AF64A, a cholinergic neurotoxin, selectively depletes acetylcholine in hippocampus and cortex, and produces long-term passive avoidance and radial-arm maze deficits in the rat

The behavioral and biochemical effects of AF64A, a presynaptic cholinergic neurotoxin, were investigated. Bilateral administration of this compound into the lateral cerebral ventricles produced transient and dose-related effects on sensorimotor function and long-term impairments of cognitive behavior. Male Fischer-F344 rats dosed with either 15 or 30 nmol of AF64A reacted 29–62% faster than CSF-injected controls in a hot-plate test 14 (but not 1, 7, 21 or 28) days following dosing. The group administered 15 nmol of AF64A was also significantly more active (41%) than controls 28 days following dosing. The activity level of this group was comparable to that of controls at other times and hyperactivity was never observed in the 30 nmol group. Retention of a step-through passive avoidance task, assessed 35 days after dosing, was impaired in both 15 and the 30 nmol groups. Their step-through latencies were significatlly shorter than the control latencies, and they exhibited more partial entries during the 24-h retention test. Radial-arm maze performance, measured 60–80 days following treatment, was markedly impaired in the treated groups. Animals treated with AF64A made fewer correct responses in their first 8 choices, required more total selections to complete the task, and had an altered pattern of spatial responding in the maze. The neurochemical changes produced by AF64A, determined 120 days after dosing, were specific to the cholinergic system and consisted of decreases of ACh in both the hippocampus (15 and 30 nmol groups) and the frontal cortex (30 nmol group). The concentrations of catecholamines, indoleamines, their metabolites and choline in various brain regions were not affected by AF64A. Furthermore, histological analysis revealed that the doses of AF64A used in the present study did not damage the hippocampus, the fimbria-fornix, the septum or the caudate nucleus. These data support the contention that cholinergic processes in the hippocampus, nd/or frontal cortex play an important role in learning and memory processes. Furthermore, based upon the behavioral and biochemical data presented, it is suggested that AF64A could be a useful pharmacological tool for examining the neurobiological substrates of putative cholinergic disorder such as senile dementia of the Alzheimer's type.     

Effect of pulmonary vein isolation on the relationship between left atrial reverse remodeling and sympathetic nerve activity in patients with atrial fibrillation

Purpose

Catheter ablation (CA) to isolate the pulmonary vein, which is an established treatment for atrial fibrillation (AF), is associated with left atrium reverse remodeling (LARR). The intrinsic cardiac autonomic nervous system includes the ganglion plexi adjacent to the pulmonary vein in the left atrium (LA). However, little is known about the effect of CA on the relationship between LARR and sympathetic nerve activity in patients with AF.

Methods

This study enrolled 22 AF patients with a normal left ventricular ejection fraction (LVEF) aged 64.6?±?12.9 years who were scheduled for CA. Sympathetic nerve activity was evaluated by direct recording of muscle sympathetic nerve activity (MSNA) before and 12 weeks after CA. Blood pressure, heart rate (HR), HR variability, and echocardiography were also measured.

Results

The heart rate increased significantly after CA (63?±?10.9 vs. 70.6?±?7.7 beats/min, p?<?0.01), but blood pressure did not change. A high frequency (HF) and low frequency (LF) of HR variability decreased significantly after ablation, but no significant change in LF/HF was observed. CA significantly decreased MSNA (38.9?±?9.9 vs. 28?±?9.1 bursts/min, p?<?0.01). Moreover, regression analysis revealed a positive correlation between the percentage change in MSNA and the LA volume index (r?=?0.442, p?<?0.05).

Conclusions

Our results show that CA for AF reduced MSNA and the decrease was associated with the LA volume index in AF patients with a normal LVEF. These findings suggest that LARR induced by CA for AF decrease sympathetic nerve activity.

     

Effects of nefiracetam on deficits in active avoidance response and hippocampal cholinergic and monoaminergic dysfunctions induced by AF64A in mice

Summary The effects of nefiracetam [DM-9384; N-(2,6-dimethyl-phenyl)-2-(2-oxo-pyrrolidinyl)acetamide] and of phosphatidylcholine on a step-up active avoidance response, locomotor activities and regional brain cholinergic and monoaminergic neurotransmitters in AF64A-treated mice were investigated. Intracerebroventricular (i.c.v.) injection of AF64A (ethylcholine mustard aziridinium ion; 8 nmol/ventricle) impaired acquisition and retention of the avoidance task, and increased vertical and horizontal locomotor activities. Regional levels of acetylcholine, noradrenaline, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased and homovanillic acid (HVA) levels were increased in the hippocampus but not in the septum, cerebral cortex or striatum of AF64A-treated animals. Administration of nefiracetam (3 mg/kg, p.o.) twice daily for 9 days to AF64A-treated animals ameliorated the deficit in active avoidance response in addition to attenuating the increase in locomotor activities. In parallel with these behavioural effects, nefiracetam reversed AF64A-induced alterations in the hippocampal profiles of cholinergic and monoaminergic neurotransmitters and their metabolites. In contrast, administration of phosphatidylcholine (30 mg/kg, p.o.) twice daily for 9 days had no significant effect on the deficit in active avoidance response, despite significantly reversing the decrease in acetylcholine levels in the hippocampus. These results indicate that the effects of nefiracetam on AF64A-induced behavioural deficits are probably due to its ability to facilitate both cholinergic and monoaminergic neurotransmitter systems.     

Effects of repeated administration of (−)-nicotine on AF64A-induced learning and memory impairment in rats

Summary. It has been reported that pretreatment with (−)-nicotine prevents glutamate- and amyloid beta protein (Aβ)-induced cytotoxicity in vitro. However, few studies on the neuroprotective effects of (−)-nicotine in vivo have been reported. We examined whether repeated administration of (−)-nicotine exhibits neuroprotective effects in AF64A-treated rats. (−)-Nicotine (0.1 and 0.2 mg/kg, s.c.) was administered once a day for 28 days. On day 14, AF64A (2.5 nmol/side) was injected bilaterally into the hippocampus. Intrahippocampal injection of AF64A showed severe impairment of learning and memory in rats in the water maze and passive avoidance tests. Repeated administration of (−)-nicotine (0.1 and 0.2 mg/kg, s.c.) did not reverse the impairment of memory induced by AF64A in the water maze test. Interestingly, the (−)-nicotine (0.1 and 0.2 mg/kg, s.c.)-treated group showed weak impairment of learning and memory after AF64A treatment compared to the (AF64A + saline)-treated group in the passive avoidance test. These results suggested that (−)-nicotine may have neuroprotective effects against the neurotoxicity induced by AF64A. Received March 1, 2001; accepted April 30, 2001     

Induction of cortical cholinergic hypofunction and memory retention deficits through intracortical AF64A infusions

Ethylcholine mustard aziridinium ion (AF64A), an irreversible inhibitor of high-affinity choline uptake on cholinergic nerve terminals, appears to selectively decrease presynaptic cholinergic markers after intracerebral injection. To restrict AF64A's action to cholinergic terminals within the frontoparietal (FP) cortex, the present study utilized multiple-site cortical infusions of the agent. Following an extensive histological analysis, a dose of 1 nmol AF64A/1 microliter was selected for determining AF64A's effects on acetylcholinesterase (AChE) staining, cortical cholinergic/non-cholinergic markers, and passive avoidance behavior. Adult rats given two infusions of AF64A into the right FP cortex had reduced AChE staining throughout 75% of the ipsilateral FP cortex at 10 days following infusion, thus suggesting an extensive cortical diffusion of the agent; minimal non-specific damage was seen (totalling only 4% of the ipsilateral FP cortex for both infusion sites) and no effects on AChE staining were observed in the striatum or hippocampus. Three weeks after bilateral AF64A infusions into the FP cortex (two injections on each side), significant frontal cortex deficits were observed in high-affinity choline uptake, acetylcholine synthesis, acetylcholine release, and hemicholinium-3 binding compared to vehicle-infused controls. However, choline acetyltransferase activity within the anterior cortex did not appear to be consistently affected by AF64A infusion. Cortical glutamic acid decarboxylase activity, as well as cortical monoaminergic markers, and neuropeptide levels were also unaffected. Moreover, animals that received bilateral AF64A infusions and were tested two weeks afterwards showed marked memory retention deficits during both the 24-h and 48-h postshock trials of passive avoidance testing. These results indicate that cortical AF64A infusion induces a specific, long-term cholinergic hypofunction of presynaptic markers within the cortex, resulting in a significant long-term memory impairment. Since the primary cholinergic innervation to the FP cortex, originating in the nucleus basalis of Meynert, appears to become dysfunctional (but not totally degenerative) in Alzheimer's disease, cortical AF64A infusions may closely reflect this cholinergic dysfunction by 'functionally' eliminating cortical cholinergic terminals.     

Alanine transaminase is predominantly increased in the active phase of anti-HMGCR myopathy

Autoantibodies against 3?hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and the signal recognition particle (SRP) are representative antibodies causing immune-mediated necrotizing myopathies (IMNM), called as anti-HMGCR and anti-SRP myopathies, respectively. Here, we analyzed the differences in routine blood test results between 56 anti-HMGCR and 77 anti-SRP myopathy patients. A higher alanine transaminase (ALT) level and a lower aspartate transaminase (AST)/ALT ratio were observed in anti-HMGCR myopathy patients [ALT, 265.7 ± 213.3 U/L (mean ± standard deviation); AST/ALT ratio, 0.88 ± 0.32] than in anti-SRP-myopathy patients (ALT, 179.3 ± 111.2 U/L, p < 0.05; AST/ALT ratio, 1.28 ± 0.40, p < 0.01). In the active phase, anti-HMGCR myopathy often showed ALT predominance, whereas anti-SRP myopathy often showed AST predominance. In addition, there were differences in erythrocyte sedimentation rate (ESR), total cholesterol (TChol) level, and high-density lipoprotein (HDL) level between anti-HMGCR and anti-SRP myopathies (ESR: HMGCR, 24.4 ± 20.8 mm/1 h; SRP, 35.7 ± 26.7 mm/1 h, p = 0.0334; TChol: HMGCR, 226.7 ± 36.6 mg/dL; SRP, 207.6 ± 40.8 mg/dL, p = 0.0163; HDL: HMGCR, 58.4 ± 13.9 mg/dL; SRP, 46.2 ± 17.3 mg/dL, p < 0.01). Additional studies on the differences in routine blood test results may further reveal the pathomechanisms of IMNM.     

Chronic epigallocatechin-3-gallate ameliorates learning and memory deficits in diabetic rats via modulation of nitric oxide and oxidative stress

Due to anti-diabetic and antioxidant activity of green tea epigallocatechin gallate (EGCG) and the existence of evidence for its beneficial effect on cognition and memory, this research study was conducted to evaluate, for the first time, the efficacy of chronic EGCG on alleviation of learning and memory deficits in streptozotocin (STZ)-diabetic rats. Male Wistar rats were divided into control, diabetic, EGCG-treated-control and -diabetic groups. EGCG was administered at a dose of 20 and 40 mg/kg/day for 7 weeks. Learning and memory was evaluated using Y maze, passive avoidance, and radial 8-arm maze (RAM) tests. Oxidative stress markers and involvement of nitric oxide system were also evaluated. Alternation score of the diabetic rats in Y maze was lower than that of control and a significant impairment was observed in retention and recall in passive avoidance test (p < 0.01) and EGCG treatment (40 mg/kg) of diabetic rats significantly improved these parameters (p < 0.05). Also, diabetic animals exhibited fewer correct choices (p < 0.01) and more errors (p < 0.005) in the RAM task and EGCG (40 mg/kg) significantly ameliorated these changes (p < 0.05). Further, pretreatment with l-arginine as a substrate for nitric oxide synthase (NOS) and/or 7-nitroindazole as a neuronal NOS inhibitor attenuated and potentiated the beneficial effect of EGCG regarding learning and memory respectively. Meanwhile, increased levels of malondialdehyde (MDA) and nitrite in diabetic rats significantly reduced due to EGCG treatment (p < 0.05). In summary, chronic green tea EGCG dose-dependently could ameliorate learning and memory deficits in STZ-diabetic rats through attenuation of oxidative stress and modulation of NO.     

Protein kinase C activity in permanent focal cerebral ischemia

Protein kinase C (PKC) activity was investigated in a model of focal stroke in the rat. Following 6 h of left middle cerebral artery occlusion, rat brains were frozenin situ. In the peripheral ischemic zone, total PKC activity declined by close to two-thirds (1.07±0.35 vs 2.77±0.12 nmol/min/mg protein;p<0.05,n=4), and the proportion of total activity associated with the particulate fraction decreased from 33.3±1.5% to 16.2±1.4% (p<0.01,n=4). Thus, overall particulate PKC activity in the ischemic zone was <20% of control. The cerebral energy metabolite profile of tissue from the ipsilateral hemisphere, corresponding to the region where samples were obtained for PKC activity assay, suggests that this tissue may have been part of the ischemic penumbra before further deterioration.     

Increased activity of tyrosine hydroxylase in the cerebellum of the X-irradiated dystonic rat

The exposure of the cephalic end of rats to repeated doses of X-irradiation (150 rad) immediately after birth induces a long-term increase in the noradrenaline (NA), content of cerebellum (CE) (+37.8%), and a decrease in cerebellar weight (65.2% of controls), which results in an increased NA concentration (+109%). This increase in the neurotransmitter level is accompanied by a dystonic syndrome and histological abnormalities: Purkinje cells (the target cells for NA afferents to CE) fail to arrange in a characteristic monolayer, and their primary dendritic tree appears randomly oriented. The injection of reserpine 0.9 and 1.2 mg/kg ip to adult rats for 18 h depletes cerebellar NA content in both controls (15.7±4 ng/CE and 2.8±1.5 ng/CE, respectively) and X-irradiated rats (17.1±1 ng/CE and 8.3±2 ng/CE, respectively). The activity of tyrosine hydroxylase (TH) in CE of adult rats, measured by an in vitro assay, is significantly increased in neonatally X-irradiated animals when compared to agematched controls (16.4±1.4 vs 6.32±0.6 nmol CO₂/h/mg prot.,p<0.01). As observed for NA levels, a net increase in TH activity induced by the ionizing radiation is also measured: 308.9±23.8 vs 408.2±21.5 nmol CO₂/h/CE,p<0.01 (controls and X-treated, respectively). These results suggest that X-irradiation at birth may induce an abnormal sprouting of noradrenergic afferents to CE. The possibility that these changes represent a response of the NA system to the dystonic syndrome is discussed.     

AF64A(ethylcholine aziridinium ion)-induced basal forebrain lesion impairs maze performance

Rats were given bilateral injections of ethylcholine aziridinium ion, AF64A (1 nmol/side) into the basal forebrain (BF). One month later, choline acetyltransferase activity was reduced by 25% in the frontal cortex (FC). There was a marked decrease in cortical uptake of [3H]choline, but [3H]GABA and [3H]dopamine uptake was not affected by the injection. Histological analysis confirmed that this dose of AF64A caused acetylcholinesterase staining in the FC to disappear. Acquisition and retention of a T-maze task were impaired in the rats with BF lesions one month after the injection. Acquisition of the water-filled multiple T-maze task was also impaired by AF64A. These observations suggest that the cholinergic component in the BF is involved in spatial memory.     

Effect of hyperbaric oxygen on prostaglandin and thromboxane synthesis in the cortex and the striatum of rat brain

The effect of a previous exposure to hyperbaric oxygen (HBO) on the synthesis capacity of prostaglandin (PG) and thromboxane (TX) was investigated in the brain of male rats. Three groups of rats were used:

1. Neurotoxic HBO (n = 11): The rats were exposed to sixfold the atmospheric pressure (101.3 kPa), i.e., 6 absolute atmospheres (ATA), of pure O₂ up to the first convulsion (6 ATA O₂);
2. Mild hyperoxia (n = 10): The rats were exposed to compressed air at the same absolute pressure and for a similar time than that of the neurotoxic HBO group (here PO₂ is 1.26 ATA);
3. Normoxia at atmospheric pressure (PO₂ is 0.21 ATA) for control.

There was no convulsion in groups 2 and 3. Decompression of the high pressure groups lasted 15 min. After decapitation, samples of the frontal cortex and the striatum were taken, weighed, washed, and then incubated in Krebs-Ringer bicarbonate for 1 h. The release of eicosanoids in the medium was determined by enzyme immunoassay. Mild hyperoxia only significantly reduced in the striatum the release of 6-keto-PGF1α (1.3±2.4 vs 10.9±6.6 pg/mg wet tissue,p< 0.001; mean±SD) and PGE₂ (3.2±2.7 vs 7.8±6.5 pg/mg wet tissue,p< 0.05), whereas TXB2 did not change. Neurotoxic hyperoxia reduced significantly in both cortex and striatum the release of 6-keto-PGF1α (8.7±5.1 vs 29.3±13.0,p< 0.001 and 3.2±4.3 vs 10.9±6.6,p< 0.01 respectively) and PGE₂ (8.3± 5.8 vs 15.2± 6.4,p < 0.05 and 3.1± 2.9 vs 7.8±6.5,p< 0.05 respectively) without affecting TXB2 release. These inactivations could be related to reactive oxygen species (ROS) induced by HBO. Taking into account the known sensitivities to ROS of the enzymes of the eicosanoid cascade, the effects of HBO on PGs could be related to a hyperoxic deactivation of PGI synthase in striatum, beginning with nonneurotoxic hyperoxia with a possible associated deactivation of PGE synthase activity in both cortex and striatum in hyperbaric neurotoxic hyperoxia. The decrease in 6-keto-PGF1α reflecting the decrease in prostacyclin could lead to vasoconstriction (which in turn decreased local oxygen partial pressure) and also to platelet aggregation, since TXB₂ was not affected in the process. As this inactivation began well before the neurotoxicity threshold of HBO, the following changes in eicosanoids may therefore take some non-specific part in the HBO-induced brain damage.     

Septal choline acetyltransferase immunoreactive neurons: dose-dependent effects of AF64A

Two experiments were performed. In the first, the cholinotoxin, AF64A (0.5, 1.0 or 1.5 nmol/ventricle), or vehicle (3.0 microliters) was injected (ICV) bilaterally into male rats (n = 23). Choline acetyltransferase (ChAT) immunoreactive (IR) perikarya in the four subgroups of the septal complex were visualized by immunocytochemistry (PAP method) 28 days postinjection, and counted using a microprojector (x40). The 0.5 nmol/ventricle dose of AF64A significantly reduced (31%) the number of ChAT-IR cell bodies in the intermediate subgroup (rostral extension of the nucleus basalis/substantia innominata). Higher doses did not produce additional reductions. The highest dose (1.5 nmol/ventricle) of AF64A resulted in significant decreases in ChAT-IR cell bodies in the dorsal (51%) and midline (35%) subgroups (medial septum), but did not affect the number of ventral subgroup (diagonal band of Broca) ChAT-IR neurons. In the second experiment, electrolytic lesions were placed in the corpus callosum, cingulum and overlying cingulate gyrus, in order to simulate the nonselective damage seen following the 1.5 nmol/ventricle dose of AF64A. In comparison to the surgical controls (n = 3), the electrolytic lesions (n = 6) failed to significantly affect the number of ChAT-IR perikarya in any of the septal subdivisions. Thus the distinct subgroups of septal ChAT-IR neurons are differentially sensitive to the toxic effects of ICV administered AF64A: intermediate much greater than dorsal greater than midline much greater than ventral subgroup.     

Behavioral effects of dehydroepiandrosterone in adult male rats

It is well-documented that dehydroepiandrosterone (DHEA) exhibits various behavioral effects in rodents, at least one of which is modulation of learning/memory processes in several test paradigms. However, little is known about the influence of DHEA on cognitive performance in the adult rodents. This work was designed to determine whether chronic DHEA administration during 10 days in the high (0.7 mg/kg, s.c.) or low (0.1 mg/kg, s.c.) doses has any effect on learning/memory abilities and behavior in the adult male rats (5- to 6-month old). Effect of DHEA was estimated in active and passive avoidance tasks, behavior was registered in the elevated "plus" maze and the "open field" test. DHEA in the high dose significantly (p<0.05) increased time spent and the number of enterings in the "open" arms of the elevated "plus" maze in intact male rats as compared with the control rats. DHEA in the low dose significantly (p<0.05) decreased horizontal and vertical locomotor activity and grooming behavior, whereas DHEA in the high dose did not significantly modify behavior in intact rats as compared with control group. Results of the ANOVA on passive avoidance performance revealed no statistically significant differences among the groups receiving DHEA in the high or low doses as compared to the control. However, DHEA in the low dose significantly (p<0.05) reduced the number of correct avoidance responses in intact rats as compared to the control rats, while in rats treated with the high dose DHEA, the active avoidance performance did not differ significantly from the control. Thus, chronic DHEA administration has a modulatory action on the learning and behavior of the adult male rats.     

Regional changes of polyamine profiles after reversible cerebral ischemia in mongolian gerbils: Effects of nimodipine and barbiturate

The present experiments were undertaken to study whether the therapeutic inhibition of ischemic cell injury affects the postischemic disturbances in polyamine metabolism. Near complete forebrain ischemia was produced in Mongolian gerbils (Meriones unguiculatus) by occluding both common carotid arteries. Gerbils were subjected to 5 min cerebral ischemia and then immediately upon recirculation injected intraperitoneally with nimodipine (1.5 mg/kg;n=5) or pentobarbital (50 mg/kg;n=5). Untreated animals received the nimodipine vehicle whilst sham-operated animals served as controls. Following 96 h recirculation animals were reanesthetized and brains were frozen in liquid nitrogen. Polyamines (putrescine, spermidine, and spermine) were measured in samples (2–4 mg each) taken from the cerebral cortex and the CA1-subfield of the hippocampus. In addition, 10 μm thick coronal sections were prepared from the level of the dorsal hippocampus to determine histologically the extent of ischemic neuronal damage; this was quantified in the CA1-subfield of the hippocampus by counting the number of total and viable neurons/mm stratum pyramidale.

In untreated animals reversible cerebral ischemia produced a significant increase in putrescine and a decrease in spermine in the CA1-subfield of the hippocampus (increase in putrescine from 11.3±0.6 to 41.8±3.6 nmol/g,p<0.01; and decrease in spermine from 351±26 to 161±16 nmol/g,p<0.05). Spermidine, in contrast, did not change during recirculation in the hippocampus. In the cerebral cortex postischemic polyamine levels were not significantly different from those found in control animals. In all untreated animals subjected to reversible cerebral ischemia severe cell necrosis could be observed in the CA1-subfield of the hippocampus. It proved possible to inhibit significantly both ischemia-induced disturbances of polyamine metabolism and ischemic cell injury in the CA1-subfield of the hippocampus by barbiturate treatment (p<0.05). The effect of nimodipine on ischemic cell injury and ischemia-induced changes of polyamine levels was not significant. In all experimental animals the putrescine levels in the CA1-sector of the hippocampus correlated with the extent of ischemic cell damage in a threshold relationship: in animals in which the putrescine levels lay below 15 nmol/g less than 5% of neurons were damaged, whereas in animals with putrescine levels above 25 nmol/g only about 5% of neurons in the stratum pyramidale survived the 5 min cerebral ischemic period. We conclude that putrescine may be viewed as an important biochemical correlate of ischemic cell injury.

     

Behavioral differences in the developing rat following postnatal anoxia or postnatally injected AF-64A, a cholinergic neurotoxin

Rat pups were submitted postnatally to one of two procedures: a 25-min exposure to 100% nitrogen or an i.c.v. bilateral injection of AF-64A, 2 nmol contained in 1-microliter saline. Throughout further development of either group, their performance in passive and active avoidance tests and in amphetamine-induced stereotype behavior was followed and compared. Both groups exhibited hyperactivity which persisted until 42 days of age in the anoxia group and beyond 120 days in the AF-64A group. Both groups were equally inferior to controls in the passive avoidance test, but only the anoxia group was inferior to controls in the active avoidance test. Amphetamine-induced stereotype behavior was much less pronounced in the anoxia group relative to AF-64A-treated rats or to controls. The results suggest that the lesion induced by the neurotoxin is more specific and less widespread than the one caused by anoxia.     

Impact of Oral Antipsychotic Medication Adherence on Healthcare Resource Utilization Among Schizophrenia Patients with Medicare Coverage

Nonadherence to antipsychotic medications is widespread and compromises the outcome of patients with schizophrenia. Using the MarketScan Medicare claims database, this study examined the impact of medication adherence on healthcare utilization among Medicare insured schizophrenia patients. The study population was separated into two cohorts defined by medication adherence, one with a medication possession ratio (MPR) ≥0.7 (high adherence) and the other with a MPR <0.7(low adherence). Of the 354 patients identified, 126 (36 %) had high adherence (mean ± SD MPR 0.94 ± 0.09) and 228 (64 %) had low adherence (MPR 0.24 ± 0.19). All cause hospitalizations (0.68 vs. 0.44; p = 0.015) and length of stay (LOS) (7.0 vs. 2.6 days; p = 0.005), and relapse hospitalizations (0.22 vs. 0.11; p = 0.028) and LOS (3.2 vs. 0.7 days; p = 0.027) were greater among patients with low adherence. Low adherent Medicare insured patients with schizophrenia require significantly more inpatient care and represent a patient population in which effective interventions are needed to improve disease management.     

Validation of a novel sleep-quality questionnaire to assess sleep in the coronary care unit: a polysomnography study

IntroductionThe sleep of patients admitted to coronary care unit (CCU) may be compromised. A feasible and cost-effective tool to evaluate sleep in this scenario could provide important data. The aim of this study was to evaluate sleep with a questionnaire developed specifically for the CCU and to validate it with polysomnography (PSG).MethodsNinety-nine patients (68% male; 56 ± 10 years old) with acute coronary syndrome were included. PSG was performed within 36 h of admission. A specific 18-question questionnaire (CCU questionnaire) was developed and applied after the PSG. Cronbach's alpha test was used to validate the questionnaire. The Spearman test was used to analyze the correlation between the PSG variables and the questionnaire, and the Kruskal–Wallis test was used to compare the PSG variables among patients with good, regular, or poor sleep.ResultsThe total sleep time was 265 ± 81 min, sleep efficiency 62 ± 18%, REM sleep 10 ± 7%, apnea/hypopnea index 15 ± 23, and the arousal index 24 ± 15. Cronbach's alpha test was 0.69. The CCU questionnaire showed correlation with the sleep efficiency evaluated by PSG (r: 0.52; p < 0.001). Sleep quality was divided into three categories according to the CCU questionnaire: patients with good sleep had a sleep efficiency of 72 ± 9%, better than those with a regular or poor sleep (60 ± 16% and 53 ± 20%, respectively; p < 0.01).ConclusionThe CCU questionnaire is a feasible and reliable tool to evaluate sleep in the CCU, showing correlation with the PSG sleep efficiency.     

Obesity may be the common pathway for sleep-disordered breathing in women with polycystic ovary syndrome

ObjectivePolycystic ovary syndrome (PCOS) is one of the most common endocrinological disorders in women of reproductive age, and is characterized by hyperandrogenism. It is associated with long-term metabolic dysfunctions including sleep-disordered breathing (SDB). We hypothesized that the increased prevalence of SDB in PCOS results from raised testosterone levels.MethodsThis was a prospective, cross-sectional, case–control study in which 50 case patients with untreated PCOS and 100 control subjects were included. All the case patients and control subjects went through a detailed clinical, biochemical, and hormonal evaluation. Overnight polysomnography was performed in all case patients and the snorers (16 of 100) in the control group.ResultsSDB was seen in 66% of the case patients and in 4% of control group with (odds ratio [OR] = 46.5, 95% confidence interval [CI] = 14.6–148.4; p <0.001). After adjustment for body mass index (BMI) and waist circumference (WC), the difference was not significant (p = 0.993 and p = 0.931, respectively). The SDB patients with PCOS showed significantly higher respiratory distress index (RDI) values than SDB patients in the control group (22.5 ± 21.5 vs 9.0 ± 5.6, p = 0.01). On the Epworth Sleepiness Scale the PCOS case patients reported feeling more sleepy than did the control subjects (12.5 ± 3.2 vs 9.32 ± 1.7, p <0.001). Free testosterone levels were also significantly higher in the PCOS group than in the control subjects (2.95 ± 3.44 vs 1.5 ± 1.0, p <0.001). There was a significant correlation between free testosterone level and RDI values (r = 0.377; p = 0.007), WC (r = 0.315; p = 0.026), and BMI (r = 0.398; p = 0.004). A significant correlation of WC (r = 0.551; p <0.001) and BMI (r = 0.572; p <0.001) was observed with RDI.ConclusionTestosterone-induced obesity is probably the common pathway for the development of SDB in PCOS.     

Noradrenaline depletion protects cholinergic neurons in rat hippocampus against AF64A-induced damage

The role of the noradrenergic system in the cholinotoxicity of ethylcholine aziridinium ion (AF64A) was studied in rats. Male Sprague-Dawley rats were treated with the noradrenergic neurotoxin DSP-4 (N-(2-chloroethyl)-n-ethyl-2-bromobenzylamine; 50 mg/kg i.p.) in the presence of the serotonin uptake inhibitor fluoxetine, 14 days prior to bilateral intracerebroventricular injection of AF64A (2 nmol/lateral ventricle). In rats in which noradrenaline (NA) was depleted by 94%, the loss of acetylcholine (ACh) in hippocampus induced by AF64A was significantly attenuated (p less than 0.02). However, when there was only a partial depletion of NA (50% reduction), the AF64A-induced loss of ACh was a pronounced as in rats with intact noradrenergic function. These findings indicate that the noradrenergic lesion has to be complete before a protective effect is apparent. Moreover, they imply that noradrenergic input is involved in AF64A-induced cholinergic damage in the hippocampus.     

Effect of acute saline volume loading on renal sympathetic nerve activity in anaesthetised fructose-fed and fat-fed rats

Experiments were conducted to investigate the effects of activation of cardiopulmonary vagal afferent nerve endings by acute saline volume expansion on sympathetic efferent renal nerve activity in anaesthetised fat-fed and fructose-fed Wistar rats. Four weeks of fat feeding caused obesity in the Wistar rats which was associated with a mild elevation in blood pressure (118±4 mmHg vs. 105±1 mmHg in the lean control rats, P<0.05). Fructose feeding in Wistar rats for 4 weeks also elicited an elevation of blood pressure (113±4 mmHg, P<0.05) and plasma glucose levels (6.3±0.3 mmol/l vs. 4.0±0.3 mmol/l lean control rats, P<0.01). The fat-fed rats displayed a higher basal renal sympathetic nerve activity (RSNA) value when compared with the lean rats (3.9±0.4 mV/s vs. 2.8±0.4 mV/s, P<0.05) whereas the RSNA levels were similar in all the other rat groups. The power spectral analysis of RSNA showed the basal values of percentage power at heart rate frequency were significantly higher in Wistars fed ad lib (P<0.01), rats fed on fructose for 2 or 4 weeks (P<0.01 and P<0.05, respectively) and fat-fed rats (P<0.01) when compared to the lean diet-controlled rats. Acute volume expansion (10% body wt) over 40 min caused efferent renal sympatho-inhibition in all the animal groups. The pattern and magnitude of response in MAP, RSNA, and power spectral analysis parameters to the volume expansion were similar in the lean control rats, the Wistar and fructose fed rats but was greater in the fat-fed rats (P<0.05) as compared to the lean control rat. The profile of the reduction in percentage power at heart rate frequency to volume expansion was greater (P<0.05) in the fat-fed rat than in the lean control rats. The present data demonstrates that the reflex efferent renal sympatho-inhibition to volume expansion was impaired in the diet-induced obese rat but not in the fructose fed rats. This suggests that a defect in the neuro-humoral regulation of kidney control of extracellular fluid volume is present which may contribute to the mild hypertension in the obese rat.