Multidisciplinary Approach to Patent Foramen Ovale Closure for Cryptogenic Stroke: Brain-Heart Board Experience.

Background and Objectives: Patent foramen ovale (PFO) is present in approximately 25% of adult population. The prevalence of PFO is high in patients with cryptogenic stroke suggesting paradoxical embolism. PFO closure in carefully selected patients is an effective secondary preventive strategy in these patients. We report predictors of management recommendations by the multidisciplinary Board and their impact on outcomes. Methods: Brain-Heart Board comprises vascular and interventional neurology and cardiology subspecialties (structural, electrophysiology, and cardiac imaging). Adult patients referred to the Board for consideration of PFO closure between October 2017 to March 2021 were included in this retrospective cohort analysis. Demographics, comorbid conditions, risk of paradoxical embolism (RoPE) score, event frequencies (transient ischemic attack [TIA] or stroke, intracranial hemorrhage [ICH], post-PFO closure cardiac arrhythmias), and modified Rankin Scale (mRS) at 1 year were compared between the groups (PFO closure vs medical management). Multivariable logistic regression was used to identify factors associated with management recommendation and chi-square tests to test differences in outcomes for patients according to management. Results: Two hundred seventy patients (229 stroke; 41 TIA) were discussed by the Board for PFO closure. 119 (44.0%) patients were recommended for PFO closure of which 117 (98.3%) had evidence of ischemic infarct on imaging. In univariate analysis, age was similar (50 ± 11.9 vs 52 ± 12.8, p = 0.17), but RoPE score was higher in closure as compared with the medical management group (6 [IQR 5-7] vs 5 [IQR 4-7], p < 0.05). In multivariable analysis, TIA as the index event was an independent predictor of Board recommendation against PFO closure (OR 0.05, 95% CI 0.01-0.19, p < 0.05). Event frequency was low in both cohorts (5.9% vs 4.8%, p > 0.05) and comprised cardiac arrhythmias (6 cases of atrial fibrillation and 1 ICH in closure group; 1 TIA and 1 recurrent stroke in medical management group). Excellent functional outcome (mRS 0-1) was similar in both cohorts (66.3% vs 70.7%, p > 0.05) at 1 year. Discussion: Multidisciplinary Brain-Heart Board provides a clinical practice model of collaborative care to ensure proper patient selection for PFO closure. TIA as the index event is associated with recommendation of medical management by the multidisciplinary Brain-Heart Board.

Hypoperfusion Intensity Ratio Is Associated with Early Neurologic Deficit Severity and Deterioration after Mechanical Thrombectomy in Large-Vessel Occlusion Ischemic Stroke.

BACKGROUND AND PURPOSE: The hypoperfusion intensity ratio is a surrogate marker for collateral status and a predictor of infarct growth, malignant cerebral edema, and hemorrhagic transformation. Its utility to predict a poor NIHSS score and early neurologic deterioration after mechanical thrombectomy for large vessel (LVO) versus distal and medium vessel occlusions (DMVO) has not been investigated. The objective of this study was to determine whether the higher hypoperfusion intensity ratio is associated with a worse NIHSS score at 24 hours post-mechanical thrombectomy and early neurologic deterioration in LVO versus DMVO acute ischemic stroke. MATERIALS AND METHODS: This was a retrospective study of 231 patients with acute ischemic stroke with LVO or DMVO amenable for mechanical thrombectomy and available CTP for hypoperfusion intensity ratio assessment pre-mechanical thrombectomy. Clinical and imaging characteristics were abstracted from the medical records. The primary outcome was the NIHSS score at 24 hours post-mechanical thrombectomy. The secondary outcome was early neurologic deterioration, defined as a >4-point increase in the NIHSS score between the initial assessment and 24 hours post-mechanical thrombectomy. All analyses were first conducted in the entire cohort and then separately for the LVO versus DMVO groups. RESULTS: The optimal hypoperfusion intensity ratio threshold to detect early neurologic deterioration was 0.54. A hypoperfusion intensity ratio ≥ 0.54 was more frequently present in LVO versus DMVO (n = 37 [77.1%] versus n = 11 [22.9%]; P < .001). On multivariable linear regression, the hypoperfusion intensity ratio ≥ 0.54 was independently associated with a worse NIHSS score at 24 hours post-mechanical thrombectomy in the entire cohort (ß = 0.163; P = .002) and the LVO group (ß = 0.210; P = .005), but not in the DMVO group. The early neurologic deterioration occurred in 26 (11.3%) subjects. On multivariable logistic regression, there was no association of the hypoperfusion intensity ratio ≥ 0.54 with early neurologic deterioration in the entire cohort. However, when analyzed separately, a hypoperfusion intensity ratio ≥ 0.54 significantly increased the odds of early neurologic deterioration in subjects with LVO (OR = 5.263; 95% CI, 1.170-23.674; P = .030) but not in the DMVO group. CONCLUSIONS: The hypoperfusion intensity ratio ≥ 0.54 was independently associated with a worse 24-hour post-mechanical thrombectomy NIHSS score and early neurologic deterioration in LVO, but not in DMVO acute ischemic stroke. Pending confirmation in future, prospective studies assessing the hypoperfusion intensity ratio may help identify patients at risk of secondary decline to improve peri-thrombectomy care and clinical decision-making.

IoT in Water Quality Monitoring-Are We Really Here?

The Internet of Things (IoT) has become widespread. Mainly used in industry, it already penetrates into every sphere of private life. It is often associated with complex sensors and very complicated technology. IoT in life sciences has gained a lot of importance because it allows one to minimize the costs associated with field research, expeditions, and the transport of the many sensors necessary for physical and chemical measurements. In the literature, we can find many sensational ideas regarding the use of remote collection of environmental research. However, can we fully say that IoT is well established in the natural sciences?

Neurogenic cardiac outcome in patients after acute ischemic stroke: The brain and heart connection.

BACKGROUND: Neurogenic cardiac impairment can occur after acute ischemic stroke (AIS), but the mapping of the neuroanatomic correlation of stroke-related myocardial injury remains uncertain. This study aims to identify the association between cardiac outcomes and middle cerebral artery (MCA) ischemic stroke, with or without insular cortex involvement, as well as the impact of new-onset atrial fibrillation (AF) after AIS on recurrent stroke. METHODS: Serial measurements of high sensitivity troponin T (TnT), brain natriuretic peptide (BNP), electrocardiography (ECG), echocardiogram, and cardiac monitoring were performed on 415 patients with imaging confirmed MCA stroke, with or without insular involvement. Patients with renal failure, recent cardiovascular events, or congestive heart failure were excluded. RESULTS: One hundred fifteen patients (28%) had left MCA infarcts with insular involvement, 122 (29%) had right MCA infarcts involving insular cortex, and 178 (43%) had no insular involvement. Patients with left MCA stroke with insular involvement tended to exhibit higher BNP and TnI, and transient cardiac dysfunction, which mimicked Takotsubo cardiomyopathy in 10 patients with left ventricular ejection fraction (LVEF) of 20-40%. Incidence of new-onset AF was higher in right MCA stroke involving insula (39%) than left MCA involving insula (4%). Nine out of fifty-three patients with new-onset AF were not on anticoagulant therapy due to various reasons; none of them experienced recurrent AF or stroke during up to a 3-year follow-up period. Statistically significant correlations between BNP or TnT elevation and left insular infarcts, as well as the incidence of AF and right insular infarcts, were revealed using linear regression analysis. CONCLUSIONS: The present study demonstrated that acute left MCA stroke with insular involvement could cause transient cardiac dysfunction and elevated cardiac enzymes without persistent negative outcomes in the setting of health baseline cardiac condition. The incidence of new-onset AF was significantly higher in patients with right MCA stroke involving the insula. There was no increased risk of recurrent ischemic stroke in nine patients with newly developed AF who were not on anticoagulant therapy, which indicated a need for further research on presumed neurogenic AF and its management.

Association of Atrial Fibrillation Detected after Stroke with Cardiac Dysfunction and Features of Neurogenic Cardiac Injury.

OBJECTIVES: Understanding the link between markers of cardiac injury and atrial fibrillation (AF) detected after stroke (AFDAS) may help refine stroke risk stratification and therapeutic approaches in AFDAS. MATERIALS AND METHODS: We retrospectively analyzed 988 adult patients admitted for acute ischemic stroke and transient ischemic attack, who presented within 4.5 h from last known well. Pertinent clinical variables including features of neurogenic cardiac injury (so-called stroke heart syndrome [SHS]) as well as electrocardiographic and echocardiographic markers of cardiac dysfunction, and AF status (no AF n = 574; known AF n = 311; AFDAS; n = 103) were collected. Multivariable logistic regression was used to determine the independent associations of variables with AFDAS. RESULTS: A total of 264 (26.7%) subjects fulfilled criteria for SHS. Of these, 174 of had SHS features other than AFDAS (non-AF SHS). Among 677 subjects without known AF, presence of non-AF SHS was associated with a 5-fold odds of AFDAS (OR 5.0, 95%-CI 3.1-8.0, p < 0.001). After adjustment, non-AF SHS (OR 3.2, 95%-CI 1.6-6.4, p = 0.001) and the left atrial volume index (OR 1.04, 95%-CI 1.01-1.08, p = 0.004) remained independently associated with AFDAS. CONCLUSIONS: The presence of non-AF SHS features and the left atrial volume index were independently associated with AFDAS indicating diverse mechanisms relating to new onset AF. A better understanding of the links between these markers and AFDAS may help uncover potentially modifiable risk factors for AFDAS as well as aid treatment decisions in patients at risk for new onset AF and ischemic stroke.

Association of Dexamethasone with Shunt Requirement, Early Disability, and Medical Complications in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Current guidelines do not support the routine use of corticosteroids in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, corticosteroids use in aSAH has been practiced at some centers by convention. The aim of the study was to determine the incidence of hydrocephalus requiring ventriculoperitoneal shunt (VPS) placement as well as functional outcome on discharge and adverse events attributed to corticosteroids in patients with aSAH treated with different dexamethasone (DXM) treatment schemes. METHODS: We retrospectively analyzed 206 patients with aSAH stratified to three groups based on the DXM treatment scheme: no corticosteroids, short course of DXM (S-DXM; 4 mg every 6 h for 1 day followed by a daily total dose reduction by 25% and then by 50% on last day), and long course of DXM (L-DXM; 4 mg every 6 h for 5-7 days followed by reduction by 50% every other day). The primary outcome measure was the placement of a VPS, and the secondary outcome was a good functional outcome [modified Rankin Scale (mRS) 0-3] at hospital discharge. Safety measures were the incidence of infection (pneumonia, urinary tract infection, ventriculitis, meningitis), presence of delirium, and hyperglycemia. RESULTS: There was no difference in the rate of external ventricular drain (EVD) (p = 0.164) and VPS placement (p = 0.792), nor in the rate of good outcome (p = 0.928) among three defined treatment regimens. Moreover, the median duration of treatment with EVD did not differ between subjects treated with no corticosteroids, S-DXM, and L-DXM (p = 0.905), and the probability of EVD removal was similar when stratified according to treatment regimens (log-rank; p = 0.256). Patients who received L-DXM had significantly more complications as compared to patients, who received no corticosteroids or S-DXM (78.4% vs. 58.6%; p = 0.005). After adjustment, L-DXM remained independently associated with increased risk of combined adverse events (OR = 2.72; 95%CI, 1.30-5.72; p = 0.008), infection (OR = 3.45; 95%CI, 1.63-7.30; p = 0.001) and hyperglycemia (OR = 2.05; 95%CI, 1.04-4.04; p = 0.039). CONCLUSIONS: DXM use among patients with aSAH did not relate to the rate of EVD and VPS placement, duration of EVD treatment, and functional disability at discharge but increased the risk of medical complications.

Mean platelet volume and its genetic variants relate to stroke severity and 1-year mortality.

OBJECTIVE: To determine whether mean platelet volume (MPV) and selected single nucleotide polymorphisms (SNPs) that have been associated with MPV in genome-wide association studies relate to stroke severity, functional outcome on discharge, and 1-year mortality in patients with ischemic stroke, we retrospectively analyzed 577 patients with first-ever ischemic stroke. METHODS: Genotyping of 3 SNPs (rs342293, rs1354034, rs7961894) was performed using a real-time PCR allelic discrimination assay. Multivariable regression was used to determine the association of MPV and MPV-associated SNPs with the NIH Stroke Scale (NIHSS) score on admission, modified Rankin Scale score on discharge, and data on 1-year mortality. RESULTS: Rs7961894, but not rs342293 or rs1354034 SNP, was independently associated with an MPV in the highest quartile (MPV Q4). MPV Q4 was associated with significantly greater admission NIHSS (p = 0.006), poor discharge outcome (p = 0.034), and worse 1-year mortality (p = 0.033). After adjustment for pertinent covariates, MPV Q4 remained independently associated with a greater admission NIHSS score (p = 0.025). The T>C variant of rs7961894 SNP was an independent marker of a lower 1-year mortality (hazard ratio, 0.30; 95% confidence interval, 0.13-0.70; p = 0.006) in the studied population. CONCLUSION: MPV is a marker of stroke severity and T>C variant of rs7961894 is independently associated with greater MPV in acute phase of ischemic stroke and relates to decreased 1-year mortality after stroke.

Prevalence of a Multiple Territory Stroke Pattern After Intravenous Thrombolysis.

BACKGROUND: It has been proposed that the presence of a multiple territory stroke pattern (MTSP) on brain imaging may aid identification of patients with covert atrial fibrillation (AF). However, it is uncertain whether this association holds true among patients treated with intravenous recombinant tissue plasminogen activator (rtPA) because clot fragmentation may affect MTSP prevalence. METHODS/DESIGN: Retrospective analysis of 149 acute ischemic stroke patients treated with intravenous rtPA who underwent brain MRI. Presence of multiple acute infarctions on brain MRI that involved more than one vascular territory was considered to denote MTSP. Stroke etiology was categorized as nonembolic, cardioembolic (CES), and embolic stroke of undetermined source (ESUS). RESULTS: In the entire cohort, subjects with CES and ESUS had significantly more often an MTSP than subjects with other determined stroke mechanism (P= .007). Although numerically relatively more patients had an MTSP as compared to a non-MTSP among subjects with CES (52% versus 33.9%) and ESUS (44% versus 34.7%), this difference did not reach significance after Bonferroni-adjustment for multiple comparisons (P> .05, each). There was no difference in the prevalence of an MTSP among subjects with known (n = 11/51; 21.6%) versus subsequently diagnosed (n = 1/3; 33.3%) AF (P= .54). CONCLUSIONS: Our findings indicate that the known association of multiterritory infarct with AF and ESUS is maintained after thrombolysis. In light of its high specificity, MTSP represents a good marker for AF-related stroke etiology; nevertheless, overall sensitivity for AF was low highlighting that an absent MTSP does not rule out AF.

Association of Baseline Cardiac Troponin With Acute Myocardial Infarction in Stroke Patients Presenting Within 4.5 Hours.

Background and Purpose- American Heart Association guidelines recommend obtaining baseline troponin in all patients with acute ischemic stroke. Yet, there is a paucity of data on the prevalence of baseline troponin elevation and specifically its diagnostic yield for acute myocardial infarction (AMI) in patients presenting within the time window for thrombolysis. Methods- We retrospectively analyzed 1072 consecutive patients admitted for acute ischemic stroke or transient ischemic attack, who presented within 4.5 hours of last known well (LKW). Patients who had baseline cardiac troponin I (bcTnI) obtained within 72 hours from LKW (n=525) were included in the study. Multivariable logistic regression was conducted to determine factors independently related to an elevated bcTnI (>0.04 ng/mL). We calculated the area under receiver operator curves, sensitivity, and specificity, to determine the diagnostic accuracy of (i) the bcTnI for AMI stratified by the time to assessment and (ii) the best time cutoff for obtaining bcTnI. Results- Among included subjects, the median time from LKW to the bcTnI was 3.8 hours and 113 (21.5%) subjects had an elevated bcTnI. Assessment of bcTnI within 4.5 hours from LKW was significantly more often associated with normal values as compared to assessment between 4.5 and 72 hours (61.7% versus 38.3%; P=0.001). Fifteen (2.9%) patients were diagnosed with AMI. After adjustment for pertinent confounders, time to bcTnI assessment was independently associated with AMI (odds ratio, 1.04 [95% CI, 1.02-1.07] P=0.001). When stratified by time, bcTnI assessed within 4.5 hours had a sensitivity of 25% and specificity of 83.7% for AMI, whereas bcTnI assessment between 4.5 and 72 hours was associated with a sensitivity of 90.9% and specificity of 74.8%. Conclusions- Assessment of bcTnI after 4.5 hours from LKW was associated with greater diagnostic accuracy than testing within 4.5 hours. This information may inform routine clinical practice.

Clinical and Radiological Characteristics of Vitamin K Versus Non-Vitamin K Antagonist Oral Anticoagulation-Related Intracerebral Hemorrhage.

BACKGROUND/OBJECTIVE: Recent studies indicated that functional outcome after intracranial hemorrhage (ICH) related to direct oral anticoagulation (DOAC-ICH) is similar, if not better, than vitamin K antagonist (VKA)-related ICH (VKA-ICH) due to a smaller initial hematoma volume (HV). However, the association with hematoma expansion (HE) and location is not well understood. METHODS: We retrospectively analyzed 102 consecutive patients with acute non-traumatic ICH on oral anticoagulation therapy to determine HV and HE stratified by hematoma location, and the relation to the 90-day outcome. RESULTS: DOAC-ICH (n = 25) and VKA-ICH (n = 77) had a similar admission HV and HE (unadjusted p > 0.05, each). Targeted reversal strategies were used in 93.5% of VKA-ICH versus 8% of DOAC-ICH. After adjustment, an unfavorable 90-day functional outcome (modified Rankin scale score 4-6) was independently associated with a lower admission Glasgow Coma Scale score (OR 1.63; 95% CI 1.26-2.10; p < 0.001) and greater HV (OR 1.03; 95% confidence interval (CI) 1.00-1.05; p = 0.046). After exclusion of patients without follow-up head computed tomography to allow for adjustment by occurrence of HE, VKA-ICH was associated with an approximately 3.5 times greater odds for a poor 90-day outcome (OR 3.64; 95% CI 1.01-13.09; p = 0.048). However, there was no significant association of the oral anticoagulant strategy with 90-day outcome in the entire cohort (OR 2.85; 95% CI 0.69-11.86; p = 0.15). CONCLUSIONS: DOAC use did not relate to worse HE, HV, and functional outcome after ICH, adding to the notion that DOAC is a safe alternative to VKA even in the absence of access to targeted reversal strategies (which are still not universally available).

Sympathetic vascular response to facial cooling is increased in flail phenotypes of amyotrophic lateral sclerosis.

OBJECTIVE: To assess cardiovascular responses to cold face test (CFT) in patients with classic-onset ALS (bulbar or limb onset, ALS-C) and in patients with flail arm and flail leg phenotypes (FA/FL). METHODS: In 18 ALS-C, eight FA/FL patients and 10 age-matched controls we continuously monitored heart rate (HR), systolic (SBP), diastolic (DBP) and mean blood pressure (MBP) during two-minute baseline and one-minute cold stimulus application. HR and BP responses to CFT were calculated as differences between the peak responses and baseline values (dHR, dSBP, dDBP, dMBP), as percent changes from baseline (dHR%, dSBP%, dDBP%, dMBP%), and also latencies and durations of HR and BP responses were assessed (LatHR, tHR, LatBP, tBP). RESULTS: There were no differences in baseline values of HR, SBP, DBP and MBP among ALS-C, FA/FL and controls (p > 0.05). A decrease in HR and increases in SBP, DBP and MBP were observed in all subjects (p < 0.05). However, in FA/FL, the magnitude of BP responses, i.e. dSBP, dSBP%, dDBP, dMBP, and dMBP% were significantly higher than in controls. Moreover, these BP responses occurred with a significantly shorter latency in FA/FL than in controls and ALS-C. Furthermore, duration of the BP changes was significantly longer in FA/FL than in ALS-C. In contrast, ALS-C patients had a significantly longer LatHR and shorter tHR than healthy persons. However, no significant differences were observed in dHR or dHR% among the three groups. CONCLUSIONS: Sympathetic vascular response to facial cooling is increased in flail phenotypes of ALS.

[Neuralgic amyotrophy--a case report]. / Neuralgia amiotroficzna--opis przypadku.

We describe a case of a 54-year-old woman reporting weakness of the right upper limb, preceded by a period of severe pain in the right shoulder. Despite several orthopedic consultations and two cycles of physical therapy, the symptoms deteriorated over a period of 6 months, and progressive paresis of the extensor muscles of the upper limb and elbow flexion contracture were observed. On the basis of the clinical presentation and results of medical tests including an electrophysiological study that showed axonal damage to the long thoracic nerve, axillary nerve, and posterior interosseous nerve, neuralgic amyotrophy was diagnosed. A treatment with prednisone was introduced, and the patient's condition significantly improved.

Dynamic cerebral autoregulation is compromised in ischaemic stroke of undetermined aetiology only in the non-affected hemisphere.

BACKGROUND AND PURPOSE: To assess dynamic cerebral autoregulation (CA) in patients with acute ischaemic stroke of undetermined aetiology, within 72h of stroke onset. MATERIALS AND METHODS: In 6 patients with ischaemic stroke of undetermined aetiology (aged 66±9 years, National Institutes of Health Stroke Scale [NIHSS] score on admission: 4.0, range: 4-11), selected based on screening of 118 consecutive ischaemic stroke patients and in 14 volunteers (aged 62±10 years), we continuously monitored RR intervals (RRI), mean arterial pressure (MAP) by means of photoplethysmography, mean cerebral blood flow velocity (CBFV) using transcranial Doppler ultrasonography, end-tidal CO2 (ETCO2) and respiration during 2-min deep breathing paced at 6min(-1) (0.1Hz). To assess CA, we evaluated the impact of breathing-induced MAP oscillations on fluctuations of CBFV in the hemispheres with stroke, the non-involved hemispheres and randomly selected hemispheres of controls by applying cross-spectral analysis and calculating coherence, transfer function gain (CBFV-MAP gain) and phase shift angle between the two oscillating signals. RESULTS: Phase shift angle between MAP and CBFV oscillations showed values >0 and was significantly reduced in the hemispheres without stroke as compared to controls (0.39±0.95 vs. -1.59±0.33rad, p=0.015), whereas in the hemispheres with stroke, phase shift angle did not differ significantly from that observed in the control hemispheres. Clinical status of stroke patients significantly improved at discharge from the hospital (NIHSS: 2.0, range: 1-8, p=0.028). CONCLUSIONS: During the first days of ischaemic stroke of undetermined aetiology, dynamic cerebral autoregulation is compromised in the non-affected hemisphere, but not in the hemisphere with ischaemic lesion.

Effects of specific multi-nutrient enriched diets on cerebral metabolism, cognition and neuropathology in AßPPswe-PS1dE9 mice.

Recent studies have focused on the use of multi-nutrient dietary interventions in search of alternatives for the treatment and prevention of Alzheimer's disease (AD). In this study we investigated to which extent long-term consumption of two specific multi-nutrient diets can modulate AD-related etiopathogenic mechanisms and behavior in 11-12-month-old AßPPswe-PS1dE9 mice. Starting from 2 months of age, male AßPP-PS1 mice and wild-type littermates were fed either a control diet, the DHA+EPA+UMP (DEU) diet enriched with uridine monophosphate (UMP) and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or the Fortasyn® Connect (FC) diet enriched with the DEU diet plus phospholipids, choline, folic acid, vitamins and antioxidants. We performed behavioral testing, proton magnetic resonance spectroscopy, immunohistochemistry, biochemical analyses and quantitative real-time PCR to gain a better understanding of the potential mechanisms by which these multi-nutrient diets exert protective properties against AD. Our results show that both diets were equally effective in changing brain fatty acid and cholesterol profiles. However, the diets differentially affected AD-related pathologies and behavioral measures, suggesting that the effectiveness of specific nutrients may depend on the dietary context in which they are provided. The FC diet was more effective than the DEU diet in counteracting neurodegenerative aspects of AD and enhancing processes involved in neuronal maintenance and repair. Both diets elevated interleukin-1ß mRNA levels in AßPP-PS1 and wild-type mice. The FC diet additionally restored neurogenesis in AßPP-PS1 mice, decreased hippocampal levels of unbound choline-containing compounds in wild-type and AßPP-PS1 animals, suggesting diminished membrane turnover, and decreased anxiety-related behavior in the open field behavior. In conclusion, the current data indicate that specific multi-nutrient diets can influence AD-related etiopathogenic processes. Intervention with the FC diet might be of interest for several other neurodegenerative and neurological disorders.

Mapping of interactions between human macrophages and Staphylococcus aureus reveals an involvement of MAP kinase signaling in the host defense.

Staphylococcus aureus is a dangerous opportunistic human pathogen that causes serious invasive diseases when it reaches the bloodstream. Recent studies have shown that S. aureus is highly resistant to killing by professional phagocytes and that such cells even provide a favorable environment for intracellular survival of S. aureus. Importantly, the reciprocal interactions between phagocytes and S. aureus have remained largely elusive. Here we have employed kinase profiling to define the nature and time resolution of the human THP-1 macrophage response toward S. aureus and proteomics to identify the response of S. aureus toward macrophages. The results of these studies reveal major macrophage signaling pathways triggered by S. aureus and proteomic signatures of the responses of S. aureus to macrophages. We also identify human proteins bound to S. aureus that have potential roles in bacterial killing and internalization. Most noticeably, our observations challenge the classical concept that macrophage responses are mainly mediated through Toll-like receptor 2 and NF-κB signaling and highlight the important role of the stress-activated MAP kinase signaling in orchestrating the host defense.

Staphylococcal PknB as the first prokaryotic representative of the proline-directed kinases.

In eukaryotic cell types, virtually all cellular processes are under control of proline-directed kinases and especially MAP kinases. Serine/threonine kinases in general were originally considered as a eukaryote-specific enzyme family. However, recent studies have revealed that orthologues of eukaryotic serine/threonine kinases exist in bacteria. Moreover, various pathogenic species, such as Yersinia and Mycobacterium, require serine/threonine kinases for successful invasion of human host cells. The substrates targeted by bacterial serine/threonine kinases have remained largely unknown. Here we report that the serine/threonine kinase PknB from the important pathogen Staphylococcus aureus is released into the external milieu, which opens up the possibility that PknB does not only phosphorylate bacterial proteins but also proteins of the human host. To identify possible human targets of purified PknB, we studied in vitro phosphorylation of peptide microarrays and detected 68 possible human targets for phosphorylation. These results show that PknB is a proline-directed kinase with MAP kinase-like enzymatic activity. As the potential cellular targets for PknB are involved in apoptosis, immune responses, transport, and metabolism, PknB secretion may help the bacterium to evade intracellular killing and facilitate its growth. In apparent agreement with this notion, phosphorylation of the host-cell response coordinating transcription factor ATF-2 by PknB was confirmed by mass spectrometry. Taken together, our results identify PknB as the first prokaryotic representative of the proline-directed kinase/MAP kinase family of enzymes.