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Background: The predictors of intracranial haemorrhagic transformation (HT) in acute ischaemic stroke (AIS) patients undergoing dual antiplatelet therapy (DAPT) are not well known., Objectives: The aim of this study is to identify the possible clinical and radiological predictors of HT in patients, irrespective of clinical indication for this treatment., Design: This study is a monocentric cohort retrospective study., Methods: We enrolled consecutive AIS patients, from our prospective register, admitted to Stroke Unit between June 2021 and June 2023 undergoing DAPT with Acetylsalicylic Acid and Clopidogrel within 72 h from symptoms onset. According to current guidelines, DAPT indication was for patients with a minor stroke, symptomatic intracranial artery stenosis and carotid angioplasty stenting. We collected clinical, demographical and radiological data. We used ABC/2 method to measure stroke volume in magnetic resonance imaging (MRI)/Diffusion-weighted imaging (DWI) sequences performed within 48 h. The primary outcome was the presence of HT at non-contrast brain computed tomography, performed 7 days after commencing DAPT., Results: One hundred ninety-four patients were included. Twenty-eight (14.4%) presented HT. Higher NIH Stroke Scale (NIHSS) and MRI/DWI lesion volume related to increased risk of HT ( p  < 0.001). Reperfusion therapy and mechanical thrombectomy (MT), stent placement and a loading dose (LD) of dual antiplatelet or Clopidogrel were associated with a higher occurrence of HT ( p  < 0.05). Furthermore, we individuated an NIHSS cut-off value >4 (area under the curve (AUC) 0.80, sensitivity 0.82, specificity 0.65) and a volume cut-off value >8.2 ml (AUC 0.82, sensitivity 0.79, specificity 0.80) associated with an increased risk of HT (respectively, adjusted odds ratio (adj. OR) 6.5, confidence interval (CI) 1.3-32.7, p  = 0.024 and adj. OR 11.0, CI 3.1-39.2, p  < 0.001)., Conclusion: In clinical practice, MT treatment, antiplatelet LD administration, stent placement and clinical severity may relate to a higher risk of HT in patients with AIS and DAPT in the acute phase. In particular, we found that lesion volume cut-off could help to identify patients at greater risk of HT, regardless of the indication for DAPT., (© The Author(s), 2024.)

Background: Approximately 30% of patients presenting with acute ischemic stroke (AIS) due to large vessel occlusion have pre-stroke modified Rankin Scale (mRS) scores ≥2. We aimed to investigate the safety and outcomes of endovascular treatment (EVT) in patients with AIS with moderate pre-stroke disability (mRS score 3) in an extended time frame (ie, 6-24 hours from the last time known well)., Methods: Data were collected from five centers in Europe and the USA from January 2018 to January 2023 and included 180 patients who underwent EVT in an extended time frame. Patients were divided into two groups of 90 each (Group 1: pre-mRS 0-2; Group 2: pre-mRS 3; 71% women, mean age 80.3±11.9 years). Primary outcomes were: (1) 3-month good clinical outcome (Group 1: mRS 0-2, Group 2: mRS 0-3) and ΔmRS; (2) any hemorrhagic transformation (HT); and (3) symptomatic HT. Secondary outcomes were successful and complete recanalization after EVT and 3-month mortality., Results: No between-group differences were found in the 3-month good clinical outcome (26.6% vs 25.5%, P=0.974), any HT (26.6% vs 22%, P=0.733), and symptomatic HT (8.9 vs 4.4%, P=0.232). Unexpectedly, ΔmRS was significantly smaller in Group 2 compared with Group 1 (1.64±1.61 vs 2.97±1.69, P<0.001). No between-group differences were found in secondary outcomes., Conclusion: Patients with pre-stroke mRS 3 are likely to have similar outcomes after EVT in the extended time frame to those with pre-stroke mRS 0-2, with no difference in safety., Competing Interests: Competing interests: T.N. Nguyen discloses advisory board for Brainomix, Aruna Bio; Associate Editor of Stroke. The other authors declare that they have no conflict of interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cardiac troponin (cTn) testing has reduced the likelihood of erroneous discharge of patients with acute coronary syndrome (ACS) from the emergency department (ED), but doubts remain about optimal clinical use. This study was planned for evaluating the predictive significance of cTn values between the limit of detection of the method and the 99th percentile in ED patients evaluated for suspected ACS., Methods: In this retrospective study all hospital records of patients admitted over a 6-month period to the ED and with at least one cTnI value comprised between the limit of detection (0.01 ng/mL) and the 99th percentile of the assay (0.05 ng/mL) were analyzed., Results: A total of 4,749 patients with cTnI value between 0.01-0.05 ng/mL were identified among 57,879 ED visits throughout the study period. Overall, 2,189 patients (46.1%) were discharged from the ED, 2,529 (53.25%) were admitted to the hospital and 31 (0.65%) died during ED stay. A total number of 289 patients out of 2,189 who were discharged (i.e., 13.2%) had additional ED visits within 30 days. Among these, 6 were diagnosed with ACS, representing 0.27% of patients discharged [negative predictive value (NPV) 0.997; 95% CI, 0.994-0.999] and 2.1% of those with second admission (NPV 0.979; 95% CI, 0.955-0.992). Only one of the 2,529 patients admitted to the hospital (i.e., 0.04%) developed an ACS during hospital stay., Conclusions: The results of our retrospective study suggest that the suitability of using a contemporary-sensitive cTnI immunoassay assay in the context of an appropriate protocol represents a safe and effective strategy for ruling in and ruling out ACS in patients presenting to the ED.

A 58 years healthy old woman was admitted to the Emergency Department (ED) with cardiac arrest due to ventricular fibrillation (VF). Appropriate cardiopulmonary resuscitation (CPR), multiple DC shocks and oro-tracheal intubation (OTI) were effective to induce recovery of spontaneous circulation (ROSC). After ROSC was achieved, the electrocardiogram (ECG) showed an idio-ventricular rhythm with atrioventricular dissociation. A transcutaneous pacing was hence applied and the patient was administered with isoproterenol. Simultaneously, her husband was evaluated in the ED for gastrointestinal symptoms occurred after assumption of home-made "tortelli" (ravioli-like pasta) stuffed with cheese and leaves of a plant which they supposed to be borage two days before admission. Borage, during the non-flowering seasons, can be easily confused with foxglove (Digitalis spp.), and this was the main clue to suspect poisoning. Both patients were given DigiFab®, a sheep antibody fragment with high affinity for digoxin. The woman was then admitted in intensive care unit (ICU), where a rapid clinical  improvement occurred, thus allowing discharge in a few days. The husband was instead discharged from the ED after clinical observation and ECG monitoring. In both cases, a significant plasma concentration of digoxin could be measured.

Gut colonization represents the main source for KPC-producing Klebsiella pneumoniae (KPC-Kp) epidemic dissemination. Oral gentamicin, 80 mg four times daily, was administered to 50 consecutive patients with gut colonization by gentamicin-susceptible KPC-Kp in cases of planned surgery, major medical intervention, or need for patient transfer. The overall decontamination rate was 68% (34/50). The median duration of gentamicin treatment was 9 days (interquartile range, 7 to 15 days) in decontaminated patients compared to 24 days (interquartile range, 20 to 30 days) in those with persistent colonization (P<0.001). In the six-month period of follow-up, KPC-Kp infections were documented in 5/34 (15%) successfully decontaminated patients compared to 12/16 (73%) persistent carriers (P<0.001). The decontamination rate was 96% (22/23) in patients receiving oral gentamicin only, compared to 44% (12/27) of those treated with oral gentamicin and concomitant systemic antibiotic therapy (CSAT) (P<0.001). The multivariate analysis confirmed CSAT and KPC-Kp infection as the variables associated with gut decontamination. In the follow-up period, KPC-Kp infections were documented in 2/23 (9%) of patients treated with oral gentamicin only and in 15/27 (56%) of those also receiving CSAT (P=0.003). No difference in overall death rate between different groups was documented. Gentamicin-resistant KPC-Kp strains were isolated from stools of 4/16 persistent carriers. Peak gentamicin blood levels were below 1 mg/liter in 12/14 tested patients. Oral gentamicin was shown to be potentially useful for gut decontamination and prevention of infection due to KPC-Kp, especially in patients not receiving CSAT. The risk of emergence of gentamicin-resistant KPC-Kp should be considered.

In a patient with mitral-aortic native-valve Streptococcus oralis endocarditis, daptomycin concentrations in aortic and mitral valves were 8.6 and 30.8 μg/g, respectively, and 26 μg/g in the mitral vegetation. In the case of porcine-aortic-valve Staphylococcus epidermidis endocarditis, the daptomycin concentrations were 53.1 μg/g in the valve and 18.1 μg/g in perivalvular tissues. Daptomycin achieved apparently adequate tissue concentrations. S. epidermidis was eradicated, whereas Streptococcus oralis persisted, and its daptomycin MIC displayed a 4-fold increase.

Background and Methods: Nine patients with cardiovascular implantable electronic device (CIED) endocarditis were treated with daptomycin after the failure of previous treatment. The blood and CIED lead cultures of 1 patient were negative. In the other 8 patients, we observed 6 monomicrobic infections and 2 polymicrobic infections. Overall, 10 strains were isolated in these patients: 4 methicillin-sensitive Staphylococcus aureus, 2 methicillin-sensitive Staphylococcus epidermidis, 1 methicillin-resistant Staphylococcus aureus, 1 methicillin-resistant Staphylococcus epidermidis, 1 methicillin-sensitive Staphylococcus hominis, and 1 Propionibacterium acnes. The CIED was removed transvenously in 7 patients. Two patients were too sick for the removal of their CIED, and were cured with 6 mg/kg of daptomycin for 60 and 110 days, respectively, without adverse events., Results: One patient died 4 days after the removal of his CIED because of a complicated abdominal aortic aneurysm. The other 8 patients were cured, with a mean follow-up of 17 ± 8 months. The removed leads were negative, after daptomycin therapy, in 4 cases out of 7. The mean ratio between peak daptomycin concentration and minimal inhibitory concentration (MIC) of the causative strains was 38.3 ± 18.5. For patients whose data were available, the ratio between peak daptomycin concentration and minimal bactericidal concentration (MBC) was 13.2 ± 3.2., Conclusion: Daptomycin monotherapy may be a useful therapeutic tool in difficult-to-treat CIED endocarditis, resulting in a high rate of cures and sterilized leads removed. The ratio between peak daptomycin concentration and MIC or MBC may be useful as predictive tool for treatment success., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Ninety-one clinical isolates of Staphylococcus aureus have been tested with the Kirby Bauer and the Etest® method to determine the susceptibility to glycopeptides in the 2007-2010 period. Five strains (5.5%) were resistant to vancomycin and nine (9.9%) to teicoplanin. Teicoplanin showed a median minimal inhibitory concentration (MIC) of 1 mg/l (range 0.125-24 mg/l), an MIC50 of 1 mg/l, and an MIC90 of 2 mg/l; vancomycin had a median MIC of 1.5 mg/l (range 0.38-4 mg/l), an MIC50 of 1.5 mg/l, and an MIC90 of 2 mg/l. More isolates were distributed on higher values of MIC for vancomycin. Inhibition halos induced by vancomycin-impregnated paper diskettes were slightly larger than those by teicoplanin. Glycopeptide resistance among methicillin-resistant Staphylococcus aureus in Italy is an underestimated phenomenon, possibly due to the described underestimation of glycopeptides MICs by the automatic broth microdilution method, when compared to agar MIC assays. A teicoplanin MIC creep, as reported for vancomycin, cannot be assumed.

Ras p21 signaling is involved in multiple aspects of growth, differentiation, and stress response [1-2]. There is evidence pointing to superoxides as relays of Ras signaling messages. Chemicals with antioxidant activity suppress Ras-induced DNA synthesis. The inhibition of Ras significantly reduces the production of superoxides by the NADPH-oxidase complex [3]. Kirsten and Harvey are nonallelic Ras cellular genes that share a high degree of structural and functional homology. The sequences of Ki- and Ha-Ras proteins are almost identical. They diverge only in the 20-amino acid hypervariable domain at the COOH termini. To date, their functions remain indistinguishable [4]. We show that Ki- and Ha-Ras genes differently regulate the redox state of the cell. Ha-Ras-expressing cells produce high levels of reactive oxygen species (ROS) by inducing the NADPH-oxidase system. Ki-Ras, on the other hand, stimulates the scavenging of ROS by activating posttranscriptionally the mitochondrial antioxidant enzyme, Mn-superoxide dismutase (Mn-SOD), via an ERK1/2-dependent pathway. Glutamic acid substitution of the four lysine residues in the polybasic stretch at the COOH terminus of Ki-Ras completely abolishes the activation of Mn-SOD, although it does not inhibit ERK1/2-induced transcription. In contrast, an alanine substitution of the cysteine of the CAAX box has very little effect on Mn-SOD activity but eliminates ERK1/2- dependent transcription.

Thyrotropin (TSH) stimulates survival and growth of thyroid cells via a seven transmembrane G protein-coupled receptor. TSH elevates the intracellular cyclic AMP (cAMP) levels activating protein kinase A (PKA). Recent evidence indicates that p21 Ras is required for TSH-induced mitogenesis, but the molecular mechanism(s) is not known. Here we report that Ras p21 activity is necessary for the Go- G1 transition in TSH induced cycle and that the downstream effector of Ras upon TSH signaling is p85-p110 PI3K. We show that PI3K inhibitors block TSH-induced DNA synthesis, cAMP-PKA stimulate the formation of the complex PI3K-p21 Ras and reduce the complex Ras-Raf1 in thyroid and other cells types. Moreover, PKA phosphorylates immunoprecipitated p85 and PKA phosphorylation of cell extracts significantly stimulates the formation of the complex PI3K-Ras. We suggest that PKA phosphorylates p85 and stabilizes the complex p110-p85, enhancing the interaction PI3K and p21 Ras. Simultaneously, cAMP inhibits Raf-1-ERK signaling by decreasing Raf1 availability to Ras. Under these circumstances PI3K signaling is favored. These results indicate that PI3K is an important mediator of Ras effects in cAMP-induced proliferation and illustrates how cAMP can selectively influence Ras effector pathways.

TSH receptor mutants in the VI transmembrane segment, found in thyroid autonomously functioning adeonomas, have been expressed in differentiated thyroid cells. All mutant receptors constitutively stimulated adenylyl cyclase. The biological activity, measured as cAMP production relative to the wild type receptor, was specific for each mutant in transient and stable transfection assays. Cells expressing these mutants proliferated in the absence of TSH. The rate of growth in the absence of TSH paralleled basal cAMP production for each mutant receptor. Low TSH concentrations stimulated the growth of mutant receptor-expressing cells, and not of the cells expressing the wild type receptor. Also, the entry in the cell cycle and the plating efficiency were markedly stimulated by the expression of the mutant receptors. These data provide a molecular link between the occurrence of TSH receptor mutations and thyroid autonomously functioning adenomas.

Injury of the arterial wall induces the formation of the neointima. This structure is generated by the growth of mitogenically activated smooth muscle cells of the arterial wall. The molecular mechanism underlying the formation of the neointima involves deregulated cell growth, primarily triggered by the injury of the arterial wall. The activated gene products transmitting the injury-induced mitogenic stimuli have been identified and inhibited by several means: transdominant negative expression vectors, antisense oligodeoxynucleotides, adenovirus-mediated gene transfer, antibodies and inactivating drugs. Results of our study show that local administration of 3',5'-cyclic AMP and phosphodiesterase-inhibitor drugs (aminophylline and amrinone) to rats markedly inhibits neointima formation after balloon injury in vivo and in smooth muscle cells in vitro. The growth inhibitory effect of aminophylline was completely reversed by the inhibition of cAMP-dependent protein kinase A (PKA). These findings indicate an alternative approach to the treatment of diseases associated with injury-induced cell growth of the arterial wall, as stimulation of cAMP signaling is pharmacologically feasible in the clinical setting.

We have discovered two somatic mutations in the VI transmembrane domain of the thyrotropin receptor gene in thyroid hyperfunctioning adenomas. The mutated amino acid residues are phenylalanine 631 (to cysteine) and threonine 632 (to isoleucine). Cloning and expression of the mutated versions of the receptor in COS cells increased significantly the basal and the TSH-induced cAMP levels compared to the wild type receptor. Moreover, the expression of a reporter gene under the control of the cAMP-inducible promoter, was likewise constitutively activated in cells expressing the 631 and 632 TSH receptor mutants relative to the wild type. These data indicate that the VI transmembrane segment in the TSH receptor and presumably in the other G-protein coupled receptors is a critical domain for the activation of G-protein signalling and that the mutations described here may be the cause of the thyroid hyperfunctioning adenoma.