Interview Survey household interview. This study is one in a series conducted for the National Center for Health Statistics (NCHS); the hypotheses tested and the techniques used were derived from preceding studies in this series. Some of the relevant prior findings are presented below.

Cortical EEG changes during the self-administration of phencyclinoids.

Female rats, implanted with cerebrocortical EEG recording electrodes, were trained to self-administer cocaine and then ketamine under a fixed ratio 10 schedule of reinforcement, during limited access sessions. Periodically, a single unit dose of either phencyclidine (0.5 mg/kg), ketamine (4 mg/kg) or 1-(1-phenylcyclohexyl)morpholine (PCM 4 mg/kg) was substituted for ketamine, while the cortical EEG was recorded. Spectrum quantities of samples of EEG, taken immediately before and after each injection, were subjected to a discriminant analysis. For each drug, the preinjection state of the EEG could be classified separately from the postinjection state, using specific EEG spectrum quantities from the global frequency range (0.1-20 Hz). Furthermore, the relevant EEG parameters, which described the change from pre- to postinjection states, were unique for each drug (phencyclidine: total power and complexity; ketamine: peak frequency, relative power and mobility; PCM: all parameters except peak frequency), indicating potential differences in the EEG, occurring with a level of intake of drug which was controlled by the subject. Overall, these data serve to model the changes in the EEG that occur during the self-administration of three phencyclinoids. Furthermore, the combination of EEG spectrum analysis with discriminant analysis is useful in detecting subtle differences in the effects of these three drugs on the EEG.

Haloperidol pretreatment unmasks the kappa opioid effects of U-50, 488H on cortical EEG and EEG power spectra in rats.

Adult female Sprague-Dawley rats were implanted with chronic cortical EEG electrodes and intravenous cannulae. U-50, 488H injection (5.0 mg/kg) produced initial EEG desynchrony and EEG spectral power that was mainly distributed over the zero to 10 Hz range, including a relatively small spectral peak in the 4-6 Hz band. In contrast, following haloperidol pretreatment (0.1 mg/kg), U-50, 488H injection produced high-voltage EEG bursts and a predominant EEG spectral peak in the 4-6 Hz band. These effects of U-50, 488H after haloperidol pretreatment were identical to those previously demonstrated with the benzomorphan kappa agonist ethylketocyclazocine. Thus, haloperidol pretreatment unmasked the kappa opioid effects of U-50, 488H.

Effects of self-administered phencyclidine on regional uptake of 2-deoxy-D-[1-14C]glucose in brain.

Phencyclidine profoundly alters cerebral metabolism in the rat. This study explored whether cerebral metabolic effects of phencyclidine differed when the drug was self-administered by trained rats, compared with when it was given acutely to naive rats. The regional cerebral uptake of 2-deoxy-D-[1-(D14C] glucose (DG) was examined following two injections of phencyclidine (0.5 mg/kg/injection, i.v.) or saline in freely-moving, drug-experienced rats. Naive controls received phencyclidine or saline according to an identical dose regimen. In self-administering and naive rats, phencyclidine produced many of the same effects on uptake of DG, including the following: decreases in the habenula, inferior colliculus, sensory cortical areas and corresponding thalamic relay nuclei; and increases in limbic areas (entorhinal and retrosplenial cortices, subicular areas). Some regions (auditory and motor cortices, medial geniculate body, globus pallidus) showed different effects in self-administering and naive rats. Another study, in which rats were not self-administering phencyclidine, but had histories of treatment with drugs similar to those of the self-administering rats, indicated that chronic exposure to drug accounted for some of the differences. Furthermore, differences between the effects of phencyclidine in self-administering, versus non-self-administering rats with similar histories suggested that activity in some regions of the brain may relate to training in drug self-administration and/or behavior.

New generation dopaminergic agents. 6. Structure-activity relationship studies of a series of 4-(aminoethoxy)indole and 4-(aminoethoxy)indolone derivatives based on the newly discovered 3-hydroxyphenoxyethylamine D2 template.

A series of 4-(aminoethoxy)indoles 7 and a related series of 4-(aminoethoxy)indolones 8 were synthesized and evaluated for their affinity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 4-aminoethoxy derivatives (i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. The indolones 8 were observed to have high affinity for the D2High receptor. Comparison of their previously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealed the chroman analogues to be more potent, whereas little loss in D2High affinity was observed when comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Several regions of the phenoxyethylamine framework were modified and recognized as potential sites to modulate the level of intrinsic activity. A conformational analysis was performed and a putative bioactive conformation was proposed which fulfilled the D2 agonist pharmacophore criteria based on the McDermed model. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.

Synthesis and SAR of adatanserin: novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT(1A) and 5-HT(2) activity as potential anxiolytic and antidepressant agents.

Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.

New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans.

A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity and selectivity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed to be the primary D2 agonist pharmacophore. The 2-methylchroman moiety was discovered to be an entirely novel scaffold which could be used to access the D2 agonist pharmacophore. Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had significant effects on selectivity for the D2High receptor vs the 5HT1A and alpha 1 receptors. A novel DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as having the highest affinity and best selectivity for the D2High receptor vs the alpha 1 and 5HT1A receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-2-AMC moiety was identified as fulfilling the McDermed model D2 agonist pharmacophoric criteria and was proposed as the D2 receptor-bound conformation. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.

Intracerebral administration of metabotropic glutamate receptor agonists disrupts prepulse inhibition of acoustic startle in Sprague-Dawley rats.

The functional role of striatal metabotropic glutamate receptors (mGluRs) was examined by measuring prepulse inhibition (PPI) of an acoustic startle response following the intracerebral administration of selective agonists in male Sprague-Dawley rats prepared with bilateral cannulae aimed at either the nucleus accumbens or dorsal striatum. mGluR subtypes (1-8) are classed in three groups based on sequence homology, signal transduction mechanism and pharmacology. Intra-accumbens IS,3R-ACPD, an agonist at group 1 and 2 mGluRs (0.5-1.0 micromol/2 microl), caused a dose-dependent loss of PPI. The effect of 1S,3R-ACPD was diminished when injected into dorsal striatum. Intra-accumbens infusion of the group 1 selective agonist 3,5-DHPG (1 micromol) and the group 2 selective agonist L-CCG-I (100 nmol) also led to statistically significant disruptions of PPI, while the group 3 selective agonist L-AP4 (0.4-1.0 micromol) had no significant effect. Although the group 1/2 mGluR antagonist (+) MCPG (0.5 micromol) had no significant effect of its own on PPI, co-administration with IS,3R-ACPD (1 micromol) blocked ACPD-induced loss of PPI. In addition, pretreatment (30 min) with haloperidol (0.3 mg/kg IP) attenuated the PPI disruption induced by 1 micromol 1S,3R-ACPD, suggesting dopamine may play a role in mGluR agonist induced loss of PPI. These results support a role for group 1 and group 2 mGluRs in the nucleus accumbens in the regulation of PPI, a measure of sensory gating. As PPI is abnormal in some patient populations, such as Huntington's and schizophrenia, mGluRs may have potential as novel therapeutic targets for these diseases.

Effects of fixed ratio size and dose on phencyclidine self-administration by rats.

Female Sprague-Dawley rats were trained to self-administer phencyclidine (PCP; 0.125, 0.25, or 0.5 mg/kg/injection) on a fixed ratio (FR) schedule of reinforcement under limited access conditions (3 h). Initial training began with cocaine, which was later replaced with ketamine and then one of the three unit doses of PCP. Baseline rates of injection were determined at FR 10. The size of the ratio was then incremented geometrically every fifth daily session. Increasing the ratio resulted in a decrease in the number of injections per session. Furthermore, this decrease was greater for the 0.25 mg/kg dose than for the 0.5 mg/kg unit dose. The self-administration of the 0.125 mg/kg dose was variable and rapidly extinguished upon the increase in fixed ratio. The results indicate that PCP is self-administered by rats under the conditions imposed in this study. Furthermore, the relative reinforcing efficacy of the different unit doses of PCP could be discriminated using this type of response cost procedure.

The anticonvulsant and behavioral effects of phencyclidine and ketamine following chronic treatment in rats.

The effects of chronic phencyclidine (PCP) or ketamine (KET) on their respective acute behavioral and anticonvulsant actions were investigated. Female rats were treated for 15 days with twice daily i.p. injections of saline, 20 mg/kg PCP or 40 mg/kg KET. Subjects treated chronically with PCP were challenged with either 10 mg/kg or 20 mg/kg i.p. PCP, while subjects treated chronically with KET were challenged with 40 mg/kg i.p. KET only. Neither chronic drug treatment induced tolerance to the acute anticonvulsant effect, nor to hyperlocomotion and stereotypy as measured by automated activity monitors. However, evidence of tolerance to the stereotypy induced by acute KET was obtained when an observer-based rating scale was employed. In addition, tolerance occurred to the ataxia induced by KET and the 10 mg/kg, but not 20 mg/kg, dose of PCP. Thus, tolerance occurs to some of the acute behavioral effects of PCP and KET while the anticonvulsant action of these compounds remains unaffected.

The convulsant and anticonvulsant effects of phencyclidine (PCP) and PCP analogues in the rat.

The pro- and anticonvulsant effects of phencyclidine (1-[1-phenylcyclohexyl]piperidine HCl, PCP), a number of its analogues, and SKF 10047 were investigated in rats. The PCP analogues were compounds produced by substitutions for the phenyl and piperidine rings of PCP and were selected to elucidate the structure-activity relationships existing between PCP and its pro- and/or anticonvulsant effects. All of the compounds, except ketamine, induced convulsions at high (12.8-25.6 mg/kg, i.v.), yet almost always sublethal doses. Ketamine failed to induce convulsions, even at lethal doses (51.2 mg/kg, i.v.). The acute pro- or anticonvulsant actions of PCP were then investigated. Rats were subjected to transorbital electroconvulsive shock subsequent to i.p. injections of saline or 0.625, 2.5, 5.0, 10.0 or 20.0 mg/kg PCP. It was found that PCP induced an acute, dose-dependent anticonvulsant effect. The acute pro- and/or anticonvulsant actions of the remaining compounds were then investigated by administration of electroconvulsive shock subsequent to i.p. injections of saline or one of two doses of each compound. The low and high doses of each compound were selected to be behaviorally equivalent to 2.5 and 10.0 mg/kg PCP i.p., respectively. With one exception, each dose of each drug induced an acute anticonvulsant action, with no difference in efficacy between the compounds tested. However, PCA (produced by substitution of an amine for the piperidine ring of PCP) induced a statistically greater anticonvulsant action at the higher, compared to the lower, dose. In addition, PCA was the only compound to eliminate all motor signs of the electrically induced seizure.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholecystokinin octapeptide alters morphine-induced effects on EEG power spectra both quantitatively and qualitatively.

In the present study, EEG analysis was used to determine if cholecystokinin octapeptide (CCK-8) has an effect on the EEG spectral profile associated with morphine-induced bursting. Adult female Sprague-Dawley rats were implanted with cortical electrodes and indwelling i.c.v. and i.v. cannulas. On the day of the experiment, each rat received an i.c.v. injection of either H2O or one of four doses of CCK-8: 8.0, 16.0, 32.0 or 64.0 ng. Ten minutes after receiving the i.c.v. injection, each rat received a 10.0 mg/kg dose of morphine by i.v. injection. Neither the i.c.v. injections of H2O nor CCK-8 produced any EEG bursting or behavioral stupor. However, the i.v. injection of morphine produced high-voltage, slow-wave EEG bursts in all rats. Analysis of EEG recorded during bursting showed that both the 32.0 and 64.0 ng doses of CCK-8 increased absolute power associated with morphine-induced bursting, and comparison of the distribution of power across the range of frequency bands between the control (H2O) and the 32.0 ng dose of CCK-8 revealed that CCK-8 caused a significant change in the pattern of distribution of power. Furthermore, significant dose-related differences were found in the global (1-50 Hz) parameters absolute power, mean frequency, mobility, complexity and edge frequency. Significant differences among the five groups were not found in the parameter of peak frequency, or in either latency to slow-wave sleep or duration of morphine-induced bursting. These results demonstrate that CCK-8 caused both quantitative and qualitative changes in the EEG spectral profile associated with morphine-induced bursting.

Animal models of intravenous phencyclinoid self-administration.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, PCP) self-administration has been demonstrated in rhesus monkeys, baboons, dogs and rats. Generally, an orderly inverted U-shaped dose-response curve for rates of self-injection has been observed. Total drug intake appears to increase slightly with increases in unit dose; however, this increase is much less than might be expected with other CNS depressants such as barbiturates or morphine. Additionally, several arylcyclohexylamine analogues of PCP and some members of the benzomorphan and dioxolane classes referred to collectively as "phencyclinoids" are self-administered by primates and dogs. New data are presented in this review profiling the self-administration of some of these drugs in rats, as well as a characterization of the self-administration of higher unit doses of PCP than previously reported. Also, preliminary results of the assessment of the reinforcing efficacy of some PCP analogues measured by the progressive ratio procedure are presented.

Rural nurse practitioners: perceptions of ethical dilemmas.

The purposes of this study were to identify ethical dilemmas encountered by rural nurse practitioners in primary practice and to identify constraints or enhancers that influenced ethical decision making. Nine nurse practitioners from Wyoming and Colorado responded to in-depth interviews. Six categories of ethical dilemmas and a list of constraints and enhancers were identified. One central concept, conflict between personal values and professional responsibility, emerged. Beneficence, nonmaleficence, justice, and patient autonomy, as core ethical principles, were related to this central conflict.

Care for the patient with AIDS in the ICU: outcomes and ethics.

HIV infection and AIDS are common diagnoses in many intensive care units (ICUs) in the United States. Although Pneumocystis carinii currently represents only one quarter of all diagnoses for which HIV-infected persons are admitted to the ICU, it is the disease with the most clinically applicable outcome data and, therefore, is a model for ethical decision-making regarding patients with HIV infection in the ICU. Despite advances in diagnosis and treatment of HIV-related P. carinii, recent studies show that only 20% to 25% of the patients with acute respiratory failure survive to hospital discharge. Although many clinical markers correlate with survival, none of the individual markers or prediction scoring systems have the accuracy needed in clinical practice. One goal of predicting outcome in the ICU is to aid both the patient and the physician in making decisions about when to pursue aggressive therapy and when to withhold or withdraw such therapy. Because our ability to predict outcome is limited, advance directives and communication with patients and families about end-of-life medical care are of utmost importance. Even though it is not always possible for patients to predict, in advance, what they would want done in various hypothetical health care scenarios, quality communication between physicians, patients, and families with realistic discussion of outcomes and maintenance of hope and dignity can facilitate decisions about the use of intensive care for patients with AIDS.