Cangrelor in contemporary patients with ST-segment elevation myocardial infarction pretreated with Ticagrelor: Pharmacodynamic data from the POMPEII study.

Background: There are limited data to assess pharmacodynamic (PD) profiles of patients with STEMI undergoing primary percutaneous coronary intervention (PCI) and receiving cangrelor after pretreatment with ticagrelor. Methods: The PharmacOdynaMic effects of cangrelor in PatiEnts wIth acute or chronIc coronary syndrome undergoing percutaneous coronary intervention (POMPEII) registry (NCT04790032) is a prospective study conducted at Federico II University of Naples enrolling all patients undergoing PCI receiving cangrelor at operator's discretion. PD assessments were performed with 3 assays: (1) the gold standard light transmittance aggregometry (LTA) (20- and 5-µM adenosine diphosphate [ADP] stimuli); (2) VerifyNow P2Y12-test; (3) Multiplate electrode aggregometry (MEA), ADP-test. Results: We analyzed 13 STEMI patients pretreated with ticagrelor within 1 h at the time they underwent primary PCI receiving cangrelor. All patients showed low maximal platelet aggregation at 30-minute during cangrelor infusion, as well as at 3 h and 4-6 h (corresponding to 1 h and 2-4 h after stopping cangrelor infusion) with no cases of high residual platelet reactivity. These results were consistent with all assays. Conclusions: PD data show that in contemporary real-world STEMI patients pretreated within 1 h with ticagrelor undergoing primary PCI, adding cangrelor resulted in fast and potent platelet inhibition, thus suggesting that cangrelor may bridge the gap until ticagrelor reaches its effect.

Spinal anaesthesia with Chloroprocaine HCl 1% for elective lower limb procedures of short duration: a prospective, randomised, observer-blind study in adult patients.

BACKGROUND: This prospective, randomised, observer-blinded study has been conducted in patients undergoing procedures of the lower extremities to evaluate the time to complete block resolution of 2-chloroprocaine 1% at three intrathecal doses (30, 40 and 50 mg). METHODS: After informed consent, we enrolled 45 male and female patients, aged 18-65 years, ASA score I-II, BMI 18-32 kg/m2, undergoing elective lower limb procedures lasting ≤40 min and with a requested dermatomeric level of sensory block ≥ T12. The patients were randomised in a 1:1:1 ratio to receive Chloroprocaine HCl 1% at one of the three different intrathecal doses (Group 30 = 30 mg, Group 40 = 40 mg or Group 50 = 50 mg). The progression and regression of both sensory and motor blocks were evaluated blindly. Urine and venous blood samples were collected for pharmacokinetic analysis. RESULTS: Times to regression of spinal blocks were 1.76 ± 0.35 h, 2.13 ± 0.46 h and 2.23 ± 0.38 h, in Group 30, 40 and 50 respectively: the 30 mg dose showed a significantly faster resolution of spinal block than the 40 mg (p = 0.034) and the 50 mg (p = 0.006). Time to readiness for surgery was significantly reduced with the dose of 50 mg when compared to dose of 30 mg (p = 0.0259). CONCLUSIONS: The doses of 50 mg and 40 mg yielded a longer resolution of spinal block than the dose of 30 mg. Nevertheless, the dose of 30 mg resulted in a higher secondary failure rate. TRIAL REGISTRATION: Registration of clinical trial: clinicaltrials.gov ( NCT02481505 ).

LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling.

During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly understood. Here, we investigate the occurrence of pericyte-to-myofibroblast trans-differentiation (PMT) in sepsis-induced AKI. In a swine model of sepsis-induced AKI, PMT was detected within 9 h from LPS injection, as evaluated by the reduction of physiologic PDGFRß expression and the dysfunctional α-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-ß, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFRß and decreased α-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and α-SMA reorganization in contractile fibers by both SMAD2/3-dependent and -independent TGF-ß signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-ß and underwent PMT also upon TGF-ß receptor-blocking, indicating the crucial pro-fibrotic role of TLR4 signaling. Our data demonstrate that the selective removal of LBP may represent a therapeutic option to prevent PMT and the development of acute renal fibrosis in sepsis-induced AKI.

Prospective, Randomized, Multicenter, Controlled Trial (TRIATHRON 1) on a New Antithrombogenic Hydrophilic Dialysis Membrane.

INTRODUCTION: Hemodialysis treatment requires anticoagulation to prevent thrombosis of the dialyzer. The Hydrolink® (NV series; Toray) has been designed to reduce thrombotic complications by increasing membrane hydrophilic properties. Previous studies have confirmed reduced platelet activation, improved removal of ß2-microglobulin and excellent small-solute removal. METHODS: We designed a prospective, multi-centered, randomized clinical study to compare the antithrombogenic effects (platelet count) of NV dialyzers versus conventional treatment. To compare the possibility of performing heparin-free dialysis, we carried out progressive heparin reduction tests. Patients with an average platelet count lower than 170,000 cells/mm3 using standard high flux membranes in the 6 months prior to the study were enrolled and randomized. Patients were either dialyzed for 6 months without changing the previous membrane (control group) or treated with the Hydrolink® membrane (NV group). After the third week, the heparin reduction test was conducted for 5 weeks in order to assess the minimum amount of anticoagulant needed to safely perform a 4-hour dialysis treatment. Performance and safety were evaluated measuring platelet count and activation, middle-molecule removal rate and nutritional status. RESULTS: We found no significant difference in platelet count, platelet activation factors ß-thromboglobulin and platelet factor 4 (PF-4), between the groups. More patients in the study group reached heparin-free dialysis without clotting events during the heparin reduction test. The NV dialyzers displayed anti-thrombogenic effects as compared to conventional dialyzers. CONCLUSIONS: The NV dialyzer series is safe with no adverse events reported. Further studies are required to understand the mechanisms of anti-thrombogenic effects.

Rationale for the Evaluation of Renal Functional Reserve in Living Kidney Donors and Recipients: A Pilot Study.

BACKGROUND: In living kidney transplantation, preoperative donors' renal functional reserve (RFR) may correlate with postoperative residual renal function in both donors and recipients. The aim of this study was to evaluate the donors' RFR before transplantation and to compare basal and stress renal function before and after transplantation in both donors and recipients. METHODS: Seven pairs of living kidney donors and recipients were considered for this observational study. RFR was measured with a renal stress test (RST) before and after the kidney transplantation through an oral protein loading test (1 g/kg of body weight). RFR was defined as the difference between the maximum value of creatinine clearance after protein load (stress glomerular filtration rate, sGFR) and baseline creatinine clearance (basal GFR, bGFR). RESULTS: Before transplantation, a significant difference between sGFR and bGFR (p = 0.04) was observed in donors, with an RFR = 30.6 (11.9-41.5) mL/min/1.73 m2. After kidney transplantation, sGFR was similar to bGFR for both donors and recipients (p = 0.13), with a limited RFR (7.9 [6.70-19.25] and 14.90 [-6.67 to 25.53] mL/min/1.73 m2, respectively). The sum of the donor's and recipient's post-transplant sGFR was similar to the pre-transplant donor's sGFR (p = 0.73). CONCLUSION: RST is a safe, feasible, easy, and an inexpensive tool that is able to quantify RFR. In living kidney transplantation, it can be used in clinical practice to measure the original global filtration capacity of the donor's kidneys (sGFR) and to quantify the susceptibility of donors and recipients in developing postoperative kidney dysfunction. However, further studies with an adequate sample size and follow-up period are needed to test this hypothesis.

Incidence of ultrasound-detected asymptomatic long-term central vein catheter-related thrombosis and fibrin sheath in cancer patients.

BACKGROUND: Most central venous catheter (CVC)-related deep vein thromboses (DVT) are asymptomatic and their incidence and clinical relevance are still under debate. Data on CVC-related fibrin sheaths are scarce. We investigated the incidence of asymptomatic DVT and fibrin sheaths in cancer patients with long-term CVC implantation who underwent Doppler ultrasound surveillance at 1, 6, and 12 months after implantation. Effects of low-weight molecular heparin (LWMH) therapy on DVT and fibrin sheaths were also analyzed. MATERIAL AND METHODS: This prospective study was performed on a large cohort (n = 400) of patients with cancer aged >18 requiring long-term CVC implantation for chemotherapy infusion. CVC was implanted by a trained qualified staff, according to standardized protocol in a specific surgery. Patients underwent ultrasound examination at 1 and 6 months after CVC implantation to detect 'early' (1 month) and 'late' (6 months) asymptomatic DVT or fibrin sheaths incidence. Sixty-nine patients underwent US examination also 12 months after CVC implantation. RESULTS: The incidence of CVC-related thrombosis was 0.10 events per 1000 catheter days. Anticoagulation therapy with LWMH resolved 50% of DVT, but no CVC needed removing. Incidence of new onset fibrin sheaths was 0.71 events per 1000 catheter days. Fibrin sheaths resolution occurred independently of LWMH therapy. DISCUSSION: The incidence of asymptomatic DVT in our patients with long-term CVC is very low and does not represent per se an indication for removal of functioning CVC in patients with cancer. Fibrin sheaths are frequent (13%) and never associated with CVC dysfunction. CONCLUSION: Asymptomatic DVT and fibrin sheaths do not represent per se an indication for removal of functioning CVC in cancer patients who need central vein access.

Natural attenuation and biosurfactant-stimulated bioremediation of estuarine sediments contaminated with diesel oil.

We evaluated the bioremediation, by natural attenuation (NA) and by natural attenuation stimulated (SNA) using a rhamnolipid biosurfactant, of estuarine sediments contaminated with diesel oil. Sediment samples (30 cm) were put into 35 cm glass columns, and the concentrations of the 16 polycyclic aromatic hydrocarbons (PAHs) prioritized by the US Environmental Protection Agency were monitored for 111 days. Naphthalene percolated through the columns more than the other PAHs, and, in general, the concentrations of the lower molecular weight PAHs, consisting of two and three aromatic rings, changed during the first 45 days of treatment, whereas the concentrations of the higher molecular weight PAHs, consisting of four, five, and six rings, were more stable. The higher molecular weight PAHs became more available after 45 days, in the deeper parts of the columns (20-30 cm). Evidence of degradation was observed only for some compounds, such as pyrene, with a total removal efficiency of 82 and 78 % in the NA and SNA treatments, respectively, but without significant difference. In the case of total PAH removal, the efficiencies were significantly different of 82 and 67 %, respectively.

Bioremediation of a tropical clay soil contaminated with diesel oil.

The removal of polyaromatic hydrocarbons (PAH) in tropical clay soil contaminated with diesel oil was evaluated. Three bioremediation treatments were used: landfarming (LF), biostimulation (BS) and biostimulation with bioaugmentation (BSBA). The treatment removal efficiency for the total PAHs differed from the efficiencies for the removal of individual PAH compounds. In the case of total PAHs, the removal values obtained at the end of the 129-day experimental period were 87%, 89% and 87% for LF, BS and BSBA, respectively. Thus, the efficiency was not improved by the addition of nutrients and microorganisms. Typically, two distinct phases were observed. A higher removal rate occurred in the first 17 days (P-I) and a lower rate occurred in the last 112 days (P-II). In phase P-I, the zero-order kinetic parameter (µg PAH g(-1) soil d(-1)) values were similar (about 4.6) for all the three treatments. In P-II, values were also similar but much lower (about 0.14). P-I was characterized by a sharp pH decrease to less than 5.0 for the BS and BSBA treatments, while the pH remained near 6.5 for LF. Concerning the 16 individual priority PAH compounds, the results varied depending on the bioremediation treatment used and on the PAH species of interest. In general, compounds with fewer aromatic rings were better removed by BS or BSBA, while those with 4 or more rings were most effectively removed by LF. The biphasic removal behavior was observed only for some compounds. In the case of naphthalene, pyrene, chrysene, benzo[k]fluoranthene and benzo[a]pyrene, removal occurred mostly in the P-I phase. Therefore, the best degradation process for total or individual PAHs should be selected considering the target compounds and the local conditions, such as native microbiota and soil type.

New perspectives in the management of post-surgical macular edema.

Post-surgical macular edema is the most common cause of vision loss after phacoemulsification, and one of the main causes of reduced vision in patients undergoing other ocular surgery. At present, there are no reliable randomized clinical trials specifically designed to define the best therapeutic approach, and little information is available regarding the treatment algorithm of acute or chronic forms. As a consequence, there is no agreement regarding the current management of post-surgical macular edema. Many therapeutic options have been proposed on the basis of the hypothesized pathogenetic mechanism of post-surgical macular edema. New therapies for post-surgical macular edema include non-steroidal anti-flammatory drugs and intraocular steroid implants. Aim of the review is to update the current management of postsurgical macular edema, reporting on the most recent therapeutic advances. In particular, we discuss the potential applications of recent patents with topical and intravitreal drugs.

Limbal stem-cell therapy and long-term corneal regeneration.

BACKGROUND: Corneal renewal and repair are mediated by stem cells of the limbus, the narrow zone between the cornea and the bulbar conjunctiva. Ocular burns may destroy the limbus, causing limbal stem-cell deficiency. We investigated the long-term clinical results of cell therapy in patients with burn-related corneal destruction associated with limbal stem-cell deficiency, a highly disabling ocular disease. METHODS: We used autologous limbal stem cells cultivated on fibrin to treat 112 patients with corneal damage, most of whom had burn-dependent limbal stem-cell deficiency. Clinical results were assessed by means of Kaplan-Meier, Kruskal-Wallis, and univariate and multivariate logistic-regression analyses. We also assessed the clinical outcome according to the percentage of holoclone-forming stem cells, detected as cells that stain intensely (p63-bright cells) in the cultures. RESULTS: Permanent restoration of a transparent, renewing corneal epithelium was attained in 76.6% of eyes. The failures occurred within the first year. Restored eyes remained stable over time, with up to 10 years of follow-up (mean, 2.91+/-1.99; median, 1.93). In post hoc analyses, success--that is, the generation of normal epithelium on donor stroma--was associated with the percentage of p63-bright holoclone-forming stem cells in culture. Cultures in which p63-bright cells constituted more than 3% of the total number of clonogenic cells were associated with successful transplantation in 78% of patients. In contrast, cultures in which such cells made up 3% or less of the total number of cells were associated with successful transplantation in only 11% of patients. Graft failure was also associated with the type of initial ocular damage and postoperative complications. CONCLUSIONS: Cultures of limbal stem cells represent a source of cells for transplantation in the treatment of destruction of the human cornea due to burns.

Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use.

A 32-year-old man with keratoconus developed corneal melting 5 days after riboflavin/ultraviolet-A corneal collagen crosslinking (CXL). Corneal scraping was positive for Acanthamoeba. The patient was unaware that he was wearing a bandage contact lens and repeatedly rinsed his face and eyelids with tap water. Because of corneal perforation, a large therapeutic keratoplasty à chaud was performed. Although CXL is considered a safe procedure, this case emphasizes the potential risks. We discuss the potential effects of deepithelialization, contact lens placement, instillation of topical nonsteroidal antiinflammatory drugs and anesthetic agents, and the possible role of apoptosis when performing CXL treatment for keratoconus.

Sedative effect of acupuncture during cataract surgery: prospective randomized double-blind study.

PURPOSE: To assess the effectiveness of acupuncture in reducing anxiety in patients having cataract surgery under topical anesthesia. SETTING: Vita-Salute University of Milan and IRCCS H. San Raffaele, Milan, Italy. METHODS: In a prospective randomized double-blind controlled trial, anxiety levels before and after cataract surgery in 3 groups (A = no acupuncture, B = true acupuncture starting 20 minutes before surgery, C = sham acupuncture starting 20 minutes before surgery) were compared using the Visual Analog Scale (VAS). Twenty-five patients scheduled for inpatient phacoemulsification were enrolled in each group. All surgeries were performed using topical anesthesia. Exclusion criteria were refusal to provide informed consent, use of drugs with sedative properties, psychiatric disease, pregnancy, knowledge of the principles of acupuncture, anatomic alterations, or cutaneous infections precluding acupuncture at the selected acupoints. RESULTS: Preoperative anxiety levels were significantly lower only in Group B (P = .001). Anxiety in Group B was significantly lower than in Group A (P = .001) and Group C (P = .037). Regarding postoperative anxiety, the mean VAS score was 39 +/- 5 in Group A, 19 +/- 3 in Group B, and 31 +/- 4 in Group C. The difference was significant only between Group A and Group B (P = .003). CONCLUSION: Acupuncture was effective in reducing anxiety related to cataract surgery under topical anesthesia.