The complex medical-surgical treatment in septical states

Clinica 2 Chirurgie „Constantin Ţîbîrnă”, Catedra 2 Chirurgie USMF „N.Testemiţanu”, Chişinău, Republica Moldova, Al XI-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” din Republica Moldova și cea de-a XXXIII-a Reuniune a Chirurgilor din Moldova „Iacomi-Răzeșu” 27-30 septembrie 2011Introducere: Conform concepţiilor moderne, sepsisul reprezintă o reacţie sistemică către agresia microbiană cu expulzia incontrolabilă a mediatorilor inflamaţiei şi dereglări grave de microcirculaţie, asociate hipoxiei tisulare. Astfel este argumentată utilizarea metodelor noi de inactivare a metaboliţilor proinflamatorii şi sistarea stresului oxidativ cu corijarea hipoxiei hemocirculatorii sistemice. Scopul studiului a constituit estimarea posibilităţilor aplicării ozonoterapiei sistemice în tratamentul complex medico-chirurgical la bolnavii cu stări septice. Material şi metode: Studiul dat include analiza retrospectivă a rezultatelor tratamentului la 382 bolnavi cu sepsis chirurgical (bărbaţi-199, femei-183, vîrsta medie-47+/-3,1 ani), trataţi în Clinicele Chirurgie şi ATI ale SCM “Sfînta Treime” în perioada aa.2005-2010. Diagnosticul de sepsis a fost stabilit conform criteriilor Bone R. Obligatoriu s-a recurs la examenul bacteriologic cu aprecierea antibioticogramei, în baza căreea s-a elaborat o schemă optimă de conduită în tratamentul antimicrobian.. Ozonoterapia sistemică s-a efectuat la 84 pacienţi prin perfuzii de Sol NaCl 0,9%-400,0 ml saturată cu ozon, cu o concentraţie a O3 în limite de 800-1200 mkg/l în amestecul ozonat-oxigenat. Rezultate: Hemocultura pozitivă a fost stabilită în 132 (34,5%) cazuri. Monoinfecţia - în 36. cazuri, inclusiv bacili Gram negativi-28 (77%); Gram pozitivi -8 (23%). La 96 bolnavi a fost identificată poliinfecţie. Durata medie de spitalizare a constituit 21+/-1,7 zile. Însănătoşirea a survenit în 317 (83%) cazuri. Au decedat 65 pacienţi, ce atestă o letalitate de 17.%. În lotul pacienţilor la care s-a aplicat ozonoterapia sistemică letalitatea a constituit 12 pacienţi (14,2%). Concluzii: Rezultatele obţinute demonstrează persistenţa dominaţiei sepsisului Gram negativ. Ozonoterapia sistemică în stările septice micşorează mortalitatea spitalicească.Introduction: According to modern concepts, sepsis is a systemic response to microbial aggression with uncontrollable expulsion of mediators of inflammation and disorders of microcirculation serious, associated with tissue hypoxia. So appear to be motivated the using of new methods for inactivation of proinflammatory metabolites and oxidative stress with correction and stopping of systemic hemocirculating hypoxia. Aim: The purpose of the study was estimation of possibility of systemic ozone therapy in the complex medical and surgical treatment in patients with sepsis. Material and methods: This study includes retrospective analysis of treatment results from 382 patients with surgical sepsis (men-199, female 183, average age, 47 + / -3.1 years) treated in the clinics of surgery and ATI SCM “Sfînta Treime”from aa.2005-2010. The diagnosis of sepsis was established according to criteria R. Bone with obligatory using of antibioticogramme. Bazed on bacterial appreciation, was have performed the scheme to prepare optimal conduct for antimicrobial treatment. Ozone therapy was performed in 84 patients by systematiically infusion of Sol. NaCl 0.9% -400.0 ml, saturated with ozone at a concentration of O3 in the range of 800-1200 mkg / l ozone-oxygen in the mixture. Results: Positive blood culture was established in 132 (34.5%) cases. Monoinfection was stabilited in 36. cases, including Gram-negative bacilli- 28 (77%), Gram positive -8 (23%). 96 patients were identified poliinfection. Average length of stay was 21 + / -1.7 days. Recovery occurred in 317 (83%) cases. Diedet 65 patients (17%). In the group of patients who received systemic Ozone therapy lethality was 12 patients (14.2%). Conclusions: The results demonstrate the domination of Gram-negative sepsis. The application of systemic Ozone therapy decreased hospital mortality in septic states

Taurine blunts doxorubicin cardiotoxicity: chronic and acute effects

Aim. To study the functional statement of the isolated heart inherent to doxorubicin cardiotoxicity under the chronic and acute action of taurine. Material and methods. Doxorubicin (Dx) cardiotoxicity manifested by heart failure development was reproduced classically by anthracycline i/p administration in rats in cumulative dose of 16 mg/kg (4 mg/kg four times during 2 weeks) – Dx series. Series with chronic action of taurine (Tr) included rats receiving this aminoacid daily per os during Dx administration (100 mg/kg) – Dx + Tr series. Rats of both series were sacrificed by euthanasia and the isolated heart was perfused by Krebs solution according to Langendorff (isovolumic heart) and Neely-Rovetto (working heart) methods in conditions of diverse hemodynamic and neuroendocrine efforts applying. Acute action of taurine was studied during its infusion in the perfusate of isolated hearts in final concentration of 40 µM. The hearts of intact rats constituted the control series. Results. Chronic action of taurine has identified certain important functional benefits, the most important being underlined beneath. The first, taurine reversed the negative inotropic effect of isolated heart on endothelin-1 (ET-1) action (10-7 M), detected in Dx series and manifested by both systolic pressure of left ventricle (LV) and cardiac output fall by about 9,1%. Taurine assured increase of these indices during ET-1 stimulation. The second, Tr notably improved both isovolumic relaxation and contraction of myocardium exhibited by significant enhancement of Veragut index (118,6 ± 9,6 vs 94,8 ± 6,5 1/sec), +dP/dPmax (8389 ± 445 vs 7216 ± 363 mm Hg/sec) and -dP/dTmax (7526 ±  378 vs 5684 ± 322 mm Hg/sec) during efforts with volume and resistance. The third, Tr significantly decreased LV end diastolic pressure (LVSDP) when coronary pressure of isovolumic heart elevated by 50% (from 80 up to 120 cm H20 column): 16,2 ± 1,2 vs 18,8 ± 1,4 mm Hg. Acute Tr action manifested by: (i) significant LVSDP diminution during 30 min of ischemia (52,4 ± 3,1 vs 63,7 ± 4,4 mm Hg) and on 45th min of reperfusion (18,3 ± 1,3 vs 22,8 ± 1,4 mm Hg), (ii) increased time of LV extrasystole appearance when the glucose content of Krebs solution was reduced by 50% (28,6 ± 2,8 vs 22,5 ± 2,4 min), and (iii) increased time of LV tachyarrhythmia appearance when the potassium content of Krebs solution raised up to 6,5 meq/L (9,2 ± 0,5 vs 6,9 ± 0,3 min). Conclusion. Taurine, a natural calcium modulator of the heart, notably improves functional reserves of the myocardium exposed to cardiotoxic action of Dx, and could be seen as a relevant remedy of primary and secondary prophylaxis of Dx induced heart failure in oncologic patients

Inflammation mitigation improves post-infarction functional recovery of the heart

Aim The in vitro evaluation of the cardiac functional effects of TNF-α antagonist administration in rats after isoproterenol induced myocardial infarction. Material and methods Myocardial infarction was reproduced using a proven model based on isoproterenol i/p administration in rats in 2 consecutive days in a similar dose, 150 mg/kg. In another group the animals after isoproterenol induced myocardial infarction (series IMI) have received daily TNF-α antagonist, a specific monoclonal antibody (ma-TNF-α) i/p in dose of 50 mg/kg during 8 days (series IMI+ma-TNF-α). In both series the animals were sacrificed after 10 days from the 1st injection and their isolated hearts ware perfused with Krebs solution according to Langendorff and Neely-Rovetto models. Results The most remarkable traits of left ventricle dysfunction in IMI in comparison to control were following: (1) diminution of cardiac output (CO), systolic pressure (SP) and +dP/dT max by respectively 28,7 and 34,7 and 23,3%; (2) negative inotropic effect to action of endothelin-1 manifested by decrease of SP and aortic jet during stimulation up to 13,9%; (3) increased cardiac arrhythmogenic activity in response to calcium overload; (4) increasing by 45,2% of ischemia induced contracture as well as decreasing by 37,5% of SP during reperfusion. The ma-TNF-α administration in post-infarction period led to noticeable benefits such as: significant enhancement of SP and CO respectively by 17,3 and 18,6% as well as positive inotropic effect developing to ET-1 action as well as significant increase of time regarding the appearance of ventricular extrasystole and ventricular tachyarrhythmia by respectively 12,9 and 11,7% as well as perceptible improvement of ischemia-reperfusion syndrome. Conclusion A sustained inflammation inhibition by ma-TNF-α administration in post-infarction period improves tangibly the cardiac functioning that proves the role of inflammatory response in myocardial infarction induced functional and structural myocardial remodeling and underlines the inflammation as a therapeutic target

Ultrahigh energy neutrinos at the pierre auger observatory

The observation of ultrahigh energy neutrinos (UHEs) has become a priority in experimental astroparticle physics. UHEs can be detected with a variety of techniques. In particular, neutrinos can interact in the atmosphere (downward-going ) or in the Earth crust (Earth-skimming ), producing air showers that can be observed with arrays of detectors at the ground. With the surface detector array of the Pierre Auger Observatory we can detect these types of cascades. The distinguishing signature for neutrino events is the presence of very inclined showers produced close to the ground (i.e., after having traversed a large amount of atmosphere). In this work we review the procedure and criteria established to search for UHEs in the data collected with the ground array of the Pierre Auger Observatory.This includes Earth-skimming as well as downward-going neutrinos. No neutrino candidates have been found, which allows us to place competitive limits to the diffuse flux of UHEs in the EeV range and above

Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial

Background: Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Method: We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. Finding: Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227–29 056) in the suspend methotrexate group and 12 326 U/mL (10 538–14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59–2·70; p<0·0001). No intervention-related serious adverse events occurred. Interpretation: 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. Funding: National Institute for Health and Care Research

Angiotensin 1-7 blunts in vitro induced acute heart failure

Background: Angiotensin 1-7 (Ang 1-7) comprises consistent evidences regarding cardiovascular regulatory benefits due to Ang II receptor AT1 modulation via mass receptor.Aim: Evaluation of the Ang 1-7 cardiac effects in the in vitro induced acute heart failure.Material and methods: Acute heart failure (AHF) was induced using the model of isolated rat pumping heart perfused by Krebs solution without glucose during20 min according to Neely-Rovetto model (glucose is a single energetic substrate in this model) – control series. In another series heart has been perfused without glucose, but Ang 1-7 was added till final concentration of 10-7 M – medicated series. Left ventricle (LV) functional parameters were assayed during inotropic stimulation by norepinephrine (NE) and endothelin 1 (ET-1) in concentration of 10-6M, or ischemia-reperfusion impact (15 min of total ischemia followed by 20 min of reperfusion) reproduced in Langendorff isovolumic isolated heart. Results: Cardiac output (CO) significantly decreased after 20 min perfusion of isolate heart without glucose by 25,9% (29,4±1,3 vs 39,7±2,1 ml/min). Action of Ang 1-7led to a less decline of CO compared to control (34,8±1,6 vs 29,4±1,3 ml/min,p<0,05). NE stimulation induced an increase of control CO by 10,7% associated by LV end-diastolic pressure (LVEDP) elevation of 30,3% while in medicated series response was better: CO increased by 14,4% and LVEDP boosted only by 17,6%((19,3±1,6 (Ang 1-7) vs 27,4±1,7 (control) mm Hg, p<0,05). Stimulated by ET-1control isolated heart responded by a negative inotropic effect, and both systolicLV pressure and CO fallen respectively by 13,2% and 9,6%. Ang 1-7 insured a positive inotropic response during ET-1 action leading to CO and LV systolic pressure increase respectively by 10,5% and 11,7%. Ang 1-7 also improved the dynamics of LVEDP during ischemia-reperfusion. Thus, LVEDP was in medicated series significantly less than control index at finish of both ischemia (41,3±3,2 vs55,4±4,4 mm Hg) and reperfusion (17,2±1,4 vs 28,7±2,2 mm Hg) periods. Conclusion: Angiotensin 1-7 is a component of renin-angiotensin-aldosterone system which has a benefic action on acutely developing heart failure due to energy privation, manifested by improvement of the inotropic response of NE and reinstate positive inotropic of ET-1 action as well as significant diminution of LVEDP during ischemia-reperfusion syndrome

Vanhoutte and Bowditch phenomena in heart failure: their relation toischemia-reperfusion impact

Aim: Evaluation of both 15,16-epoxyeicosatrien (15,16-EET) induced coronaro dilation and Bowditch’s staircase in experimental heart failure (HF) as well as their influence on ischemic contracture and functional recovery of isolated heart during reperfusion.Material and methods:HF was reproduced by doxorubicin administration in rat (16mg/kg in 2 weeks). Vanhoutte’s phenomenon was estimated by coronary flow raising rate in isovolumic isolated heart perfused by Langendorff method during action of15,16-EET (10-4 M). Bowditch’s staircase was assayed by electrically induced heart rate (HR) rise till maximal level suitable to left ventricle (LV) systolic pressure elevation(LVSP). Ischemic contracture was appreciated by LV end-diastolic pressure (LVEDP)at the end of global 20 min ischemia period followed by 30 min period of reperfusion when LVSP dynamics has been recorded. Likewise, ischemia-reperfusion impact was attested in condition of 15,16-EET action during pre-ischemia (20 min) and reperfusion as well as after maximal HR reaching.Results:Coronarodilation effect of 15,16-EET has not been compromised in HF,because the coronary flow increased like in control comparatively to basal value(13,2±1,2% vs 13,9±1,1%). However, Bowditch’s staircase was earlier interrupted in comparison to control according to maximal HR matching to positive slope of LSD: 285±22,6 vs 372±29,4 1/min (p<0,05). Maximal ischemic LVEDP was significantly higher in HR: 47,6±3,3 vs 24,9±1,8 mmHg (p<0,001). On the other hand LVSP was at the end of reperfusion lower than control: 72,4±6,5 vs112,3±7,5 mmHg (p<0,01). Remarkably, 15,16-EET action before ischemia and during reperfusion notably improved dynamics of LVEDP and LVEDP in both control and HF (in the last even more evidently). Relative diminution of LVEDP measured14,3±1,4% in HF and 12,5±1,2% in control, and LVESP increment: 15,1±1,5%vs 13,7±1,3%. If the ischemia-reperfusion onset started after frequency pacingischemic contracture and functional LV recovery worsened similarly in both control and HF series: LVEDP increased by 19-20% while LVSP decreased by 17-18%.Conclusions:1. Derived (in cytochrome P450 biochemical way) from arachidonic acid 15,16-EET increases coronary flow in HF similarly to control and could be an important factor of coronary regulation by hyperpolarization mechanism in cases of endothelium dependent compromised coronary reactivity.2. 15,16-EET mitigates ischemia-reperfusion impact in HF while HR elevationworsens ischemic contracture and LV contraction recovery in reperfusion

Inflammation inhibition effects in diabetes induced heart failure

Background:Inflammation is appreciated as a leading factor regarding car-diovascular disorders triggering and exacerbation. Nevertheless a promisingantinflammatory treatment concerning cardiac mismatch improvement is not yetconsolidated.Aim:The in vitro evaluation of cardiac effects of the TNF-alpha antagonist adminis-tration during diabetes-induced heart failure (DHF).Material and methods:DHF was classically reproduced in rats by i/p adminis-tration of streprozotocin (50 mg/kg, 5 days) – series 1 (of reference). TNF-alphaantagonist, TNF-McAb (TNF monoclonal antibody, analog of infliximab) has beenadministered i/p during DHF modeling and 5 days after – series 2. After 10 daysanimals of both series have been euthanized, and isolated heart was perfused inisovolumic regimen (Langendorff model) or exterior working (Neely-Rovetto model).Cardiac reactivity was assayed in: (1) hemodynamic effort due to pre- and afterload increase; (2) neuroendocrine activation modulated by action in diverse concentra-tions of norepinephrine, angiotensin II and endothelin-1 (ET-1); (3) in ischemia (30min) followed by reperfusion (45 min) syndrome.Results:TNF-alpha inhibition led to significant increase of cardiac output (CO) ineffort with volume and resistance respectively by 23,7 and 26,2% comparativelyto reference indices. Systolic pressure of left ventricle (LV) was in series 1 higher inall induced hemodynamic stress levels, but on aortic pressure of 100 and 120 cmH20 the increment was significant and averagely represented 18-19%. DHF wascharacterized by LV lusitropic function impairment, whose principal parameters,telediastolic pressure (LVTDP) and index of diastolic myocardial rigidity significantlydecreased during TNF-alpha inhibition by 26-28%. The norepinephrine action ledin DHF to inotrop-chronotropic effect dissociation, but endothelin-1 (ET-1) induceda negative inotropic effect, associated by CO reducing by 10,3%. TNF-alpha inhibi-tion led to appearance of positive inotropic effect to ET-1 action and cardiac outputincrease by 11%. Myocardial ischemic contracture assayed after 30 min of ischemiathereby of LVTDP is doubly more in DHF vs control pattern (56,3±3,6 vs 28,4±1,9mm Hg) and remains above on 45th min of reperfusion (39,2±2,5 vs 18,8±1,2mm Hg). TNF-McAb notably attenuated consequences of ischemia-reperfusionsyndrome, leading to LVTDP drop by 29,3% at finish of ischemia and by 26,8% atfinish of reperfusion.Conclusions:1. TNF-alpha inhibition during diabetes-induced heart failureimproved cardiac functionality, confirming the pathogenical role of inflamma-tion and, on the other hand, the therapeutic relevance of TNF-McAb regardingoutworn heart functioning in hemodynamic and neuroendocrine efforts.2. Most conspicuous TNF-McAb benefit has referred to appearance of positiveinotropic effect to ET-1 action and significant decrease of LV telediastolic pressureby around 29% in ischemia-reperfusion syndrome