Characteristics and Outcomes of Left Ventricular-Assist Device-Associated Cerebrovascular Events in Setting of Infectious Intracranial Aneurysms.

BACKGROUND AND PURPOSE: The study aims to identify the characteristics and neurological outcomes of the left ventricular-assist device (LVAD)-associated cerebrovascular events (CVE) and infections, particularly in the setting of infectious intracranial aneurysms (IIA). METHODS: A single-center retrospective review of patients having undergone LVAD implantation between 2011 and 2017 was conducted using institutional registries and screened for CVE. Patients with CVE were assessed for concurrent bacteremia; neurovascular imaging was then used to isolate patients with IIA. A review of comorbidities, imaging characteristics, and management were performed to determine predictors of neurological outcomes, as defined by the 90-day modified Rankin scale (mRS) scores. RESULTS: Of the 383 HeartMate II LVAD implantations performed, 43 all-cause stroke events were identified across 35 (9%) patients. The majority of the events were hemorrhagic CVE (n=28) with 21 events complicated by bacteremia. Of patients with hemorrhagic CVE and bacteremia, Staphylococcus aureus (n=10) and Pseudomonas aeruginosa (n= 8) infection were the most frequently associated organisms. Severe disability or death (90-day mRS > 4) was observed in 15 patients (63%). Seven patients had confirmed findings of IIA on diagnostic cerebral angiogram and were associated with distal middle cerebral artery (MCA) territory involvement (n=6; 86%) with concurrent Staphylococcus (n=5, 71%) and/or Pseudomonas (n=4, 57%) infections. Overall, a higher incidence of acute and chronic bacteremia was observed in the hemorrhagic CVE subgroup compared to the ischemic CVE subgroup (74% vs 36% & 71% vs 29%, respectively; p <0.05). Despite endovascular and/or surgical intervention in patients with IIA, four patients failed management and elected for comfort measures. CONCLUSION: Our results indicate that P. aeruginosa and S. aureus bacteremia are associated with a greater incidence of intracranial hemorrhage and worse neurological outcomes. Future management considerations may include pre-implantation cerebrovascular imaging to assess vascular pathology including prior aneurysms and intracranial atherosclerotic disease burden as a screen for higher-risk patients, as well as more aggressive antibiotic therapy at bacteremia onset.

Treating Hallucinations and Delusions Associated With Parkinson's Disease Psychosis.

PURPOSE OF REVIEW: We discuss features of Parkinson's disease psychosis (PDP) including symptomology and pathophysiology. Treatment options, including non-pharmacologic strategies, dose reduction of offending agents, and the addition of non-dopaminergic antipsychotics, are addressed. The efficacy of second-generation antipsychotics and novel agents is examined. RECENT FINDINGS: Pimavanserin, a 5-HT2A/C receptor inverse agonist with no other receptor activity, has shown efficacy and tolerability and is now FDA approved for PDP treatment. Research into novel targets is ongoing. PDP is a morbid complication of Parkinson's disease with complex incompletely understood mechanisms. Treatment is directed towards mitigation of psychosis without worsening of motor features.

Binding of isoxazole and pyrazole derivatives of curcumin with the activator binding domain of novel protein kinase C.

The protein kinase C (PKC) family of serine/threonine kinases is an attractive drug target because of its involvement in the regulation of various cellular functions, including cell growth, differentiation, metabolism, and apoptosis. The endogenous PKC activator diacylglycerol contains two long carbon chains, which are attached to the glycerol moiety via ester linkage. Natural product curcumin (1), the active constituent of Curcuma L., contains two carbonyl and two hydroxyl groups. It modulates PKC activity and binds to the activator binding site (Majhi et al., Bioorg. Med. Chem.2010, 18, 1591). To investigate the role of the carbonyl and hydroxyl groups of curcumin in PKC binding and to develop curcumin derivatives as effective PKC modulators, we synthesized several isoxazole and pyrazole derivatives of curcumin (2-6), characterized their absorption and fluorescence properties, and studied their interaction with the activator-binding second cysteine-rich C1B subdomain of PKCδ, PKCε and PKCθ. The EC(50)s of the curcumin derivatives for protein fluorescence quenching varied in the range of 3-25 µM. All the derivatives showed higher binding with the PKCθC1B compared with PKCδC1B and PKCεC1B. Fluorescence emission maxima of 2-5 were blue shifted in the presence of the C1B domains, confirming their binding to the protein. Molecular docking revealed that hydroxyl, carbonyl and pyrazole ring of curcumin (1), pyrazole (2), and isoxazole (4) derivatives form hydrogen bonds with the protein residues. The present result shows that isoxazole and pyrazole derivatives bind to the activator binding site of novel PKCs and both carbonyl and hydroxy groups of curcumin play roles in the binding process, depending on the nature of curcumin derivative and the PKC isotype used.

Binding of curcumin and its long chain derivatives to the activator binding domain of novel protein kinase C.

Protein kinase C (PKC) is a family of serine/threonine kinases that play a central role in cellular signal transduction. The second messenger diacylglycerol having two long carbon chains acts as the endogenous ligand for the PKCs. Polyphenol curcumin, the active constituent of Curcuma longa is an anti-cancer agent and modulates PKC activity. To develop curcumin derivatives as effective PKC activators, we synthesized several long chain derivatives of curcumin, characterized their absorption and fluorescence properties and studied their interaction with the activator binding second cysteine-rich C1B subdomain of PKCdelta, PKCepsilon and PKCtheta. Curcumin (1) and its C16 long chain analog (4) quenched the intrinsic fluorescence of PKCdeltaC1B, PKCepsilonC1B and PKCthetaC1B in a manner similar to that of PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA). The EC(50)s of the curcumin derivatives for fluorescence quenching varied in the range of 4-11 microM, whereas, EC(50)s for TPA varied in the range of 3-6 microM. Fluorescence emission maxima of 1 and 4 were blue shifted and the fluorescence anisotropy values were increased in the presence of the C1B domains in a manner similar to that shown by the fluorescent analog of TPA, sapintoxin-D, confirming that they were bound to the proteins. Molecular docking of 1 and 4 with novel PKC C1B revealed that both the molecules form hydrogen bonds with the protein residues. The present result shows that curcumin and its long chain derivatives bind to the C1B subdomain of novel PKCs and can be further modified structurally to improve its binding and activity.

Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis.

BACKGROUND: We hypothesized that cytomegalovirus (CMV) may contribute to the vasculopathy observed in cardiac allograft recipients by impairing the endothelial nitric oxide synthase pathway. We focused on asymmetric dimethylarginine (ADMA, the endogenous inhibitor of nitric oxide synthase) as a potential mediator of the adverse vascular effect of CMV. METHODS AND RESULTS: Heart transplant recipients manifested elevated plasma ADMA levels compared with healthy control subjects. Transplant patients with CMV DNA-positive leukocytes had higher plasma ADMA concentrations and more extensive transplant arteriopathy (TA). Human microvascular endothelial cells infected with the CMV isolates elaborated more ADMA. The increase in ADMA was temporally associated with a reduction in the activity of dimethylarginine dimethylaminohydrolase (DDAH, the enzyme that metabolizes ADMA). Infected cultures showed high levels of oxidative stress with enhanced endothelial production of superoxide anion. CONCLUSIONS: CMV infection in human heart transplant recipients is associated with higher ADMA elevation and more severe TA. CMV infection in endothelial cells increases oxidative stress, impairs DDAH activity, and increases ADMA elaboration. CMV infection may contribute to endothelial dysfunction and TA by dysregulation of the endothelial nitric oxide synthase pathway.

Preferential involvement of larger vessels in a rat model of diabetes-induced graft vasculopathy.

Using previously described models of diabetes-induced transplant coronary artery atherosclerosis (TxCAD), we quantitatively assessed TxCAD using computer-assisted morphometric measurements. More than 95% of the evaluated vessels were intramyocardial vessels. The first and last tertile of the vessel size distribution were evaluated for the presence of TxCAD. Severe TxCAD, defined as a luminal occlusion > or =75%, was more prevalent in the larger vessels. We observed a differential involvement based on vessel size in diabetes-induced TxCAD.

Reversal of diabetes-induced rat graft transplant coronary artery disease by metformin.

BACKGROUND: Induction of diabetes in rat heterotopic heart transplantation models leads to an accelerated form of severe transplant coronary artery disease (TxCAD). We undertook this study to determine whether treatment of diabetes with metformin would favorably affect TxCAD. METHODS: Heterotopic abdominal heart transplantation was performed in rat isograft and allograft models. After transplantation, diabetes was induced with streptozotocin. Fifty percent of the animals received metformin at 500 mg/kg twice daily. We quantitatively assessed TxCAD using histologic sections of harvested hearts at 30 and 60 days with computer-assisted morphometry. We compared vessels in the first tertile of the area distribution with vessels in the last tertile. RESULTS: Fasting glucose levels in metformin-treated animals were 161 +/- 45 mg/dl compared with 400 +/- 120 mg/dl (p < 0.05) in untreated rats. Treatment with metformin led to decreased diabetes-induced TxCAD in the larger vessels. This effect was sustained during the study course in the isografts but not in the allografts. Treatment with metformin did not prevent progression of TxCAD in the smaller vessels at 60 days. CONCLUSIONS: Metformin reduced luminal occlusion and severe TxCAD in the larger vessels but did not alter the course of TxCAD in the smaller vessels. These results may have therapeutic implications for patients.

Mycophenolic acid concentrations in long-term heart transplant patients: relationship with calcineurin antagonists and acute rejection.

BACKGROUND: When used in conjunction with steroids and cyclosporin, mycophenolate mofetil (MMF) has been shown to significantly reduce mortality and incidence of rejection in the first year after heart transplantation. It also appears that in this early post-transplantation period, the monitoring of immunosuppressive therapies may be warranted. The current study was undertaken to determine if such monitoring is still useful more than 1 yr after heart transplantation. METHODS: Twenty-six patients who had survived the first year after orthotopic heart transplantation and had been on MMF therapy for more than 3 months were prospectively followed. At the time of their routine endomyocardial biopsy blood samples were taken to monitor immunosuppressive therapy. Most patients had two samples taken, on average 109 d apart. RESULTS: There were 22 episodes of asymptomatic rejection documented on a total of 48 biopsies. Of these, only two were of ISHLT (International Society for Heart and Lung Transplantation) grade 3A the remainder being of ISHLT grades 1 or 2. There was no relation between immunosuppressive regimen (tacrolimus and MMF or cyclosporin and MMF) and rejection. There was no relation between monitored immunosuppressive levels and rejection. Patients with the combination of MMF and tacrolimus had significantly higher plasma mycophenolic acid levels despite significantly lower daily MMF dose. CONCLUSION: There does not appear to be a benefit in continued monitoring of plasma mycophenolic acid levels beyond the first year of heart transplantation. There were significant differences in plasma mycophenolic acid levels depending on the type of calcineurin inhibitor concomitantly used.