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Background: Caregivers of stroke survivors often suffer depressive symptoms that interfere with their own health. Early recognition may lead to attenuation of symptoms and better health and well-being for caregivers. Objective: We examined characteristics of caregivers and stroke survivors associated with caregivers’ depressive symptoms in the early poststroke period. Methods: We conducted a prospective, longitudinal exploratory observational study with a convenience sample of 63 caregivers of older adult (≥ 65 years) stroke survivors recruited from urban acute-care settings. We enrolled caregivers by 2 weeks poststroke (T1) and revisited them 4 weeks later (T2). Depressive symptoms were measured using the Patient Health Questionnaire-9. A separate unadjusted linear mixed model was computed to explore significant associations between each caregiver or stroke-survivor characteristic and depressive symptoms. Results: Caregivers, on average, reported mild depressive symptoms at T1 and T2. Each of the following characteristics was independently associated with caregiver depressive symptoms over the first 6 weeks poststroke: caregiver uncertainty (p p p = 0.858 on waking, p = 0.231 evening), coping (p p = 0.006), race (p = 0.022), income (p = 0.001), time spent on care (p = 0.039), and stroke-survivor race (p = 0.033) and functional status (p = 0.003). At T2, caregiver depressive symptoms were correlated with evening cortisol level (p = 0.001). Conclusions: Caregiver and stroke-survivor characteristics may help identify caregivers at highest risk for early depressive symptoms and guide interventions aimed at their resolution.

Caregivers' stress following a family member's stroke is likely accentuated by its associated uncertainty. The purpose of the current study was to examine the effect of uncertainty on caregivers' perceived and physiological stress (i.e., salivary cortisol). A prospective, longitudinal observational study was conducted with a convenience sample of 40 caregivers and stroke survivors recruited from acute care settings. Linear mixed models were used. Greater uncertainty was associated with higher perceived stress ( p < 0.001), but not with physiological stress ( p = 0.32 on waking, p = 0.06 evening), over the first 6 weeks post-stroke. A significant association between uncertainty and evening salivary cortisol level was found at 6 weeks post-stroke ( p = 0.009). Recognition of uncertainty early in the caregiving period and targeted interventions may be useful in reducing perceived stress for this group. [ Journal of Gerontological Nursing, 43 (11), 30–40.]

Studies show that self-care improves diabetes mellitus (DM) outcomes; however, previous studies have focused on self-care maintenance, and little is known about self-care management. The objective of this study is to examine the influence of DM self-care maintenance and management on number of hospitalizations and hospitalization days. A cohort design with secondary analysis of data from the Health and Retirement Study 2002-2004 was used. Data from 726 adults with DM were analyzed with logistic regression and negative binomial regression adjusting for covariates. Self-care maintenance and management were significant determinants of hospitalization outcomes. Establishing a goal for HbA1c (self-care management) and eating ≥2 snacks or desserts per day (self-care maintenance) were associated with a decrease in hospitalizations (IRR = 0.860, p = .001; IRR = 0.914, p = .043, respectively). DM self-care maintenance and management influence health outcomes but in different ways. These data provide evidence that both elements are needed in the education of patients about DM.

Neurohormonal activation is a commonly cited array of phenomena in the body's physiologic response to heart failure. Although various neurohormones and pharmacologic agents that moderate their pathophysiologic effects have been reviewed in the nursing literature, both the mechanisms of neurohormonal system activation and cellular and organ system effects have been described only in brief. Accordingly, this article reviews mechanisms of neurohormonal activation and describes cellular and cardiovascular effects of the (1) sympathetic nervous system, (2) renin-angiotensin-aldosterone system, (3) kallikrein-kininogen-kinin system, (4) vasopressinergic system, (5) natriuretic peptide systems, and (6) endothelin in the context of heart failure. This article implicitly details the physiologic basis for numerous current and potential future pharmacologic agents used in the management of heart failure. It is intended that this article be used as a reference for advanced clinical nursing practice, research, and education.

Academic health centers are strategically positioned to impact the health of lesbian, gay, bisexual and transgender (LGBT) populations by advancing science, educating future generations of providers, and delivering integrated care that addresses the unique health needs of the LGBT community. This report describes the early experiences of the Penn Medicine Program for LGBT Health, highlighting the favorable environment that led to its creation, the mission and structure of the Program, strategic planning process used to set priorities and establish collaborations, and the reception and early successes of the Program.

Caregivers of stroke survivors experience high rates of mental and physical morbidity. Stroke has sudden onset, and the outcome is not immediately known. Uncertainties surrounding the new caregiving role may not only necessitate major changes in the lives of family caregivers but also contribute to negative health outcomes for the caregiver.The purposes of this study were to describe caregiver uncertainty across the early weeks after a family member's stroke and to explore characteristics of caregivers and stroke survivors associated with that uncertainty.A prospective, longitudinal exploratory observational study was conducted with a convenience sample of 40 caregivers and older adult (≥65 years) stroke survivors recruited from urban acute care settings in the mid-Atlantic region. Caregivers were enrolled by 2 weeks poststroke (T1) and revisited 4 weeks later (T2). Uncertainty was measured usingthe Mishel Uncertainty in Illness Scale for Family Members. An unadjusted linear mixed model was computed to examine significant associations between each caregiver or stroke survivor characteristic and repeated measures of uncertainty.Uncertainty at T1 (83.73 ± 23.47) was higher than reported in other caregiver populations and remained high 6 weeks poststroke (T2: 85.23 ± 23.94). Each of the following characteristics was independently associated with greater caregiver uncertainty: caregivers' older age (p = .019), being a spouse (p = .01), higher stress (p.001), more depressive symptoms (p = .001), more comorbidities (p = .035), and poorer coping capacity (p = .002) and stroke survivors' recurrent stroke (p = .034), poorer functional status (p = .009), and insurance type (p = .008).Caregivers experienced persistently high uncertainty during the first 6 weeks poststroke. Better understanding of uncertainty, its associated characteristics, and its outcomes may help clinicians identify caregivers at highest risk who may benefit from targeted interventions.

Hypoglycemia resulting from excess of exogenous or endogenous insulin elicits central nervous system activation that contributes to counterregulatory hormone secretion. In adult humans without diabetes, hypoglycemia occurring during sleep usually produces cortical activation with awakening. However, in adult humans with type 1 diabetes, hypoglycemic arousal appears blunted or absent. We hypothesized that insulin injection sufficient to produce hypoglycemia would induce awakening in adult male rats. Polysomnographic studies were carried out to characterize the effect of insulin injection on measures of sleep and waking during a circadian time of increased sleep. Compared to a baseline day, insulin treatment more than doubled the time spent awake, from 18.4 ± 2.6% after saline injection to 48.0 ± 5.5% after insulin. Insulin injection also reduced rapid eye movement sleep (REMS) from 27.3 ± 1.8% to 5.6 ± 1.3%. The percent of time in non-REM sleep (NREMS) sleep was not different between saline and insulin days, however, NREMS after insulin was fragmented, with increased number and decreased duration of episodes. These electrophysiological data indicate that insulin-induced hypoglycemia is an arousing stimulus in rats, as in nondiabetic adult humans. We also studied the effect of insulin on activation of selected arousal-related neurons using immunohistochemical detection of Fos. Fos-immunoreactivity increased in orexin (OX) neurons after insulin, from 8.7 ± 4.9% after saline injection to 37 ± 9% after insulin. Basal forebrain cholinergic nuclei also showed increased Fos-immunoreactivity after insulin. These correlated behavioral and histological data provide targets for future studies of the neural pathways underlying hypoglycemic arousal.

Many women complain of difficulty maintaining euglycemia during the luteal phase of the menstrual cycle. This pilot study's objective was to evaluate possible differences in insulin sensitivity between follicular and luteal phases in women with type 1 diabetes.Women using insulin infusion pumps (n = 5, mean age 29.2 +/- 10.9 years, mean body mass index 24 +/- 1.8 kg/m(2)) underwent frequently sampled intravenous glucose tolerance tests during each cycle phase. Insulin sensitivity and glucose effectiveness were determined by Minimal Model analysis.Non-insulin-mediated glucose disposal increased during the luteal phase (0.009 +/- 0.004 min(1)) versus the follicular phase (0.005 +/- 0.003 min(1)) (P0.05). Although no significant differences were found in mean insulin sensitivity between follicular (0.76 +/- 0.27 x 10(4)/min(1) /microU/mL) and luteal phase (0.58 +/- 0.26 x 10(4)/min(1) /microU/ mL), three of the five subjects had a decline in insulin sensitivity.Elevated blood glucose during the luteal phase may increase insulin-independent glucose disposal. Some individuals appear more responsive to menstrual cycle effects on insulin sensitivity. Women should be encouraged to use available self-monitoring technology to identify possible cyclical variations in blood glucose that might require clinician review and insulin dosage adjustments.

Insulin resistance is a component of several health disorders, most notably impaired glucose tolerance and type 2 diabetes mellitus. Insulin-resistant individuals have an impaired biological response to the usual action of insulin; that is, they have reduced insulin sensitivity. Various methods are used to assess insulin sensitivity both in individuals and in study populations. Validity, reproducibility, cost, and degree of subject burden are important factors for both clinicians and researchers to consider when weighing the merits of a particular method. This article describes several in vivo methods used to assess insulin sensitivity and presents the advantages and disadvantages of each.

To improve outcomes for patients with many serious clinical problems, multifactorial research approaches by nurse scientists, including the use of animal models, are necessary. Animal models serve as analogies for clinical problems seen in humans and must meet certain criteria, including validity and reliability, to be useful in moving research efforts forward. This article describes research considerations in the development of rodent models. As the standard of diabetes care evolves to emphasize intensive insulin therapy, rates of severe hypoglycemia are increasing among patients with type 1 and type 2 diabetes mellitus. A consequence of this change in clinical practice is an increase in rates of two hypoglycemia-related diabetes complications: hypoglycemia-associated autonomic failure (HAAF) and resulting hypoglycemia unawareness. Work on an animal model of HAAF is in an early developmental stage, with several labs reporting different approaches to model this complication of type 1 diabetes mellitus. This emerging model serves as an example illustrating how evaluation of validity and reliability is critically important at each stage of developing and testing animal models to support inquiry into human disease.

Adaptation to infectious diseases or models of infectious diseases such as immune stimulation with exogenous administration of bacterial lipopolysaccharide (LPS) or cytokines involve complex autonomic, endocrine, and behavioral responses mediated by the central nervous system. The purpose of this study is to determine the neural pathways from the brainstem activating the central nucleus of the amygdala after LPS injections in rats. Fos immunohistochemistry was performed as a marker of neuronal activation in rats prepared with injections of the retrograde tracing agents Fluorogold or cholera toxin B subunit directed at the central nucleus of the amygdala, and subsequently treated with intravenous LPS. The dose of LPS was titrated to achieve behavioral suppression (“sickness behavior”) and fever, while avoiding hypotension and shock. Low-dose LPS induced Fos in central amygdala afferent neurons in the periaqueductal gray, lateral parabrachial nucleus, and solitary nucleus, as indicated by neurons containing both Fos and retrograde tracing agent. The lateral parabrachial nucleus had approximately 10-fold higher numbers of double-labeled cells than the solitary nucleus and periaqueductal gray; 95% of the double-labeled neurons in the lateral parabrachial nucleus were located in the outer zone of the external lateral subnucleus. These results suggest that a prominent source of limbic activation from the brainstem after LPS involves a restricted subdivision of the lateral parabrachial nucleus.

Caregiving for stroke survivors is a known risk factor for morbidity and mortality. Little has been reported on caregiving in the early poststroke period, a time when uncertainty is probably at its highest. Uncertainty has been related to poor health outcomes in other populations. In the early poststroke period caregivers may be uncertain about the potential for recovery and their sudden assumption of the new caregiver role, but factors affecting uncertainty in these caregivers are not known. Methods: We conducted a prospective, longitudinal observational study and recruited 40 caregivers (68% female, mean age 58±14.22 years, 60% children) and their stroke-survivor relatives (38% male, mean age 76±7.80 years) from acute care settings in the northeastern US. We measured caregivers’ uncertainty using the Perception of Uncertainty in Illness Scale for Family Members (range: 31-155, higher scores: greater uncertainty) and collected caregiver and stroke-survivor sociodemographic, clinical and response characteristics (e.g., coping capacity, caregiver comorbidity, social support, severity of stroke and stroke-survivor functional status and comorbidity) by self-report and chart abstraction. Multivariate stepwise regression was used to examine factors affecting uncertainty within 2 weeks following stroke (T1) and at 6 weeks poststroke (T2). Results: Uncertainty was high in caregivers at both time points (T1: 83.73±23.47, T2: 85.23±23.94). Caregiver older age ( p = 0.001 at T1 and T2) and lower coping capacity ( p < 0.001 at T1 and T2) at both time points and stroke-survivor lower functional status at T1 ( p = 0.047) were associated with greater caregiver uncertainty. Conclusions: Caregivers experience persistently high uncertainty during the first 6 weeks poststroke. Caregiver age and coping capacity and stroke-survivor functional status may help identify stroke-survivor caregivers at highest risk for early uncertainty. These caregivers may be in the greatest need of interventions.

The acetylcholinesterase inhibitor neostigmine (2 microg) was microinjected into the lateral cerebral ventricle (i.c.v.) of unanesthetized rats to activate central cholinergic receptors. Changes in arterial blood pressure were correlated with changes in Fos-like immunoreactivity in the hypothalamus and forebrain following cholinergic stimulation. Neostigmine increased mean arterial pressure by 39 +/- 3 mmHg at peak (P0.05) from a pretreatment level of 104 +/- 4 mmHg. Blood pressure remained elevated for more than 30 min. Distinct Fos-like immunoreactivity was found in the posterior hypothalamic nucleus, the paraventricular nucleus and the supraoptic nucleus of the hypothalamus, the ventral premamillary nucleus, the central nucleus of amygdala, the lateral septum and the medial preoptic area. In contrast, only a very small amount of Fos-like immunoreactivity was scattered in those regions in a control group injected i.c.v. with saline. Pretreatment with the muscarinic receptor antagonist methylatropine (i.c.v., 0.5 microg) prevented the pressor response to neostigmine and evoked a reduced Fos-like immunoreactivity compared to animals given neostigmine without methylatropine. The pressor response to neostigmine was blocked after pretreatment with phenoxybenzamine, however, this did not prevent the development of Fos-like immunoreactivity. These results indicate that the pressor response induced by central cholinergic stimulation may result from muscarinic receptor activation in specific regions of the hypothalamus and the forebrain that are implicated in regulating cardiovascular activity.

The distribution and time course of Fos expression in neurons in the central nucleus of the amygdala (CeA) were studied in endotoxemic rats in two separate experiments. In each case, the severity of the endotoxin (lipopolysaccharide; LPS) challenge was characterized by using physiological outcome variables, including blood pressure and heart rate. Throughout the rostrocaudal extent of the CeA, extensive Fos staining was found 3 hours after injection with a hypotensive dose of Salmonella enteritidis LPS. Hypotension alone has been reported to induce Fos in the CeA; therefore, the remaining experiments were performed by using a lower dose of Escherichia coli LPS that did not cause hypotension. The nonhypotensive dose of E. coli LPS also induced Fos in large numbers of neurons of the CeA, with peak staining at 2 hours and Fos staining persisting for 6 hours after LPS injection. Tachycardia and fever after LPS also persisted for at least 6 hours. CeA Fos staining during nonhypotensive endotoxemia was predominantly located in the lateral subnucleus, although Fos-stained medial subnucleus neurons were also present. Additional forebrain regions that showed persistent Fos staining 6 hours after LPS included the parvocellular paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the medial preoptic area. Forebrain regions that contained Fos-stained nuclei at earlier time points, but not at 6 hours, included the supraoptic nucleus, magnocellular regions of the paraventricular nucleus of the hypothalamus, the subfornical organ, and the organum vasculosum of the lamina terminalis. Few CeA neurons showed Fos staining in rats that were restrained in a ventilated plastic tube. Neurons in the lateral septal nucleus and the medial amygdaloid nucleus, which have numerous Fos-stained nuclei after stressors such as footshock or restraint, did not show Fos staining above control levels after LPS administration. Activation of CeA neurons after intravenous LPS may indicate persistent drive from vagal afferents and may implicate the CeA in the autonomic, neuroendocrine, and/or behavioral responses to this treatment. J. Comp. Neurol. 379:592–602, 1997. © 1997 Wiley-Liss, Inc.

Background: Self-care is believed to improve heart failure ( HF ) outcomes, but the mechanisms by which such improvement occurs remain unclear. Methods: We completed a secondary analysis of cross-sectional data collected on adults with symptomatic HF to test our hypothesis that effective self-care is associated with less myocardial stress and systemic inflammation. Multivariate logistic regression modeling was used to determine if better HF self-care reduced the odds of having serum levels of amino-terminal pro-B-type natriuretic peptide and soluble tumor necrosis factor [alpha] receptor type 1 at or greater than the sample median. Heart failure self-care was measured using the Self-care of Heart Failure Index. Results: The sample ( n = 168 ) was predominantly male ( 65.5% ), and most ( 50.6% ) had New York Heart Association III HF ( mean left ventricular ejection fraction, 34.9% [SD, 14.0%] ); mean age was 58.8 ( SD, 11.5 ) years. Self-care management was an independent factor in the model ( block [chi]2 = 14.74; P = .005 ) after controlling for pertinent confounders ( model [chi]2 = 52.15; P < .001 ). Each 1-point increase in self-care management score ( range, 15-100 ) was associated with a 12.7% reduction in the odds of having levels of both biomarkers at or greater than the sample median ( adjusted odds ratio, 0.873; 95% confidence interval, 0.77-0.99; P = .03 ). Conclusion: Better self-care management was associated with reduced odds of myocardial stress and systemic inflammation over and above pharmacological therapy and other common confounding factors. Teaching HF patients early symptom recognition and self-care of symptoms may decrease myocardial stress and systemic inflammation.

Lapses in self-care are commonly cited as a major cause of poor outcomes in persons with heart failure (HF). Not surprisingly, self-care is assumed to be central to improving health outcomes in this patient population. Empirically, however, this assumption is not well supported, and mechanistically, relationships between self-care and outcomes in HF have not yet been described. In this review, it is proposed that effective self-care maintenance (adherence) and self-care management (symptom evaluation and management) practices are complementary to optimal medical management in delaying HF progression and improving health outcomes in this population. Potential mechanisms through which effective HF self-care practices are complementary to pharmacological therapy in improving outcomes include (a) facilitating partial blockade and partial deactivation of deleterious neurohormones, (b) limiting inflammatory processes, (c) decreasing the need for administration of detrimental pharmacological agents, and (d) minimizing myocardial hibernation. Because these mechanisms are hypothetical, research findings are required to establish their validity. Several strategic research questions are proposed.

The objective of this pilot study was to evaluate possible differences in insulin sensitivity, food intake, and cravings between the follicular and luteal phases of the menstrual cycle in women with premenstrual syndrome (PMS).Subjects were screened for PMS using the Penn Daily Symptom Rating (DSR) scale. Each subject had two overnight admissions (once in each cycle phase) to the Hospital of the University of Pennsylvania. They performed 3-day diet histories prior to each hospitalization. After admission, subjects received dinner and a snack, then were fasted until morning, when they underwent a frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity was determined by Minimal Model analysis. Blinded analysis of diet histories and inpatient food intake was performed by a registered dietitian.There was no difference found in insulin sensitivity between cycle phases (n = 7). There were also no differences in proportions of macronutrients or total kilocalories by cycle phase, despite a marked difference in food cravings between cycle phase, with increased food cravings noted in the luteal phase (p = 0.002). Total DSR symptom scores decreased from a mean of 186 (+/-29.0) in the luteal phase to 16.6 (+/-14.2) in the follicular phase. Women in this study consumed relatively high proportions of carbohydrates (55%-64%) in both cycle phases measured.These findings reinforce the suggestion that although the symptom complaints of PMS are primarily confined to the luteal phase, the neuroendocrine background for this disorder may be consistent across menstrual cycle phases.

To determine the degree to which increased sympathetic activity contributes to the increase in renin secretion produced by a low sodium diet, the β-adrenergic blocking drug propranolol or saline vehicle was injected through indwelling jugular cannulas in rats fed a normal diet and rats fed a low sodium diet for 9 days. Plasma renin activity (PRA) and plasma renin concentration (PRC) were elevated by the low sodium diet, and these values were reduced 42–45% by propranolol, although they were still higher than in the normal diet controls. Plasma corticosterone was moderately elevated in cannulated rats on regular diet, compared to decapitated controls, but corticosterone did not differ between cannulated and decapitated rats on low salt diet; propranolol reduced plasma corticosterone. However, PRA and PRC were comparable in cannulated rats and decapitated controls on both the normal and the low sodium diets, and propranolol did not produce a significant reduction in PRA and PRC in rats fed the normal diet. This indicates that the effects of propranolol on PRA and PRC in the low sodium rats were not simply due to reduction of a stress-induced increase in renin secretion. The results indicate that increased sympathetic activity makes a substantial contribution to the increase in renin secretion produced by 9 days of dietary sodium restriction.

Background Despite advances in management, heart failure is associated with high rates of hospitalization, poor quality of life, and early death. Education intended to improve patients' abilities to care for themselves is an integral component of disease management programs. True self-care requires that patients make decisions about symptoms, but the cognitive deficits documented in 30% to 50% of the heart failure population may make daily decision making challenging. After describing heart failure self-care as a naturalistic decision making process, we explore cognitive deficits known to exist in persons with heart failure. Problems in heart failure self-care are analyzed in relation to neural alterations associated with heart failure. As a neural process, decision making has been traced to regions of the prefrontal cortex, the same areas that are affected by ischemia, infarction, and hypoxemia in heart failure. Resulting deficits in memory, attention, and executive function may impair the perception and interpretation of early symptoms and reasoning and, thereby, delay early treatment implementation. Conclusions There is compelling evidence that the neural processes critical to decision making are located in the same structures that are affected by heart failure. Because self-care requires the cognitive ability to learn, perceive, interpret, and respond, research is needed to discern how neural deficits affects these abilities, decision-making, and self-care behaviors.

Intensive insulin therapy in patients with type 1 diabetes mellitus reduces long-term complications; however, intensive therapy is also associated with a three-fold increase in hypoglycemic episodes. The present study in conscious rats characterizes the physiologic and neuropathologic consequences of a single episode of moderate hypoglycemia. In this model, intravenous insulin is used to reduce plasma glucose to 30 to 35 mg/dL for 75mins. This single hypoglycemic insult acutely induces hypoglycemia-associated autonomic failure (HAAF), with epinephrine responses to hypoglycemia reduced more than 36% from control. Neuropathology after this insult includes the appearance of dying cells, assessed with the marker Fluoro-jade B (FJ). After hypoglycemic insult, FJ+ cells were consistently seen in subdivisions of the medial prefrontal cortex, the orbital cortex, and the piriform cortex. There was a significant correlation between depth of hypoglycemia and number of FJ+ cells, suggesting that there is a critical threshold below which vulnerable cells begin to die. These data suggest that there is a population of cells that are vulnerable to moderate levels of hypoglycemia commonly experienced by patients with insulin-treated diabetes. These cells, which may be neurons, are primarily found in cortical regions implicated in visceral perception and autonomic control, raising the possibility that their loss contributes to clinically reported deficits in autonomic and perceptual responses to hypoglycemia.

Posttraumatic hyperthermia (PTH) is a noninfectious elevation in body temperature that negatively influences outcome after traumatic brain injury (TBI). We sought to (1) characterize a clinically relevant model and (2) investigate potential cellular mechanisms of PTH. In study I, body temperature patterns were analyzed for 1 week in male rats after severe lateral fluid percussion (FP) brain injury ( n=75) or sham injury ( n=17). After injury, 27% of surviving animals experienced PTH, while 69% experienced acute hypothermia with a slow return to baseline. A profound blunting or loss of circadian rhythmicity (CR) that persisted up to 5 days after injury was experienced by 75% of brain-injured animals. At 2 and 7 days after injury, patterns of cell loss and inflammation were assessed in selected brain thermoregulatory and circadian centers. Significant cell loss was not observed, but PTH was associated with inflammatory changes in the hypothalamic paraventricular nucleus (PVN) by one week after injury. In brain-injured animals with altered CR, reactive astrocytes were bilaterally localized in the suprachiasmatic nucleus (SCN) and the PVN. Occasional IL-1 β+/ED-1+ macrophages/microglia were observed in the PVN and SCN exclusively in brain-injured animals developing PTH. In animals with PTH there was a significant positive correlation ( r=0.788, P

Hypoglycemia-associated autonomic failure (HAAF) is a complication of recurrent hypoglycemia in patients with diabetes. The present experiments were performed to study the contribution of brain glucose-sensitive structures to HAAF. In conscious rats, brain glucoprivation was elicited by injection of 2 deoxy- d -glucose (2-DG) into the third cerebral ventricle (intracerebroventricular, ICV), while controls received saline ICV. Two days after ICV injection, hormone responses to systemic hypoglycemic challenge were measured. The epinephrine response 60 min after insulin injection was reduced by 46% in rats treated with prior ICV 2-DG, relative to saline-treated controls (SAL: 10,050±970 pg/ml; 2-DG: 5590±880 pg/ml). Thus, the adrenomedullary response to sustained hypoglycemia is attenuated after prior brain glucoprivation induced by intracerebroventricular injection of 2-DG. These data support the hypothesis that the brain contributes to the loss of responsiveness to repeated hypoglycemia that may ultimately result in HAAF.

Background: Long-term anticoagulation therapy with warfarin is recommended for LVAD patients. Compared to other warfarin-treated patients, the LVAD population has a higher rate of suboptimal INRs and a lower average time in the therapeutic window. Suboptimal anticoagulation is a major reason for hospital readmission. We describe our experience with the use of half-dose enoxaparin (0.5 mg/kg/dose) bridging therapy, as a potential alternative to hospital readmission for LVAD-patients with subtherapeutic INRs who may be at higher risk of thrombotic events. Methods: LVAD outpatients with sub-therapeutic INRs were selected to receive half therapeutic dose enoxaparin as bridge therapy based on our VAD anticoagulation protocol. Selection criteria included current INR, VAD type and timing of implantation, history of bleeding or thrombotic events, renal function, medication adherence, and ability to effectively administer enoxaparin injections. The general threshold for bridging was an INR ! 1.6. Enoxaparin was dosed as 0.5 mg/kg every 12 hours. Outpatient INR monitoring and follow-up was conducted by the VAD Coordinator and pharmacist. Within 24 hours of initiation of therapy, a pharmacist telephoned the patient to reinforce proper administration technique and to answer medication-specific questions. Additional telephone communications were conducted by the pharmacist and VAD Coordinator to assess for bleeding complications and duration of therapy. Patients are monitored routinely for thrombus at each ambulatory clinic visit. Results: During the initial 6 months of this program, 15 patients (11 HeartMate II, 3 HeartWare LVAD, 1 Heartware BiVad) were treated with half-dose enoxaparin. The mean INR upon initiation of therapy was 1.4 (range 1.2 to 1.7). Patients received an average of 7.2 enoxaparin doses (range 4 to 14) for a mean duration of therapy of 3.5 days (range 2 to 7). In total, 108 doses were administered accounting for 54 patient days of therapy. No patient was admitted to a hospital due to bleeding or thrombotic events. Minor bleeding, described as mild bleeding at the injection site and increased bruising, was reported in 5 patients (30%). During the observation period, 14 patients (93.3%) completed the protocol with achievement of a therapeutic INR; one patient discontinued therapy due to hospital admission not related to anticoagulation management. Conclusion: In this small series, half-dose enoxaparin appears to be a feasible strategy to bridge selected ambulatory VAD patients with sub-therapeutic INRs. Further investigation is needed to determine its safety and efficacy in a larger population of patients

Immunocytochemical detection of Fos protein was used to evaluate the activation of neurons in sympathetic preganglionic regions of rat spinal cord after systemic treatment with endotoxin. Administration of relatively low doses of bacterial lipopolysaccharide (LPS) to conscious rats caused transient hypotension and stress hormone elevation. Three hours after LPS injection, Fos protein was detected in large numbers of neurons throughout the thoracic spinal cord. Fos-immunoreactive neurons were found in spinal cord segments T3–T13 in the four sympathetic preganglionic nuclei: the intermediolateral cell column (77.7%), the intercalated nucleus (10.6%), the central autonomic nucleus (10.1%) and the lateral funiculus (1.5%). These regions in control animals showed no Fos staining. We conclude that sublethal endotoxemia is a potent stimulus causing Fos expression in sympathetic preganglionic regions.

In previous studies we found that plasma angiotensinogen levels were reduced by lesions of the hypothalamic paraventricular nuclei. To determine if the decrease was caused by decreased secretion of hormones that normally stimulate angiotensinogen secretion by the liver, we correlated the changes in plasma angiotensinogen produced by paraventricular lesions with changes in plasma LH, ACTH, and thyroid hormones; compared the changes in plasma angiotensinogen and other hormones to those produced by hypophysectomy; and determined the effects of treatment with ACTH and T4 in animals with paraventricular lesions. In male Sprague-Dawley rats, bilateral lesions destroying more than 50% of the paraventricular nuclei decreased plasma angiotensinogen to 787 +/- 52 ng angiotensin-I/ml in 7 days compared to 1576 +/- 142 ng angiotensin-I/ml in sham-operated controls. Plasma T3 and T4 were also reduced, whereas there were no statistically significant changes in plasma ACTH or LH. Hypophysectomy produced a comparable decline in plasma angiotensinogen and thyroid hormone levels. Daily administration of a single dose of ACTH had no effect on plasma angiotensinogen in rats with paraventricular lesions, but T4 treatment restored plasma angiotensinogen to normal levels. The data indicate that the decline in circulating angiotensinogen produced by lesions of the paraventricular nuclei is caused by the decrease in the secretion of thyroid hormones produced by these lesions. They also demonstrate that in addition to regulating circulating renin via the sympathetic nervous system, the brain has an effect on circulating angiotensinogen via neuroendocrine control of thyroid function.

1. Excitability properties of afferent axons and terminal regions in frog dorsal roots (DR) and spinal cords in vitro were investigated by antidromic activation from three sites--the root, the entry zone (dorsal white matter or DW), and deep within the dorsal horn (DH)--while recordings were made from the DR. 2. Two approaches were used to assess physiological differences between telodendria and trunk axons. Rheobases and strength-duration time constants (tau sd) of single DR fibers were measured by stimulation in the DH or in the DW. Conduction velocity was estimated on the basis of onset latencies of evoked spikes (the time from stimulation to action potential arrival at the recording electrodes). Population supernormality was evaluated on the basis of responses to conditioned and unconditioned submaximal stimuli delivered to the DH or to the proximal end of isolated DRs. 3. Single-fiber action potentials occurred at longer latencies after DH stimulation than after DW stimulation. Estimated intraspinal conduction velocity was congruent to 0.6 m/s. Extraspinal conduction velocity in these fibers averaged 22.2 m/s. Average tau sd was longer in the DH than in the DW (670 microseconds vs. 204 microseconds). 4. DH and DR test responses evoked 10-150 ms after a conditioning stimulus had increased areas relative to unconditioned test responses. Conditioning-associated changes in evoked responses were greater with the DH stimulation site than with the DR stimulation site, and these changes were not altered by treatment designed to block synaptic transmission. 5. We conclude that membrane properties determining tau sd differ between large afferent axons and fine terminal regions of those axons.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The effects of potassium channel blockade on afferent axons and terminal regions in frog dorsal roots and spinal cords, respectively, were investigated in vitro. 2. A condition-test (C-T) protocol was used to assess the population relative refractory period. Characteristics of main axons were evaluated by stimulation at the proximal end of transected dorsal roots (DR). Characteristics of terminal regions were tested by stimulation at the base of the dorsal horn (DH). 3. DH recovery of excitability was delayed by low concentrations of 4-aminopyridine (4-AP) and tetraethylammonium (TEA) alone or combined. The same treatments did not affect recovery to DR stimulation. 4. DH recovery of excitability was not delayed by solutions suppressing terminal calcium influx. 5. We conclude that sensitivity of the relative refractory period to potassium channel blocking agents differs between main axons and axon terminal regions. This may indicate differences between axon terminals and main axons in the mechanism of action potential repolarization. 6. We hypothesize that rapid action potential repolarization by pharmacologically sensitive potassium channels in presynaptic terminal regions keeps terminal action potentials short. Terminal action potential brevity would limit calcium influx, thus preventing terminal calcium overload but contributing to transmission failures at spinal synapses.