Veterinary medicine - Repository of PHD, master's thesis
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Volume resuscitation in patients during anaesthesia
No full textPerioperativna nadoknada volumena važna je komponenta anesteziološke skrbi jer omogućuje
održavanje hemodinamske stabilnosti, adekvatne perfuzije tkiva i elektrolitske homeostaze.
Tijekom operacije pacijenti su podložni značajnim gubicima tekućine zbog krvarenja,
evaporacije, preoperativnog gladovanja i pomaka tekućine u treći prostor, što može dovesti do
hipovolemije i smanjenja oksigenacije tkiva. Volumen tjelesne tekućine raspodijeljen je
između unutarstaničnog i izvanstaničnog prostora, a kretanje tekućine regulirano je osmotskim
i hidrostatkim silama prema Starlingovim načelima. Infuzijske otopine dijele se na kristaloide
i koloide. Kristaloidi su otopine malih molekula koje se brzo distribuiraju u ekstracelularni
prostor, dok koloidi sadrže visokomolekularne tvari koje zadržavaju vodu u intravaskularnom
prostoru povećanjem onkotskog tlaka. Od kristaloida, fiziološka otopina i balansirane otopine
poput Ringerova laktata i Plasma-Lytea najčešće su u primjeni. Balansirane otopine imaju
povoljniji učinak na acidobaznu ravnotežu i niži rizik od hiperkloremijske acidoze. Koloidne
otopine uključuju želatine, hidroksietil škrob, dekstrane i otopine humanog albumina, no
njihova primjena zahtijeva oprez zbog mogućih nuspojava poput koagulopatija, anafilaktičkih
reakcija i oštećenja bubrega. Procjena volumnog statusa temelji se na kombinaciji kliničkih
znakova i hemodinamskog monitoringa. Parametri poput središnjeg venskog tlaka, srednjeg
arterijskog tlaka, srčanog minutnog volumena i zasićenosti kisikom pružaju uvid u učinkovitost
perfuzije. Ciljano vođena terapija infuzijama smanjuje učestalost komplikacija i skraćuje
boravak u bolnici. Kod posebnih skupina bolesnika, perioperativni rizik je povećan stoga
volumna nadoknada mora biti prilagođena jer neadekvatan unos tekućine može pogoršati
ishode lijećenja. Prekomjerna nadoknada povećava rizik od edema, zatajenja organa i
produljene hospitalizacije. Stoga je nužna individualizirana, fiziološki utemeljena i pažljivo
nadzirana infuzijska terapija.Perioperative fluid resuscitation is a key component of anaesthetic care, as it enables the maintenance of haemodynamic stability, adequate tissue perfusion, and electrolyte homeostasis. During surgery, patients are exposed to significant fluid losses due to bleeding, evaporation, preoperative fasting, and fluid shifts into the third space, which may lead to hypovolemia and impaired tissue oxygenation. Body fluid volume is distributed between the intracellular and extracellular compartments, with fluid movement regulated by osmotic and hydrostatic forces in accordance with Starling’s principles. Intravenous fluids are classified as crystalloids and colloids. Crystalloids are solutions of small molecules that rapidly distribute into the extracellular space, whereas colloids contain high-molecular-weight substances that retain water in the intravascular space by increasing oncotic pressure. Among crystalloids, normal saline and balanced solutions such as Ringer’s lactate and Plasma-Lyte are most commonly used. Balanced solutions have a more favourable effect on acid–base balance and carry a lower risk of hyperchloremic acidosis. Colloids include gelatins, hydroxyethyl starch, dextrans, and human albumin; however, their use requires caution due to potential adverse effects such as coagulopathy, anaphylactic reactions, and kidney injury. Assessment of volume status is based on a combination of clinical signs and haemodynamic monitoring. Parameters such as central venous pressure, mean arterial pressure, cardiac output, and oxygen saturation provide insight into the adequacy of tissue perfusion. Goal-directed fluid therapy reduces the incidence of complications and shortens hospital stay. Fluid resuscitation must be adapted when treating patient populations with increased perioperative risk as inappropriate fluid administration may worsen their clinical outcomes. Excessive fluid administration increases the risk of oedema, organ failure, and prolonged hospitalisation. Therefore, individualised, physiologically guided, and closely monitored infusion therapy is essential
Chronic coronary syndrome
No full textKronični koronarni sindrom (CCS) obuhvaća širok spektar kliničkih prezentacija stabilne ishemijske bolesti srca. U velikog broja bolesnika može se prepoznati na temelju tipičnih anginoznih simptoma koji se javljaju u naporu i ublažavaju mirovanjem ili primjenom nitroglicerina, osobito u prisutnosti čimbenika rizika za aterosklerotsku kardiovaskularnu bolest (ASKVB) ili već poznate ASKVB. Ipak, zahvaljujući novijim spoznajama o patofiziološkim mehanizmima nastanka ishemije, CCS se više ne povezuje isključivo s opstruktivnom aterosklerotskom bolešću epikardijalnih koronarnih arterija, već i s funkcionalnim i strukturnim poremećajima mikrovaskularizacije, vazospazmom i endotelnom disfunkcijom, osobito u okviru angine/ishemije bez opstrukcije koronarnih arterija (ANOCA/INOCA). Dijagnostička obrada zahtijeva multimodalni pristup koji uključuje neinvazivne (koronarna kompjutorizirana tomografska angiografija (CCTA), stres-ehokardiografija, perfuzijsko oslikavanje) i invazivne metode (invazivna koronarna angiografija (ICA) uz evaluaciju FFR/iFR i mikrocirkulacije), čime se omogućuje postavljanje etiološki usmjerene dijagnoze. Posebno se naglašava potreba za pravovremenim prepoznavanjem ANOCA/INOCA, koja često ostaje nedijagnosticirana unatoč značajnom morbiditetu, narušenoj kvaliteti života i dugoročnim kardiovaskularnim ishodima. Integracijom kliničke procjene i navedenih dijagnostičkih metoda provodi se stratifikacija rizika od neželjenih kardiovaskularnih događaja (MACE), koja je neophodna za sve bolesnike s novootkrivenom ishemijskom bolesti srca, te odabir optimalnog terapijskog modaliteta. Liječenje obuhvaća promjene životnih navika, ciljanju farmakološku terapiju antianginoznim, antitrombotskim, hipolipemijskim i ostalim lijekovima te selektivnu primjenu metoda revaskularizacije (PCI i CABG) kod visokorizičnih bolesnika. Iako su prepoznati višestruki mehanizmi koji dovode do ishemije miokarda, dijagnostički, prognostički i terapijski algoritmi i dalje su primarno usmjereni na opstruktivnu koronarnu bolest, dok je u području zbrinjavanja neaterosklerotskih uzroka ishemije ostvaren ograničen napredak.Chronic coronary syndrome (CCS) encompasses a broad range of clinical manifestations of stable ischemic heart disease. In most patients, CCS can be identified based on typical anginal symptoms that occur in exertion and are relieved with rest or nitroglycerin, particularly in the presence of either risk factors for or known atherosclerotic cardiovascular disease (CAD). However, insights into the pathophysiological mechanisms of myocardial ischemia have expanded the understanding of CCS beyond obstructive CAD. It now includes structural and functional abnormalities of the coronary microcirculation, coronary vasospasm and endothelial dysfunction, particularly in the context of ANOCA/INOCA (angina/ischemia with non-obstructive coronary arteries). A comprehensive diagnostic approach is required, incorporating both non-invasive (such as coronary computed tomography angiography (CCTA), stress echocardiography and myocardial perfusion imaging) and invasive tests (including invasive coronary angiography (ICA) with assessment of FFR/iFR and microvascular function). The recognition of ANOCA/INOCA is particularly important, as these conditions are frequently underdiagnosed despite being associated with significant morbidity, impaired quality of life and adverse long-term cardiovascular outcomes. Integration of clinical assessment with diagnostic findings supports risk stratification for major adverse cardiovascular events (MACE), which is essential in all patients with newly diagnosed ischemic heart disease and guides the selection of an individualized treatment strategy. Management includes lifestyle modification, pharmacotherapy, as well as selective application of revascularization procedures (PCI or CABG) in high-risk patients. While multiple mechanisms contributing to myocardial ischemia have been identified, current diagnostic, prognostic and therapeutic algorithms remain predominantly focused on obstructive CAD while progress in the management of non-atherosclerotic causes of ischemia remains limited
Recent Insights into the Pathogenesis, Diagnostics, and Treatment of BK Virus Infections in Children After Hematopoietic Stem Cell Transplantation
No full textBK polyomavirus (BKPyV) is a pathogen responsible for infectious complications in hematopoietic stem cell transplant (HSCT) recipients. This review aims to give an insight into recent data about the structure and genomic organization, epidemiology, clinical manifestations, diagnosis, and current treatment options of BKPyV infections in children after HSCT. News regarding viral replication and pathogenesis include the generation of miRNA, new mechanisms of viral shedding by releasing infectious particles via extracellular vesicles, and human bladder microvascular endothelial cells probably acting as viral reservoirs enabling low-level viral replication and persistence. In studies conducted over the past five years, BKPyV hemorrhagic cystitis (BKPyV-HC) has a prevalence rate of 4 to 27% in children undergoing HSCT. Diagnostics still has unsolved dilemmas like whole blood or plasma samples as well as the standardization of molecular methods to allow for reporting in international units. In terms of treatment, new approaches have been used in the past five years, including the use of mesenchymal stem cells (MSCs), virus-specific T cells (VSTs), and recombinant human keratinocyte growth factor (rH-KGF), although the efficacy of some of these treatments has only been documented in isolated studies. This complication continues to pose a substantial clinical challenge, characterized by an absence of effective preventive and therapeutic measures
Adverse cutaneous drug reactions
No full textNuspojave lijekova neželjene su reakcije na lijekove primijenjene u propisanoj dozi. Skup aktivnosti, kojima se prikupljaju saznanja o štetnim učincima lijekova kako bi se u budućnosti prevenirale nuspojave i poboljšala sigurnost primjene istih, naziva se farmakovigilancija. Biotransformacija proces je koji može rezultirati smanjenom ili pojačanom aktivnošću lijeka, pa i toksičnim svojstvima nekih njegovih produkata, što može rezultirati nuspojavama. Istodobna primjena više lijekova predstavlja rizik od njihove međusobne interakcije, povećavajući šansu za nastanak nuspojava. Kožne nuspojave lijekova klasificiraju se prema težini, patogenezi i kliničkoj slici. Hartwigova skala za procjenu težine razvrstava kožne nuspojave u sedam razina, a ugrubo ih dijelimo na blage, umjerene, teške i letalne. Patogeneza kožnih nuspojava može biti imunološka ili neimunološka. Trenutno je poznato 29 do 35 kliničkih oblika kožnih nuspojava, od najblažeg eritema pa sve do opsežnih nekrotičnih morfa sa sistemskom simptomatologijom. Antibiotici, nesteroidni protuupalni lijekovi i antiepileptici najčešće su skupine lijekova koji uzrokuju kožne nuspojave. Zbog svoje široke primjene i čestog propisivanja, psihotropni lijekovi također pripadaju toj grupi. U dijagnostici kožnih nuspojava kliničari se uglavnom oslanjaju na anamnezu i kliničku sliku. Liječenje se temelji na ukidanju lijeka uzročnika ili smanjenju njegove doze, u slučaju blažih nuspojava. Kod ozbiljnijih nuspojava, samo ukidanje lijeka često nije dovoljno, već je u procesu liječenja nužna pažljivo odabrana suportivna terapija, a u posebno teškim slučajevima i hospitalizacija.Adverse drug reactions are unwanted responses to medications administered in the prescribed dosage. The set of activities aimed at gathering knowledge about the harmful effects of drugs to prevent adverse reactions in the future and improve the safety of their use is called pharmacovigilance. Biotransformation is a process that can lead to either reduced or increased drug activity, as well as toxic properties of some of its metabolites, which may result in adverse effects. The simultaneous use of multiple medications carries the risk of drug interactions, thereby increasing the likelihood of adverse reactions. Adverse cutaneous drug reactions are classified according to severity, pathogenesis and clinical presentation. The Hartwig severity assessment scale categorizes cutaneous reactions into seven levels, broadly divided into mild, moderate, severe and lethal. The pathogenesis of adverse cutaneous reactions can be immunological or non-immunological. Currently, 29 to 35 clinical forms of adverse cutaneous reactions are known, ranging from the mildest erythema to extensive necrotic morphologies with systemic symptoms. Antibiotics, nonsteroidal anti-inflammatory drugs and antiepileptics are the most common drug groups causing skin reactions. Due to their widespread use and frequent prescribing, psychotropic drugs also fall into this category. In diagnosing adverse cutaneous drug reactions, clinicians primarily rely on patient history and clinical presentation. The treatment is based on discontinuation of the causative drug or dose reduction in cases of mild reactions. In more serious adverse reactions, discontinuing the drug alone is often insufficient. Carefully selected supportive therapy is essential in the treatment process and hospitalization may be required in particularly severe cases
Effects of anabolic steroid use on endocrine system
No full textAnabolički androgeni steroidi (AAS) su hormoni čije se anaboličko djelovanje očituje izgradnjom mišića i smanjenjem tjelesne masti, a androgeno razvojem sekundarnih muških spolnih osobina. Najpoznatiji anabolički steroid je testosteron, a danas postoji nekoliko stotina sintetskih AAS kojima je testosteron ishodišna molekula . Testosteron je prvi put sintetiziran u laboratoriju 1935. U početku se koristio u medicini za liječenje brojnih bolesti. Ubrzo je prepoznat njegov potencijal kao sredstva za doping u sportu te je prvi put korišten u te svrhe 1954. AAS postaju zabranjene tvari u sportu 1967., a tek 1996. je znanstveno dokazan njihov učinak na poboljšanje performansi. Poznate nuspojave uključuju hipertrofiju miokarda, hiperlipidemiju, endokrinu disrupciju i tumore. S obzirom da se najviše koriste za doping, AAS se dijele na one za direktni i indirektni doping. Tvari za direktni doping izravno djeluju na testosteronske receptore, a za indirektni doping povećavaju sekreciju endogenih anaboličkih steroida. AAS se najčešće uzimaju u ciklusima koji traju od 6-12 tjedana, a doza se može i smanjivati pred kraj ciklusa. Često se kombiniraju direktni i indirektni doping. AAS se mogu primjenjivati parenteralno, oralno, transdermalno, preko sluznica i intramuskularno. Korištene doze više su od fizioloških i do nekoliko stotina puta. Većina korisnika su muškarci, a procjenjuje se da je 1 do 5% muškaraca u svijetu nekad koristilo AAS. Testosteron je glavni AAS u ljudskom tijelu, a sintetizira se u spolnim žlijezdama. Adrenalni androgeni drugi su najznačajniji endogeni AAS, a nastaju u kori nadbubrežne žlijezde. Sintetski AAS strukturno su slični testosteronu, ali imaju brojne modifikacije koje im poboljšavaju farmakokinetiku. Svi AAS povećavaju mišićnu masu i imaju maskulinizirajuće učinke, a metabolizam im je vrlo sličan. Endokrine nuspojave najizraženije su na sustav spolnih hormona. Kod muškaraca može doći do neplodnosti, atrofije testisa, ginekomastije zbog viška estrogena, erektilne disfunkcije i hiperplazije prostate. Kod žena dolazi do supresije stvaranja ženskih spolnih hormona, disregulacije menstrulanog ciklusa, razvoja sekundarnih muških spolnih obilježja i neplodnosti. AAS povisuju razinu prolaktina što dovodi do smanjenog libida i ginekomastije. Također mijenjaju sustav hormona štitnjače što može dovesti do klinički manifestnih bolesti štitnjače. Indirektno,stimulirajući izlučivanja aldosterona, AAS dovode i do hipertenzije. AAS povisuju i razinu hormona rasta koji smanjuje osjetljivost na inzulin, što je dugoročno rizični faktor za razvoj dijabetesa tipa II. Brojni prikazi slučajeva povezuju korištenje AAS sa pankreatitisom zbog čega se može razviti dijabetes tip I, a poznato je i da AAS smanjuju toleranciju na glukozu.Anabolic-androgenic steroids (AAS) are hormones whose anabolic effects manifest as increased muscle mass and reduced body fat, while their androgenic effects involve the development of secondary male sexual characteristics. The most well-known anabolic steroid is testosterone, and today there are hundreds of synthetic AAS. Testosterone was first synthesized in a laboratory in 1935. Initially, it was used medically to treat various conditions. Its potential as a doping agent in sports was soon recognized and it was first used for this purpose in 1954. AAS were classified as banned substances in sports in 1967, and it was not until 1996 that their performance-enhancing effects were scientifically proven. Known side effects include myocardial hypertrophy, hyperlipidemia, endocrine disruption, and tumors. Since AAS are most commonly used for doping, they are categorized into those used for direct and indirect doping. Substances used for direct doping act directly on testosterone receptors, while those for indirect doping increase the secretion of endogenous anabolic steroids. AAS are typically taken in cycles lasting 6 to 12 weeks, and the dose may be tapered toward the end of the cycle. Direct and indirect doping agents are often combined. AAS can be administered parenterally, orally, transdermally, via mucous membranes and intramuscularly. The doses used are often several hundred times higher than physiological concentrations. Most users are men and it is estimated that 1 to 5% of men worldwide have used AAS at some point. Testosterone is the main AAS in the human body and is synthesized in the gonads. Adrenal androgens are the second most significant endogenous AAS and are produced in the adrenal cortex. Synthetic AAS are structurally similar to testosterone but include various modifications that improve their pharmacokinetics. All AAS increase muscle mass and have masculinizing effects, with very similar metabolic pathways. Endocrine side effects are most pronounced in the reproductive hormone system. In men, AAS use can cause infertility, testicular atrophy, gynecomastia due to excess estrogen, erectile dysfunction and prostate hyperplasia. In women, AAS suppress the production of female sex hormones, disrupt the menstrual cycle, cause the development of secondary male sexual characteristics and lead to infertility. AAS also increase prolactin levels, resulting in reduced libido and gynecomastia. They also alter the thyroid hormone system, which can lead to clinically manifest thyroid disorders. Indirectly, by stimulating aldosterone secretion, AAS contribute to hypertension. AAS also increase growth hormone levels, which reduce insulin sensitivity, posing a long-term risk for the development of type 2 diabetes. Numerous case reports link AAS use to pancreatitis, which can lead to type 1 diabetes, and AAS are also known to reduce glucose tolerance
Intracerebral hematoma
No full textIntracerebralni hematom (ICH) ozbiljno je kliničko stanje karakterizirano nakupljanjem krvi unutar moždanog parenhima. Svrstava se u hemoragijski moždani udar s udjelom od 10 do 15% u svim moždanim udarima i obilježava ga visoka stopa mortaliteta i morbiditeta. Primarni spontani ICH odgovoran je za 85% svih ICH, a uzroci su kronična hipertenzija i cerebralna amiloidna angiopatija. Sekundarno krvarenje najčešće je povezano s hemoragijskom dijatezom (iatrogena, kongenitalna, stečena), arteriovenskim malformacijama i tumorima. Pacijenti se najčešće prezentiraju iznenadnim fokalnim neurološkim deficitom, ovisno o lokalizaciji i veličini hematoma. Ostali česti simptomi su poremećaj svijesti, glavobolja, mučnina, povraćanje, epileptički napadaji. Među najvažnije čimbenike rizika za razvoj ICH spadaju hipertenzija, cerebralna amiloidna angiopatija, pušenje cigareta, prekomjerna konzumacija alkohola, antikoagulantna i antitrombocitna terapija, starija dob i muški spol. Komjuterizirana tomografija (CT) predstavlja zlatni standard u dijagnostici ICH. Prioriteti prilikom zbrinjavanja pacijenta su brzi prijem pacijenta na odjel za moždani udar ili odjel neurointenzivne te rano započinjanje liječenja, već u hitnoj službi, u što spadaju hitno snižavanje krvnog tlaka i korekcija koagulopatije. Antihipertenzivnu terapiju potrebno je što prije započeti s ciljnim tlakom od 140 mmHg. Jedna od češćih komplikacija koje prati ICH, a zahtijeva terapijsku intervenciju je povišen intrakranijalni tlak. Terapijski pristup ICH može biti konzervativan ili kirurški, a odluka se temelji na težini kliničke slike, veličini hematoma, prisutnosti edema i povišenog intrakranijalnog tlaka. Preporučuje se da se svim pacijentima omogući multidisciplinarna rehabilitacija sa što ranijim početkom.Intracerebral hematoma (ICH) is a serious clinical condition characterized by the accumulation of blood within the brain parenchyma. It is classified as a hemorrhagic stroke, accounting for 10–15% of all strokes, and is associated with a high mortality rate and high morbidity rate. Primary spontaneous ICH accounts for approximately 85% of all cases, with chronic hypertension and cerebral amyloid angiopathy identified as the most common causes. Secondary hemorrhage is most often associated with hemorrhagic diathesis, arteriovenous malformations, and tumors. Patients typically present with a sudden focal neurological deficit, depending on the location and size of the hematoma. Other common symptoms include impaired consciousness, headache, nausea, vomiting, seizures. The most important risk factors for developing ICH include hypertension, cerebral amyloid angiopathy, cigarette smoking, excessive alcohol consumption, anticoagulant and antiplatelet therapy, advanced age, and male sex. CT is considered the gold standard for diagnosing ICH. Management priorities include rapid admission to a stroke unit or neurointensive care unit and early initiation of treatment, starting in the emergency department. This includes urgent blood pressure reduction and reversal of coagulopathy. Antihypertensive therapy should be initiated as early as possible with a target systolic blood pressure of 140 mmHg. One of the common complications associated with ICH is elevated intracranial pressure. Management of ICH may be conservative or surgical, with the decision based on the severity of the clinical presentation, hematoma volume, presence of edema, and elevated intracranial pressure. It is recommended that all patients receive multidisciplinary rehabilitation, with initiation as early as possible
Tibial Tuberosity–Tibial Intercondylar Midpoint Distance Can Be Interchangeably Measured on Axial CT and MRI: Retrospective Cross-Sectional Comparative Study
No full textBackground and Objectives: It is unknown whether the tibial tuberosity–tibial intercondylar midpoint (TT–TIM) distance can be interchangeably measured on axial computed tomography (CT) and magnetic resonance imaging (MRI). The objective of this retrospective cross-sectional comparative study was to evaluate the intermethod agreement of the TT–TIM distance on axial CT and MRI and its bias towards tibial rotation (TR), age, sex, and body side.
Materials and Methods: On axial CT and MRI of 15 consecutive knee pairs where each pair belonged to the same patient with no pathology affecting the tibial circumference and tibial tuberosity, TT–TIM distance and TR were measured by two blinded radiologists at 2-week intervals. Upon checking the symmetry of distributions (Shapiro–Wilk test), differences between matched knee pairs (Wilcoxon signed-rank test), intermethod (Bland–Altman plot) and interrater agreement (intraclass correlation coefficient [ICC]), and correlations (Spearman rank correlation) were assessed. Results: The mean intermethod difference in TT–TIM distance was not statistically significant (−0.4 mm [−1.82, 0.96]; p = 0.52). The TT–TIM distance did not differ between knee pairs (p = 0.68), its interrater agreement was almost perfect (ICC > 0.81), and no bias towards TR (p > 0.66), age (p > 0.14), sex (p = 0.66), and body side (p > 0.37) was found.
Conclusions: The TT–TIM distance can be interchangeably measured on axial CT and MRI with almost perfect interrater agreement, unbiased towards TR, age, sex, and body side
Exploring awareness and perceptions of palliative care: a descriptive cross-sectional survey study in Central Europe
No full textAim: To assess awareness, knowledge, and preferences regarding palliative care in two Central European countries (Slovenia and Croatia) and the Austrian federal state of Styria. The study explored differences in the sources of information, public perceptions, and preferred settings for end-of-life care.
Methods: In this descriptive cross-sectional survey, we enrolled a community-based sample of adults (≥18 years) residing in the three regions. Propensity score matching was applied to balance demographic variables in the analysis. Overall and matched samples were reported for the three regions.
Results: The study enrolled 1586 respondents; 78.2% had at least heard of palliative care. In the matched sample (n=462), respondents from Austria had the highest awareness of palliative care goals (74.4%), and those from Slovenia had the highest preference for obtaining information from traditional media (54.4%). Opinions on death discussions varied significantly; in Austria, there was the highest percentage (69.5%) of respondents who felt death was insufficiently discussed in society. The preferred end-of-life care setting was home, with Austrians having the highest preference for this setting (70.8%).
Conclusion: The study revealed notable disparities in awareness, knowledge, and preferences regarding palliative care, although the sample size varied between countries. These differences should be addressed by tailored communication strategies and public health campaigns, which should align health care services with the preferences and needs of the population. The findings provide insights into how to improve end-of-life care and enhance public understanding of palliative services in three Central European regions
Botulinum Toxin Type A Exerts Direct Trans-Synaptic Action at Bilateral Spinal Nociceptive Circuits
No full textBotulinum toxin type A (BoNT-A) induces a bilateral analgesic effect following unilateral injection in rodent bilateral or mirror pain models. This occurs either by indirect plasticity-related actions, or by the toxin’s direct central action in bilateral spinal circuits. Herein, we aimed to resolve this question by assessing the role of trans-synaptic toxin traffic in a bilateral inflammatory pain model. The analgesic effect of the toxin was examined in rats pre-treated with unilateral intraplantar BoNT-A (7 U/kg) and subsequently challenged with bilateral carrageenan-evoked hind-paw inflammation (2%, 50 µL/paw, 6 days post BoNT-A). Specific neutralizing antitoxin injected into the lumbar intrathecal space (2 IU, 24 h post BoNT-A), aimed at preventing the spinal trans-synaptic traffic of BoNT-A, abolished its bilateral analgesic effect. The toxin trans-synaptic effect was associated with reduced c-Fos neuronal activation and BoNT-A-mediated cleavage of synaptosomal-associated protein 25 (SNAP-25) in the bilateral dorsal horn. Here, we showed that, in bilaterally occurring pain, BoNT-A exerts a direct contralateral analgesic action extending beyond the level of the dorsal root ganglion sensory neuron that directly links the hindlimb injection site to the primary sensory region. This points to the crucial role of the toxin’s central trans-synaptic traffic, and its direct action at propriospinal nociceptive circuits in its pain-relieving efficacy
Evolution of β-Lactam Antibiotic Resistance in Proteus Species: From Extended-Spectrum and Plasmid-Mediated AmpC β-Lactamases to Carbapenemases
No full textThe management of infectious diseases has proven to be a daunting task for clinicians worldwide, and the rapid development of antibiotic resistance among Gram-negative bacteria is making it even more challenging. The first-line therapy is empirical, and it most often comprises β-lactam antibiotics. Among Gram-negative bacteria, Proteus mirabilis, an important community and hospital pathogen associated primarily with urinary tract and wound infection, holds a special place. This review’s aim was to collate and examine recent studies investigating β-lactam resistance phenotypes and mechanisms of Proteus species and the global significance of its β-lactam resistance evolution. Moreover, the genetic background of resistance traits and the role of mobile genetic elements in the dissemination of resistance genes were evaluated. P. mirabilis as the dominant pathogen develops resistance to expanded-spectrum cephalosporins (ESC) by producing extended-spectrum β-lactamases (ESBL) and plasmid-mediated AmpC β-lactamases (p-AmpC). β-lactamase-mediated resistance to carbapenems in Enterobacterales, including Proteus spp., is mostly due to expression of carbapenemases of class A (KPC); class B (metallo-β-lactamases or MBLs of IMP, VIM, or NDM series); or class D or carbapenem-hydrolyzing oxacillinases (CHDL). Previously, a dominant ESBL type in P. mirabilis was TEM-52; yet, lately, it has been replaced by CTX-M variants, particularly CTX-M-14. ESC resistance can also be mediated by p-AmpC, with CMY-16 as the dominant variant. Carbapenem resistance in Proteus spp. is a challenge due to its intrinsic resistance to colistin and tigecyclin. The first carbapenemases reported belonged to class B, most frequently VIM-1 and NDM-5. In Europe, predominantly France and Belgium, a clonal lineage positive for OXA-23 CHDL spreads rapidly undetected, due to its low-level resistance to carbapenems. The amazing capacity of Proteus spp. to accumulate a plethora of various resistance traits is leading to multidrug or extensively drug-resistant phenotypes