Rosiglitazone in the management of older patients with type 2 diabetes mellitus.

The prevalence of type 2 diabetes increases dramatically with age in all populations. This report describes a post-hoc analysis of eight rosiglitazone monotherapy studies to characterise the efficacy and safety of rosiglitazone in older patients with type 2 diabetes, using a designation of > or = 70 years for elderly. A total of 3,127 patients were randomised to rosiglitazone (<70 years: n=2099; > or = 70 years: n = 427) or placebo (<70 years: n = 497; > or = 70 years: n=104). In both age groups, rosiglitazone 4 mg/day and 8 mg/day reduced HbA1c and fasting plasma glucose compared with baseline and placebo at week 26 with no difference between age groups. There was no difference between the nature, severity or type of adverse events experienced by older or younger patients. Rosiglitazone improves glycaemic control and is well tolerated in older as well as younger patients with type 2 diabetes.

Effects of glucagon on renal and hepatic glutamine gluconeogenesis in normal postabsorptive humans.

Glutamine is an important gluconeogenic amino acid in postabsorptive humans. To assess the effect of glucagon on renal and hepatic glutamine gluconeogenesis, we infused six normal healthy postabsorptive subjects with glucagon at a rate chosen to produce circulating glucagon concentrations found during hypoglycemia and, using a combination of isotopic and net balance techniques, determined the systemic, renal, and hepatic glucose release and renal and hepatic production of glucose from glutamine. Infusion of glucagon increased systemic and hepatic glucose release (both P < .02), but had no effect on renal glucose release (P = .26). Systemic and hepatic glutamine gluconeogenesis increased from 0.45 +/- 0.3 and 0.11 +/- 0.02 micromol x kg(-1) x min(-1), respectively, to 0.61 +/- 0.04 (P = .002) and 0.31 +/- 0.03 micromol x kg(-1) x min(-1) (P = .001), respectively, whereas renal glutamine gluconeogenesis was unchanged (from 0.33 +/- 0.03 to 0.30 +/- 0.04 micromol x kg(-1) x min(-1), P = .20). The hepatic contribution to systemic glutamine gluconeogenesis increased from 25.2% +/- 6.2% to 51.6% +/- 5.5% (P = .002), while that of the kidney decreased from 74.8% +/- 6.2% to 48.4% +/- 5.5% (P = .003). Glucagon had no effect on the renal net balance, fractional extraction, or uptake and release of either glucose or glutamine. We thus conclude that glucagon stimulates glutamine gluconeogenesis in normal postabsorptive humans, predominantly due to an increase in hepatic glutamine conversion to glucose. Thus, under certain conditions such as counterregulation of hypoglycemia, the liver may be an important site of glutamine gluconeogenesis.

Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity.

To assess the contribution of the human kidney to gluconeogenesis (GN) and its role in conversion of glutamine and alanine to glucose, we used a combination of isotopic and organ balance techniques in nine normal postabsorptive volunteers and measured both overall and renal incorporation of these precursors into glucose before and after infusion of epinephrine. In the postabsorptive basal state, renal incorporation of glutamine (27 +/- 2 mumol/min) and alanine (2.1 +/- 0.5 mumol/min) into glucose accounted for 72.8 +/- 3.3 and 3.9 +/- 0.5% of their overall incorporation into glucose (37 +/- 2 and 51 +/- 6 mumol/min, respectively) and 19.0 +/- 3.5 and 1.4 +/- 0.2%, respectively, of overall renal glucose release. Infusion of epinephrine, which increased systemic and renal glucose release more than twofold (P < 0.001), increased overall glutamine and alanine incorporation into glucose (both P < 0.001) and increased renal GN from glutamine (P < 0.001) but not from alanine (P = 0.15). Renal glutamine GN now accounted for 90.3 +/- 4.0% of overall glutamine GN (P = 0.01 vs. basal), whereas renal alanine GN still accounted for only 4.8 +/- 1.7% of overall alanine GN (P = 0.36 vs. basal). With the assumption that kidney and liver are the only gluconeogenic organs in humans, these results indicate that glutamine GN occurs primarily in kidney, whereas alanine GN occurs almost exclusively in liver. Isotopic studies of glutamine and alanine incorporation into plasma glucose may provide a selective, noninvasive method to assess hepatic and renal GN.

Meeting the need. A primary health care model for a community-based/nurse-managed health center.

Long before the World Health Conference at Alma-Ata, when 113 nations agreed to incorporate the concepts and principles of primary health care in their health care systems (World Health Organization [WHO], 1978), nurses were practicing primary health care. Indeed, such care has been practiced since the time of Florence Nightingale. Here, in the United States, the records show that public health nurses were involved in numerous primary health care activities in the early and mid-1900s (Fitzpatrick, 1975).

Steady-state and non-steady-state measurements of plasma glutamine turnover in humans.

To compare steady-state glutamine turnover using nitrogen, carbon, and hydrogen tracers and to test the validity of monocompartmental equations to determine plasma glutamine turnover under non-steady-state conditions, we infused 10 normal postabsorptive volunteers simultaneously with [3,4-3H]glutamine, [2-15N]glutamine, and [U-14C]glutamine for 4 h to isotopic steady state. Eight of the ten subjects were subsequently infused in a stepwise fashion with exogenous glutamine. Plasma glutamine enrichment and specific activities fit a monoexponential model well (r = 0.89, 0.92, and 0.92 for [2-15N]-, [U-14C]-, and [3,4-3H]glutamine, respectively). Volumes of distribution for each tracer (362 +/- 58, 433 +/- 51, and 446 +/- 63 ml/kg) and the transfer rate constants (0.0224 +/- 0.0020, 0.0222 +/- 0.0020, and 0.0240 +/- 0.0023 min(-1)) for [2-15N]-, [U-14C]-, and [3,4-3H]glutamine, respectively, were not significantly different from one another. However, turnover of glutamine determined with [3,4-3H]glutamine (6.14 +/- 0.54 micromol x kg(-1) x min(-1)) exceeded that determined with [U-14C]glutamine (5.72 +/- 0.541 micromol x kg(-1) x min(-1); P < 0.03), which in turn exceeded that determined with [2-15N]glutamine (4.67 +/- 0.39 micromol x kg(-1) x min(-1), P < 0.01). The monocompartmental non-steady-state equations of both DeBodo et al. (DeBodo, R., R. Steele, A. Dunn, and J. Bishop. Rec. Prog. Horm. Res. 19: 445-448, 1963) and Finegood et al. (Finegood, D., R. Bergman, and M. Vranic. Diabetes 36: 914-924, 1987) yielded acceptable approximations of predicted rates of glutamine plasma appearance with deviations from predicted rates from 0.2 to 1.6% (Finegood et al.) and from 0.1 to 8.2% (DeBodo et al.). Use of a 0.75 pool fraction most closely approximated predicted rates.

Recognition of tubo-ovarian abscess in adolescents with pelvic inflammatory disease.

PURPOSE: Ultrasonography of the pelvis is commonly used to diagnose tubo-ovarian abscess (TOA) in patients with pelvic inflammatory disease (PID). Our objective was to determine whether the clinical features of PID differ in adolescents with and without TOA. METHODS: A retrospective design was used to derive and validate a clinical model differentiating adolescents with PID who did and did not have TOA. The study population consisted of hospitalized adolescents with a discharge diagnosis of PID. Of the 208 patients discharged from January 1, 1990, to July 31, 1993, 87 (42%) met published criteria for PID and comprised the derivation set. Of the 63 patients from August 1, 1993, to June 24, 1994, 30 (48%) met criteria and comprised the validation set. All patients had pelvic ultrasonography performed during hospitalization. The ultrasonography records were reviewed retrospectively for TOA, ovarian and uterine size, clarity of tissue planes, and endometrial or cul-de-sac fluid. Medical records were reviewed for sociodemographic characteristics, medical and sexual history, physical examination, laboratory results, and hospital course. RESULTS: TOA was present in 17% of the derivation set and 20% of the validation set. A six-variable model developed on the derivation set performed best in differentiating the TOA and non-TOA groups: last menstrual period > 18 days prior to admission (60% and 17%), previous PID (53% and 22%), palpable adnexal mass (13% and 3%), white blood cell count > or = 10,500/microliters (33% and 64%), erythrocyte sedimentation rate > 15 mm/h (33% and 64%), and heart rate > 90/min (40% and 78%). In the derivation and validation sets, the model correctly identified 78 and 83% of the TOA groups and 88 and 77% of the non-TOA groups. The area under the receiver operating characteristic curve of the model was 0.92 in the derivation set and 0.87 in the validation set. CONCLUSIONS: We conclude that clinical characteristics help identify adolescents with acute PID who have TOA. These patients may have fewer signs of acute illness than those without TOA and may develop symptoms later in the menstrual cycle.

A double-blind, randomized study to provide safety information on switching fluoxetine-treated patients to paroxetine without an intervening washout period.

BACKGROUND: The long elimination half-lives of fluoxetine and norfluoxetine, the active metabolite of fluoxetine, are of potential consequence when alternative antidepressant agents are introduced after the termination of fluoxetine therapy. It is not known whether paroxetine, an antidepressant agent in the same pharmacologic class as fluoxetine, can be substituted for fluoxetine without the need for an intervening washout period. The objective of this trial was to assess the tolerability of an immediate switch from fluoxetine to paroxetine therapy. METHOD: Patients who were treated for moderate to moderately severe major depressive disorder (DSM-III-R 296.2 or 296.3) with a stable dose of fluoxetine for a minimum of 6 weeks' duration were randomized in a double-blind fashion to one of two treatment groups. One group (N = 123) was started on 20 mg of paroxetine daily the morning after their last dose of fluoxetine, and the other group (N = 119) was started on 20 mg of paroxetine daily following a 2-week placebo-washout period. Patient visits were scheduled at weekly intervals for a total of 4 weeks. Adverse experience monitoring was conducted at each visit. RESULTS: There was no difference in the proportion of patients who discontinued prematurely from the trial due to an adverse experience. Eight patients in the immediate-switch group and 6 patients in the placebo-washout group withdrew from the trial in response to an adverse experience (p = .63, chi-square). The overall profile of adverse experiences was similar in the two treatment groups over the 4-week period. The incidence of adverse experiences in the first 2 weeks following the initiation of paroxetine was generally lower in the group with the intervening 2-week placebo-washout period. CONCLUSION: The immediate switch from fluoxetine to paroxetine was as well tolerated as the switch to paroxetine after a 2-week placebo-washout period.

Clinical ladder development: implementing contract learning.

Expanding the clinical ladder concept in nursing at the Presbyterian Hospital in New York prompted the Department of Education, Research, and Development to further implement contract learning as an innovative adult education technique. The process was applied in orienting new Clinical Nurse IIs (experienced nurse preceptors) and Clinical Nurse IIIs (assistants to the Nursing Care Clinicians) to their advanced clinical roles. The process of implementation, the development of learning contracts, and the week-long workshop designed for each of the new clinical leaders is discussed.

Thyrotropin-releasing hormone: an inhibitory regulatory peptide of feline lower esophageal sphincter.

The functional role of thyrotropin-releasing hormone (TRH) at the lower esophageal sphincter (LES) was examined in the cat. The specific aims of this study were to determine: 1) the relative distribution of TRH throughout the feline gastrointestinal tract and 2) the effect of TRH on LES basal pressures and its response to exogenously induced contractions. TRH concentrations were determined by radioimmunoassay in tissue extracts from 12 sites. The mean concentration of TRH at the manometrically determined LES was 240 +/- 85 pg/g wet wt tissue, and the maximal concentration was just distal to the LES (659 +/- 189 pg/g wet wt). TRH concentration was higher in the mucosa than the underlying muscle layer of the fundus, antrum, duodenum, and ileum. In physiological studies, TRH given selectively via the left gastric artery had no effect on basal LES or esophageal pressures. TRH (2.8 x 10(-8) mol/kg) decreased the LES response to the D50 of substance P by 47.2% (34.8 +/- 3.1 to 18.4 +/- 2.9 mmHg, P < 0.01). In the presence of tetrodotoxin, TRH gave a similar inhibition of substance P-induced contractions (53.5%). TRH also decreased bombesin-induced contractions by 47.5% (29.6 +/- 6.0 to 15.8 +/- 3.9 mmHg, P < 0.025). TRH, however, had no effect on bethanechol-induced contractions. We conclude that 1) TRH is present throughout the gastrointestinal tract, with highest concentrations in the region distal to the LES; 2) TRH has no effect on basal LES tone; and 3) TRH inhibits the LES response to endogenously released and exogenous substance P but not the LES response to bethanechol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of hypothyroidism on rat circadian activity and temperature rhythms and their response to light.

Male rats made hypothyroid by administration of propylthiouracil plus sodium ipodate in drinking water were compared to controls in terms of period of circadian activity and temperature rhythms, amount of gross motor activity, and mean temperature. Animals were studied under entrainment, constant darkness (DD), and constant dim light (LL). There was no difference in the period of the circadian activity rhythm between groups in DD. However, hypothyroid rats showed significant blunting of the period-lengthening response to increasing ambient illumination. As expected, the period of the circadian temperature rhythm increased in controls with increasing ambient illumination. In contrast, the period of the circadian temperature rhythm in hypothyroid animals actually shortened under LL compared to DD. This blunting of the period-lengthening response to increasing ambient illumination of both activity and temperature rhythms in hypothyroid animals could not be explained by differences in activity level or mean temperature between the groups.

Thyrotropin-releasing hormone-immunoreactive projections to the dorsal motor nucleus and the nucleus of the solitary tract of the rat.

Thyrotropin-releasing hormone-immunoreactive nerve terminals heavily innervate the dorsal motor nucleus and nucleus of the solitary tract, whereas cell bodies containing thyrotropin-releasing hormone residue most densely in the hypothalamus and raphe nuclei. By using double-labeling techniques accomplished by retrograde transport of Fluoro-Gold following microinjection into the dorsal motor nucleus/nucleus of the solitary tract combined with immunohistochemistry for thyrotropin-releasing hormone, it was demonstrated that thyrotropin-releasing hormone-immunoreactive neurons projecting to the dorsal motor nucleus/nucleus of the solitary tract reside in the nucleus raphe pallidus, nucleus raphe obscurus, and the parapyramidal region of the ventral medulla, but not in the paraventricular nucleus of the hypothalamus. The parapyramidal region includes an area along the ventral surface of the caudal medulla, lateral to the pyramidal tract and inferior olivary nucleus and ventromedial to the lateral reticular nucleus. Varying the position of the Fluoro-Gold injection site revealed a rostral to caudal topographic organization of these raphe and parapyramidal projections.

Destruction of the nucleus raphe obscurus and potentiation of serotonin-mediated behaviors following administration of the neurotoxin 3-acetylpyridine.

Systemic administration of the neurotoxin 3-acetylpyridine (3-AP) to rats produced spontaneous episodes of spasmodic movement involving the trunk and limbs including torticollis, contortions of the trunk and rigid extension of the limbs. Because the neurotransmitter serotonin (5-HT) has been implicated in various human involuntary movement disorders, the functional and anatomical integrity of the 5-HT system in rats treated with 3-AP were examined. 5-HT-containing neurons in the brain stem were studied using immunohistochemical labeling with antiserum to 5-HT. Cells in the nucleus raphe obscurus were found to be altered following 3-AP treatment as shown by a decrease in 5-HT immunoreactivity as compared to control rats. No changes in 5-HT immunoreactivity were observed in any other region containing 5-HT cell bodies. Behaviorally, rats treated with 3-AP were 2.5-fold more sensitive to the ability of the 5-HT1A agonist 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.33-3.3 mg/kg) to produce the 5-HT syndrome. Similarly, 3-AP-treated rats were 2-fold more sensitive to the selective 5-HT2 agonist 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB; 0-1.0 mg/kg) at producing the head shake response. Although these behaviors associated with brain stem 5-HT receptors were potentiated by 3-AP, the hypothermic effect of 8-OH-DPAT which involves ascending mesencephalic 5-HT neurons was unchanged following 3-AP treatment. Treatment with 3-AP did not produce significant alterations of 5-HT or 5-hydroxyindoleacetic acid (5-HIAA) content in any brain region studied. Quantitative autoradiographic analysis of the density of 5-HT1A receptors labeled with [3H]8-OH-DPAT revealed that these sites were unchanged in regions of the brain (frontal cortex, hippocampus and brain stem) and in the spinal cord. Similarly, few changes in the density of 5-HT2 receptors measured with [3H]ketanserin were observed in various brain regions. These results suggest that neurons from the nucleus raphe obscurus are involved in the elicitation of 5-HT-mediated behavioral responses by 5-HT1A and 5-HT2 receptor agonists that are though to be mediated through brain stem and spinal cord mechanisms. In addition, because of the close neuroanatomical relationship of the nucleus raphe obscurus with various brain regions known to be involved in motor control, the destruction of this region by 3-AP may contribute to the spasmodic motor behaviors observed following 3-AP treatment.

Reduction of thyrotropin-releasing hormone concentrations in central nervous system of African lungfish during estivation.

Thyrotropin-releasing hormone (TRH) has been implicated as an important modulator of arousal state in mammals. Changes in the content of TRH in several brain regions accompany hibernation in the ground squirrel. In the present study, the involvement of TRH in the regulation of arousal was further investigated in the African lungfish, Protopterus annectens, which contain high concentrations of TRH throughout its central nervous system and enter a hibernation-like state, estivation. Lungfish were divided into three groups. Group 1 was fed normally, group 2 was starved while aquatic, and group 3 was allowed to enter into a state of estivation. After 3 months, the lungfish were sacrificed and the concentrations of TRH, norepinephrine, dopamine, and serotonin were determined in the telencephalon, diencephalon, medulla, and spinal cord. In estivation, there was a significant decline in the concentration of TRH in the diencephalon, with no alteration in other regions. Starvation had no effect on regional TRH concentrations. The concentration of norepinephrine, dopamine, and serotonin did not change in estivation; however, a significant elevation of norepinephrine in the diencephalon and dopamine in the telencephalon was observed in starvation. Starvation and estivation were associated with significant declines in the protein content of the diencephalon and medulla. The estivation-linked decline in TRH in the diencephalon of the lungfish is similar to the decrease in TRH content in the hypothalamus in hibernating ground squirrels. These findings lend further support to the importance of TRH in the regulation of arousal state.

Systemic administration of kainic acid produces elevations in TRH in rat central nervous system.

Several studies have suggested that the concentration of thyrotropin releasing hormone (TRH) in the central nervous system (CNS) is influenced by the level of CNS activation. Hibernation in the ground squirrel and estivation in the lungfish result in region-specific decreases in TRH concentrations. Repeated electroconvulsive shock (ECS) and amygdaloid kindling have been shown to result in elevations of TRH in limbic brain regions. In the present study, limbic seizures induced by systemic administration of kainic acid resulted in substantial increases in the TRH content of posterior cortex and of dorsal and ventral hippocampus, and in moderate elevations in anterior cortex, amygdala/piriform cortex and corpus striatum. Maximal elevations in TRH were observed 2-4 days after kainic acid administration, and by 14 days TRH levels were similar to control values, with the exception of the dorsal hippocampus, which exhibited more prolonged elevations in TRH levels. Prior exposure to limbic seizure activity attenuated the magnitude of TRH elevation in response to a second administration of kainic acid in the posterior cortex but in no other region. These results indicate that seizure-related processes or events influence TRH systems in the CNS. Neuronal populations involved in limbic seizure induced damage may be involved in the modulation of posterior cortical TRH levels.

Ultrastructural localization of thyrotropin-releasing hormone immunoreactivity in the dorsal vagal complex in rat.

Thyrotropin-releasing hormone-like immunoreactivity (TRH-LI) was localized at the ultrastructural level in the dorsal vagal complex (DVC: dorsal motor nucleus of the vagus (DMV) and the nucleus of the solitary tract (NST] in rat. TRH-LI was concentrated in large granular vesicles in axons, presynaptic terminals, and non-synaptic axon varicosities. TRH-LI presynaptic terminals established both asymmetric and symmetric synaptic contacts with dendrites. These observations are consistent with recently described direct inhibitory and facilitatory effects of TRH on the electrical activity of neurons in the DVC.

TRH and TRH receptors in the spinal cord.

Over the past 12 years, substantial progress has been made in delineating the localization of TRH and TRH receptors in spinal cord. High concentrations of both the peptide and its receptor have been observed in the ventral horn in the region of the motoneurons and in the dorsal horn in the substantia gelatinosa. As noted, pharmacological effects of TRH administration on various parameters of spinal cord function have been reported in a number of studies. To date, however, substantial questions remain regarding the physiological role of TRH in the spinal cord. Nevertheless, it is hoped that the extensive information that has been obtained on localization of TRH and TRH receptors in spinal cord will provide a basis for answering these complex questions.

Characterization of thyrotropin-releasing hormone in the central nervous system of African lungfish.

Central administration of thyrotropin-releasing hormone (TRH) produces potent effects on various physiological parameters, such as arousal, respiration, and cardiovascular function, in several species. As part of an investigation into the evolution of this tripeptide as a central modulator of these parameters, we examined its distribution in the central nervous system of the African lungfish (Protopterus). Lungfish brains were dissected into three regions: telencephalon, diencephalon, and medulla. Each region was assayed for TRH by radioimmunoassay and for norepinephrine, dopamine, and serotonin by HPLC/electrochemical methods. TRH immunoreactivity (IR-TRH) was present in all regions of lungfish brain examined. The telencephalon contained the highest concentrations of TRH, the diencephalon also contained a high concentration of TRH, and the medulla contained a markedly lower concentration. Similar concentration gradients (telencephalon greater than diencephalon greater than medulla) were observed for norepinephrine, dopamine, and serotonin. The identity of IR-TRH as authentic TRH was confirmed by elution profiles on HPLC. The results of this investigation demonstrated that TRH and the monoamine neurotransmitters are present in high concentrations in various regions of lungfish brain. The lungfish may represent a promising model for further studies of the interactions of TRH with these neurotransmitter systems.

Effects of intrabulbar injections of 6-hydroxydopamine on ethyl acetate odor detection in castrate and non-castrate male rats.

The function of norepinephrine-containing neurons which project to the olfactory bulb is poorly understood. Although there has been suggestion that norepinephrine (NE) may modulate general olfactory sensitivity by attenuating the inhibitory feedback of granule cells upon mitral and tufted cells, behavioral indices of olfactory sensitivity have not been measured in animals with depletions of bulbar NE. The present experiment used computerized olfactometry and signal detection methodology to assess the odor detection performance of castrate and non-castrate male rats to a range of perithreshold concentrations of ethyl acetate following 6-hydroxydopamine (6-OHDA) depletion of bulbar NE. Such depletion had no significant influence on odor detection performance at any of the odorant concentrations examined in either castrate or non-castrate animals, as indexed by the non-parametric sensitivity measure SI. This observation implies that general olfactory sensitivity is unaltered by major depletion of intrabulbar NE, but does not preclude the possibility that NE modulates sensitivity to select odorants or odorant mixtures, or alters detection ability under atypical states of arousal.

Reduction of feeding behavior by the serotonin uptake inhibitor sertraline.

Administration of the selective serotonin (5-HT) uptake inhibitor sertraline produced a dose-dependent reduction of food intake in rats. Doses of sertraline of 10 mg/kg or greater reduced the intake of solid pellets significantly (P less than 0.01) during the 1st hour of a 4-h feeding test in rats deprived of food and water for 24 h. Food intake during the remaining 3 h and water intake during the feeding test was unaffected by sertraline. Sertraline (2-18 mg/kg IP) also reduced milk consumption in food-deprived rats. Pretreatment with the nonselective 5-HT antagonists metergoline (2 mg/kg IP) or methysergide (3.3 mg/kg IP) blocked sertraline's inhibition of dry food intake, whereas pretreatment with the selective 5-HT2 receptor antagonist ketanserin (3.3 mg/kg IP) or the peripheral 5-HT2 antagonist xylamidine (2.5 mg/kg IP) failed to block sertraline's anorexic effect. The feeding-suppressant effect of 10 mg/kg sertraline was prevented following the destruction of central 5-HT neurons by the 5-HT neurotoxic agent, 5,7-dihydroxytryptamine (200 micrograms ICV). This result is consistent with sertraline's anorexic effect depending on intact 5-HT neurotransmission. Therefore, sertraline appears to reduce feeding by enhancing the action of endogenous serotonin at central synapses mediated by 5-HT1 rather than 5-HT2 receptors.