Interleukin (IL)-1 and IL-6 regulation of neural progenitor cell proliferation with hippocampal injury: differential regulatory pathways in the subgranular zone (SGZ) of the adolescent and mature mouse brain.

Current data suggests an association between elevations in interleukin 1 (IL-1)α, IL-1ß, and IL-6 and the proliferation of neural progenitor cells (NPCs) following brain injury. A limited amount of work implicates changes in these pro-inflammatory responses with diminished NPC proliferation observed as a function of aging. In the current study, adolescent (21day-old) and 1year-old CD-1 male mice were injected with trimethyltin (TMT, 2.3mg/kg, i.p.) to produce acute apoptosis of hippocampal dentate granule cells. In this model, fewer 5-bromo-2'-deoxyuridine (BrdU)+ NPC were observed in both naive and injured adult hippocampus as compared to the corresponding number seen in adolescent mice. At 48h post-TMT, a similar level of neuronal death was observed across ages, yet activated ameboid microglia were observed in the adolescent and hypertrophic process-bearing microglia in the adult. IL-1α mRNA levels were elevated in the adolescent hippocampus; IL-6 mRNA levels were elevated in the adult. In subgranular zone (SGZ) isolated by laser-capture microdissection, IL-1ß was detected but not elevated by TMT, IL-1a was elevated at both ages, while IL-6 was elevated only in the adult. Naïve NPCs isolated from the hippocampus expressed transcripts for IL-1R1, IL-6Rα, and gp130 with significantly higher levels of IL-6Rα mRNA in the adult. In vitro, IL-1α (150pg/ml) stimulated proliferation of adolescent NPCs; IL-6 (10ng/ml) inhibited proliferation of adolescent and adult NPCs. Microarray analysis of SGZ post-TMT indicated a prominence of IL-1a/IL-1R1 signaling in the adolescent and IL-6/gp130 signaling in the adult.

The relative contribution of efflux and target gene mutations to fluoroquinolone resistance in recent clinical isolates of Pseudomonas aeruginosa.

The clinical utility of fluoroquinolones (FQs) for the treatment of Pseudomonas aeruginosa (PA) and other serious Gram-negative infections is currently decreasing due to the rapid emergence of resistance. Because previous studies have shown that efflux is a common mechanism contributing to FQ resistance in PA, one suggested approach to extend the longevity of this class of drugs is combination therapy with an efflux pump inhibitor (EPI). In order to determine the viability of this approach, it is necessary to understand the relative contribution of efflux- vs. target-mediated mechanisms of FQ resistance in the clinic. A set of 26 recent PA clinical isolates were characterized for antibiotic resistance profiles, efflux pump expression, topoisomerase mutations, and FQ susceptibility with and without an EPI. The contribution of OprM to the overall antibiotic resistance was assessed in a subset of these strains. Our results suggest that the co-administration of an EPI with FQs or other antibiotics currently in use would not be sufficient to combat the complexity of resistance mechanisms now present in many clinical isolates.

Destabilizing effects of mental stress on ventricular arrhythmias in patients with implantable cardioverter-defibrillators.

BACKGROUND: The incidence of sudden cardiac death increases in populations who experience disasters such as earthquakes. The physiological link between psychological stress and sudden death is unknown; one mechanism may be the direct effects of sympathetic arousal on arrhythmias. To determine whether mental stress alters the induction, rate, or termination of ventricular arrhythmias, we performed noninvasive programmed stimulation (NIPS) in patients with defibrillators and ventricular tachycardia (VT), which is known to be inducible and terminated by antitachycardia pacing, at rest and during varying states of mental arousal. METHODS AND RESULTS: Eighteen patients underwent NIPS in the resting-awake state (nonsedated). Ten underwent repeat testing during mental stress (mental arithmetic and anger recall). Induced VT was faster in 5 patients (P=0.03). VT became more difficult to terminate in 5 patients during mental stress; 4 required a shock (P=0.03). There was no change in ease of induction with mental stress. There was no evidence of ischemia on ECG or continuous ejection fraction monitoring. Eight patients received a shock in the resting-awake state and did not perform mental stress. Four underwent repeat NIPS after sedation; 3 then had induced VT terminated with antitachycardia pacing. All patients with an increase in norepinephrine of >50% had alterations in VT that required shock for termination (P<0.01). CONCLUSIONS: Mental stress alters VT cycle length and termination without evidence of ischemia. This suggests that mental stress may lead to sudden death through the facilitation of lethal ventricular arrhythmias.

Failure to improve left ventricular function after coronary revascularization for ischemic cardiomyopathy is not associated with worse outcome.

Background-Preoperative identification of viable myocardium in patients with ischemic cardiomyopathy is considered important because CABG can result in recovery of left ventricular (LV) function. However, the hypothesis that lack of improvement of LV function after CABG is associated with poorer patient outcome is untested. Methods and Results-Outcome was compared in patients with ischemic LV dysfunction (LVEF 0.05 increase in LVEF (group A) and 36 (35%) had no significant change, or

Genetic susceptibility to the development of retinopathy in insulin-dependent diabetics.

HLA types and blood glucose control were investigated in 127 insulin-dependent diabetics with different grades of severity of retinopathy. The means of all afternoon clinic blood glucose levels from the diagnosis of diabetes were 9.9 +/- 2.1 mmol/L for patients with no retinopathy, 11.8 +/- 2.1 mmol/L for patients with background retinopathy, and 12.4 +/- 2.1 mmol/L for patients with proliferative retinopathy (P less than 0.0001). HLA-DR4 was present in 61 of 87 patients (70%) with background or proliferative retinopathy and 21 of 39 (54%) with no retinopathy. The frequency of HLA-DR4 was lowest in patients with no retinopathy despite "poor control" (mean blood glucose greater than or equal to 11.5 mmol/L) and highest in those who had developed retinopathy despite "good control;" the frequencies of HLA-DR2 showed the reverse pattern. Mantel-Haenszel tests were used to calculate the odds ratios for the presence of retinopathy associated with "poor control" and with HLA-DR4, since each modified the effect of the other. The odds ratio for retinopathy associated with "poor control" was 6.7 (P less than 0.0001). The odds ratio with HLA-DR4 was 3.7 (P less than 0.005). When both risk factors were present, the odds ratio increased to 33.3 (P less than 0.0001). Genetically determined factors appear to influence susceptibility to retinopathy in insulin-dependent diabetics.

Rapid self-terminating ventricular tachycardia induced during electrophysiologic study: a prospective evaluation.

The clinical significance of rapid self-terminating ventricular tachycardia induced during electrophysiologic study was prospectively evaluated in three patient groups with clinical ventricular arrhythmias. Group A (11 patients) had inducible rapid self-terminating ventricular tachycardia only (mean cycle length less than or equal to 250 ms and greater than or equal to 10 beats in duration). In Group B (22 patients) induction of this arrhythmia was followed by the induction of sustained ventricular tachycardia. In Group C (82 patients) sustained ventricular tachycardia was induced without preceding rapid self-terminating ventricular tachycardia. All clinical characteristics of Group B patients were similar to those of Group C patients but differed markedly from those of Group A patients. Compared with Group A patients, Group B patients had a lower left ventricular ejection fraction (32 +/- 13% versus 52 +/- 17%, p = 0.004) and a greater prevalence of coronary artery disease (82% versus 0%, p less than 0.0001), structural heart disease and a history of clinical sustained ventrical arrhythmias. Similarly, the induced self-terminating ventricular tachycardia differed in Group A and Group B patients. The arrhythmias in Group B patients were more often monomorphic, were more often induced with one or two extrastimuli and had a longer cycle length than those in Group A patients. In Group B patients, the electrophysiologic characteristics of the self-terminating and the sustained induced ventricular tachycardias were similar. Cardioversion was required in 50% of Group B patients compared with 27% of Group C patients (p = 0.038).(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic effects of thrombolytic therapy in patients with a transmural anterior myocardial infarction complicated by left ventricular aneurysm formation.

To assess the effects of early thrombolytic therapy on the incidence of clinical and induced ventricular arrhythmias in high risk postmyocardial infarction patients, 32 patients with a transmural anterior myocardial infarction complicated by left ventricular aneurysm formation were prospectively evaluated. Sixteen patients (Group A) received routine care because of contraindication to thrombolytic therapy or other factors and 16 (Group B) received either tissue plasminogen activator or streptokinase within 6 h of the onset of chest pain. The two groups were similar in left ventricular ejection fraction (mean +/- SD, 28 +/- 9% [Group A] versus 30 +/- 8% [Group B]) and occurrence of spontaneous nonsustained ventricular tachycardia, new bundle branch block and congestive heart failure. Group B patients had higher peak creatine kinase MB levels (446 +/- 336 versus 205 +/- 120 IU; p = 0.017) and earlier time to peak creatine kinase values (13.4 +/- 6.6 versus 19.1 +/- 6.1 h; p = 0.006). Twenty patients who had no clinical sustained ventricular arrhythmias underwent electrophysiologic study 13 +/- 6 days after infarction. Ventricular tachycardia was induced during the study in 7 (88%) of 8 Group A patients, but in only 1 (8%) of 12 Group B patients given thrombolytic therapy (p = 0.0008). During a mean follow-up period of 11 +/- 8 months, eight Group A patients (50%) died suddenly or were resuscitated from sustained ventricular tachycardia; all Group B patients are alive and have had no clinical arrhythmic events (p = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Double sequential external shocks for refractory ventricular fibrillation.

OBJECTIVES: A technique for terminating refractory ventricular fibrillation is described. BACKGROUND: Refractory ventricular fibrillation can occur in up to 0.1% of electrophysiologic studies. Animal studies have shown that rapid sequential shocks may reduce ventricular fibrillation threshold. METHODS: Five patients of 2,990 consecutive patients in a 3-year period experienced refractory ventricular fibrillation during 5,450 routine electrophysiologic studies. Multiple shocks were delivered by means of a single defibrillator. Double sequential shocks were delivered externally 0.5 to 4.5 s apart by means of two defibrillators with separate pairs of electrodes. RESULTS: In all patients, standard defibrillation was unsuccessful, but all were successfully resuscitated using the double sequential shocks. CONCLUSIONS: This report stresses the importance of an additional defibrillator being readily available during electrophysiologic testing. This technique of rapid, double sequential external shocks may have general applicability, providing a simple and potentially lifesaving approach to refractory ventricular fibrillation.

Nutrient-responsive promoter elements of the V4 gene of Dictyostelium discoideum.

Expression of the V4 gene of Dictyostelium discoideum is required for the transition from growth to development in response to an altered nutrient environment. In addition, the expression itself is sensitive to the types and amounts of nutrients supporting growth. We describe the structure of the two copies of the V4 gene and the relationship between these genes and the two V4 mRNA species produced during growth. In addition, three regions were identified within the upstream sequences of the V4b gene that are important for proper transcription. At least two of the regions can, independently of the others, confer deactivation of transcription upon initiation of development and thus serve as redundant regulatory sequences. However, the regions are differentially responsive to the types and amounts of nutrients present in the cell's environment and thus are distinct from one another.

Situational panic attacks. Behavioral, physiologic, and biochemical characterization.

To investigate the pathophysiology of nonpharmacologically induced panic attacks, 18 drug-free agoraphobic patients and 13 matched healthy subjects underwent structured exposure to phobic situations. Heart rate, blood pressure, and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG), cortisol, growth hormone, and prolactin levels were measured before, during, and after exposure. Fifteen patients experienced situational panic attacks during exposure. Panicking patients displayed significantly greater increases in heart rate but not blood pressure or plasma free MHPG or cortisol in comparison with the healthy subjects. Growth hormone and prolactin responses tended to be smaller in the patients. If brain noradrenergic hyperactivity occurs during situational panic attacks, it may be too brief or too restricted in regional localization to affect MHPG levels in plasma. Chronically recurrent attacks may cause an adaptation of neuroendocrine mechanisms activated by anxiety or stress.

Early carotid endarterectomy for critical carotid artery stenosis after thrombolysis therapy in acute ischemic stroke in the middle cerebral artery.

BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) has been shown to be effective for acute ischemic stroke. However, if a high-grade cervical carotid stenosis remains despite tPA therapy, patients are at risk for recurrent stroke. Carotid endarterectomy (CEA) has been shown to be effective in symptomatic patients with high-grade cervical carotid stenosis in reducing the risk of stroke, but it is unknown whether CEA can be performed safely after tPA thrombolysis. We describe our experience with 5 patients who underwent early (<48 hours) CEA for residual high-grade cervical carotid stenosis after thrombolytic therapy for acute ischemic stroke in the middle cerebral artery territory. METHODS: All patients had a critical (>99%) carotid artery stenosis on the symptomatic side after tPA therapy. All patients received intravenous tPA; 3 patients also received intra-aortic tPA. Three patients received intravenous heparin infusion immediately after administration of tPA. All patients showed marked improvement in their National Institutes for Health Stroke Scale scores after treatment with tPA. CEA was then performed within 45 hours (6 hours in 1 patient, 23 hours in 2, 26 hours in 1, and 45 hours in 1). RESULTS: All 5 patients underwent successful CEA. There were no complications related to surgery. At discharge, 2 patients had a normal examination, and the remaining patients had mild deficits. In a long-term follow-up of 5 to 22 months, no patient had a recurrent cerebrovascular event. CONCLUSIONS: Early CEA can be performed safely and successfully in patients after tPA treatment for acute ischemic stroke in appropriately selected patients.

Day-to-day reproducibility of responses to right ventricular programmed electrical stimulation: implications for serial drug testing.

The day-to-day reproducibility of responses to right ventricular programmed electrical stimulation was analyzed in 77 patients studied in the baseline state twice within 72 hours. Of 66 in whom ventricular tachycardia (VT) was inducible at the first study (C1), VT was reproduced in 53 (80%) at the second control study (C2). Among 41 patients in whom VT was inducible using 1 or 2 programmed electrical stimuli (PES) at C1, VT remained inducible in 39 (95%) at C2, whereas only 14 of 25 patients (56%) who required 3 or more PES for VT induction at C1 had VT reproduced at C2. The difference in the reproducibility of VT induction in these 2 patient groups was highly significant (p less than 0.001). Although VT was inducible in 50% of patients using the identical stimulation mode at each study, 35% required a more intense mode for VT induction at C2; this included 11 of 35 patients (31%) in whom VT was initially inducible with 1 or 2 PES who required 3 or more PES for induction of VT at C2. Thus, patients in whom VT is initially inducible with 1 or 2 PES demonstrate reproducible day-to-day responses to programmed electrical stimulation and appear to be excellent candidates for electrophysiologically guided antiarrhythmic drug therapy. Because VT induction was significantly less reproducible in patients who required 3 or more PES at C1, day-to-day reproducibility of VT induction should be confirmed in such patients if electropharmacologic therapy is attempted.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation by serial electrophysiologic studies of an abbreviated oral loading regimen of amiodarone.

Optimal loading and maintenance regimens for amiodarone are undefined. Serial electrophysiologic testing was used in 25 patients with ventricular tachycardia to assess the adequacy of a 1-week oral loading regimen at 1,200 mg/day, to modify maintenance dosing at the conclusion of loading, and to evaluate the appropriateness of maintenance dosing after 2 months of therapy. During the loading period, highly significant (p less than 0.001) increases occurred in the AH interval (88 +/- 22 vs 120 +/- 31 ms), HV interval (49 +/- 10 vs 61 +/- 11 ms), AV nodal Wenckebach cycle length (390 +/- 92 vs 537 +/- 147 ms), ventricular refractory period (247 +/- 17 vs 276 +/- 23 ms), mean ventricular tachycardia cycle length (254 +/- 38 vs 298 +/- 52 ms) and return cycle length (294 +/- 55 vs 360 +/- 87 ms). Ventricular tachycardia inducibility decreased in only a minority of cases, and when observed in association with a more than 10% increase in ventricular refractory period, resulted in a lower maintenance dose. After 2 months of maintenance therapy no additional change occurred in any of these parameters except for an increase in ventricular tachycardia cycle length (298 +/- 52 vs 330 +/- 65 ms, p less than 0.017). Ventricular tachycardia inducibility again showed no consistent response. It is concluded that patients can be discharged after 1 week of therapy with oral amiodarone loading at 1,200 mg/day and that maintenance dosing modified by electrophysiologic assessment results in steady perpetuation of the cardiac amiodarone effect, as indicated by the time course of change in electrophysiologic variables consistently affected.

Mechanisms and relevance of arrhythmias induced by high-current programmed ventricular stimulation.

Programmed ventricular stimulation was performed at 10 mA with up to 3 extrastimuli in 15 patients studied for indications other than sustained ventricular tachycardia and with no sustained arrhythmias induced at twice diastolic threshold. Stimulation with 10 mA produced 6 new instances of ventricular fibrillation (VF), 1 of which may have been clinically relevant. No sustained ventricular tachycardia was induced. VF was induced with triple extrastimuli in 5 of 6 cases. The increased arrhythmogenicity of 10-mA stimulation was related to shortened ventricular refractory periods (S2 267 +/- 21 vs 231 +/- 22 ms, p less than 0.0001; S3 217 +/- 15 vs 178 +/- 15 ms, p less than 0.0005) and did not occur without at least 2 extrastimulus coupling intervals being less than was possible at twice diastolic threshold. Stimulation with 10 mA also resulted in greater increments in extrastimulus local conduction time (27 +/- 19 vs 54 +/- 15 ms, p less than 0.001) and intraventricular conduction time (27 +/- 17 vs 45 +/- 18 ms, p less than 0.005) as coupling intervals were shortened from 360 ms to just beyond ventricular refractoriness. VF was induced more frequently in patients with cardiomyopathy (p less than 0.05). Thus, the increase in arrhythmogenicity with 10-mA stimulation with triple extrastimuli is predominantly manifest as VF, which occurs with considerable frequency and is of uncertain clinical significance. This technique should be used with great caution, and only after other stimulation modalities have been attempted.

Coil occlusion of the parent artery for treatment of symptomatic peripheral intracranial aneurysms.

BACKGROUND AND PURPOSE: Peripheral intracranial aneurysms can be difficult to treat with traditional surgical or embolization techniques that spare the parent vessel. We report the results of our use of coil occlusion of the parent vessel for the treatment of nine peripheral intracranial aneurysms. METHODS: During approximately a 4-year period, nine patients (six men and three women, 27 to 68 years old; average age, 42 years) presented to our institution with peripheral intracranial aneurysms. The aneurysms were located on branches of the right posterior inferior cerebellar artery (n = 2), the right superior cerebellar artery (n = 1), the right anterior inferior cerebellar artery (n = 1), the right posterior cerebral artery (n = 3), the left middle cerebral artery (n = 1), and the left anterior cerebral artery (n = 1). Parent vessel occlusion was performed using microcoils after test injection with amobarbital (Amytal) in eight of the nine cases (one patient was comatose and could not be tested before occlusion). RESULTS: Angiography immediately after the procedure showed aneurysmal occlusion in every patient. Follow-up arteriography, performed in six patients 2 to 12 months after treatment, documented continued aneurysmal occlusion in every case. Three patients exhibited mild, nondisabling neurologic deficits after coil placement; the rest had no new deficits, although one patient was severely disabled from the initial hemorrhage and one patient died of an unrelated cause. CONCLUSION: Our results lend support to the use of parent vessel occlusion for peripheral aneurysms that are difficult to treat surgically or that are not amenable to intra-aneurysmal coil placement.

After-death interviews with surrogates/bereaved family members: some issues of validity.

After-death interviews with bereaved respondents are an important tool in the repertoire of researchers evaluating the quality of end-of-life care or investigating the experiences of people at the end of life. Despite the importance of after-death interviews to our understanding of the last months of life, the validity of the information gathered has received little attention. In this article, we review some of the available information, drawing on evidence from cognitive psychology as well as from palliative care studies. Findings from cognitive psychology indicate that memory is a dynamic process, influenced by emotion state and the individual's perspective at the time of the event and at recall. Further research is therefore needed to understand better the circumstances, types of information and research questions for which bereaved relatives are valid surrogates for people who have died.

Judging the quality of care at the end of life: can proxies provide reliable information?

A major challenge in research into care at the end of life is the difficulty of obtaining the views and experiences of representative samples of patients. Studies relying on patients' accounts prior to death are potentially biased, as they only represent that proportion of patients with an identifiable terminal illness, who are relatively well and therefore able to participate, and who are willing to take part. An alternative approach that overcomes many of these problems is the retrospective or 'after death' approach. Here, observations are gathered from proxies, usually the patient's next of kin, following the patient's death. However, questions have been raised about the validity of proxies' responses. This paper provides a comprehensive review of studies that have compared patient and proxy views. The evidence suggests that proxies can reliably report on the quality of services, and on observable symptoms. Agreement is poorest for subjective aspects of the patient's experience, such as pain, anxiety and depression. The findings are discussed in relation to literature drawn from survey methodology, psychology, health and palliative care. In addition to this, factors likely to affect levels of agreement are identified. Amongst these are factors associated with the patient and proxy, the measures used to assess palliative care and the quality of the research evaluating the validity of proxies' reports. As proxies are a vital source of information, and for some patients the only source, the paper highlights the need for further research to improve the validity of proxies' reports.

Tumor resection in a shared-resource magnetic resonance operating room: experience at the University of Cincinnati.

INTRODUCTION: At the University of Cincinnati, we have developed a shared-resource magnetic resonance operating suite that facilitates performance of both neurosurgical and diagnostic procedures in a single unit. METHODS: The shared-resource magnetic resonance operating suite utilizes a Hitachi AIRIS II, 0.3-T, vertical field, open MRI unit located in the MROR. This magnet can be used for both diagnostic and interventional procedures. The addition of a rotating-operating table permits neurosurgical procedures to be performed outside of the 5-G line using standard neurosurgical equipment and operating microscopes. RESULTS: We review our results with the shared-resource magnetic resonance operating room including the tabulated results from 30 transsphenoidal procedures and 63 glioma procedures. In addition, 2832 diagnostic procedures have been performed in the first 4 years of use. CONCLUSION: The shared-resource intraoperative MRI facility produces high-quality intraoperative imaging studies, equal to those of high-resolution magnets, and is valuable in enabling the surgeon to achieve the planned degree of resection of glioma and pituitary tumors. The ability to perform diagnostic procedures in a shared unit has been a cost-effective solution for our institution.

Implantable cardioverter defibrillator: a review.

Sudden cardiac death claims 400,000 to 450,000 lives annually. It is believed that sudden cardiac death results predominantly from ventricular fibrillation or sustained ventricular tachycardia that deteriorates into ventricular fibrillation. Conventional treatments for patients who suffer from ventricular arrhythmias have been limited to antiarrhythmic drugs or surgery. These treatments have proved ineffective to a portion of arrhythmia sufferers. The implantable cardioverter defibrillator offers hope to a segment of ventricular arrhythmia sufferers whose disease is resistant to conventional therapies.

Regulation of animal care and research? NIH's opinion.

It is the position of the National Institutes of Health (NIH) that investigators and institutions who use animals have the responsibility to provide for the animals' humane care and use. NIH policy requires that recipients of its awards assure NIH that they are carrying out this responsibility. NIH uses the National Academy of Sciences--National Research Council "Guide for the Care and Use of Laboratory Animals" to define acceptable animal care standards and a set of 12 "Principles for the Use of Animals" to define humane animal use.