Učinak regionalne vs. opće anestezije na imuni odgovor u kirurgiji karcinoma dojke; pregled literature

For breast cancer patients, surgery remains the cornerstone in treatment. Perioperative and postoperative period is associated with impaired immune function that can have profound implications for cancer patients in terms of tumor recurrence and metastases. The three main factors include surgery and related neuroendocrine stress response, anesthetic drugs, including opioid analgesics and postoperative pain. The most investigated immune cells are natural killer (NK) cells that are affected by both anesthesia and surgery. It has been demonstrated that ketamine, thiopental, volatile anesthetics, fentanyl and morphine, but not propofol, remifentanil or tramadol reduce the number of circulating NK cells and depress their toxicity. The level of NK cells’ cytotoxicity is inversely proportional to the stage and spread of cancer. Regional anesthesia and its potential beneficial effects on the perioperative immune response and long-term outcome after surgery has been investigated as an alternative to general anesthesia in patients undergoing breast cancer surgery. In this paper, we present a review of literature aimed to assess the impact of regional anesthesia techniques on the immune response in patients undergoing breast cancer surgery and how it compares to general anesthesia.Za pacijente s rakom dojke operacija je neizostavni dio terapijskog postupka. Predoperativno i postoperativno razdoblje je povezano s oslabljenom imunološkom funkcijom koja može imati značajne posljedice za bolesnike s karcinomom u smislu recidiva tumora i metastaza. Tri su glavna čimbenika odgovorna za takve promjene i uključuju operaciju i s njom povezan neuroendokrini stresni odgovor, anestetike uključujući opioidne analgetike i postoperativnu bol. Najčešće istraživane imunološke stanice su prirodne stanice ubojice (NK) na koje utječu i anesteziološki i kirurški postupak. Pokazano je da ketamin, tiopental, hlapljivi anestetici, fentanilimorfin, ali ne i propofol, remifentanil i tramadol, smanjuju broj cirkulirajućih NK stanica i njihovu citotoksičnost. Razina citotoksičnosti NK stanica obrnuto je proporcionalna stadiju i proširenosti karcinoma. Regionalna anestezija i njezin mogući povoljan učinak na predoperativni imunološki odgovor i dugoročni ishod nakon operacije istraživani su kao alternativa općoj anesteziji u bolesnica koje su podvrgnute operaciji karcinoma dojke. Cilj ovog pregleda literature je procjena utjecaja regionalne anestezije na imunološki odgovor u pacijentica podvrgnutih operaciji karcinoma dojke te njezina usporedba s općom anestezijom

The approach to a child with severe asthma

Teška astma je složena i heterogena bolest obilježena neprimjerenom kontrolom unatoč visokom stupnju liječenja. Procjenjuje se kako je prisutna u 2 - 5% djece s astmom, češće u djece starije od 10 godina i u dječaka. Iako je teška astma rijetka, ova skupina djece ima povećani rizik nuspojava liječenja, kao i teških i po život opasnih egzacerbacija. Povećani su izravni i neizravni troškovi u vidu potrošnje lijekova, češćih redovitih i hitnih posjeta liječniku, hospitalizacija, izostanaka s nastave i roditeljskih odsustava s posla. Definicije teške astme nisu ujednačene, ali im je svima zajednička potreba za kombinacijskim liječenjem inhalacijskim kortikosteroi- dima i bronhodilatatorima dugog djelovanja u visokim dozama neophodnima za kontrolu simptoma, ili, čak nedostatnima za punu kontrolu bolesti. Nekontrolirana astma zahtijeva iscrpno preispitivanje koje uključuje diferencijalno dijagnostičku reevaluaciju i nedvojbenu potvrdu dijagnoze astme, otkrivanje otegotnih čimbenika poput neredovitog uzimanja i/ili loše tehnike primjene inha- lacijskih lijekova, utjecaja okoliša (izloženost alergenima i iritansima) te komorbiditeta (bolesti gornjeg dišnog puta, gastroezofagu- sni refluks, pretilost i anksioznost). Ukoliko je dijagnoza astme potvrđena, a otegotni čimbenici ispravljeni, te je postignuta kontrola bolesti, radi se o teško lječivoj astmi (engl. difficult-to-treat asthma). Ako se ovim mjerama ne postigne kontrola, radi se o teškoj rezi- stentnoj astmi (engl. severe, therapy-resistant asthma). U pristupu djetetu s teško lječivom astmom slijedimo sistematičnu evaluaciju kojom u približno dvije trećine bolesnika djelovanjem na modificirajuće čimbenike ispunjavamo dugoročne ciljeve liječenja kroz postizanje kontrole simptoma te smanjenje rizika za po- goršanja i nepovratna oštećenja bronha/komplikacija liječenja. U preostale djece, u koje primjena ovih mjera ne dovodi do usposta- ve kontrole, radi se o teškoj, na terapiju rezistentnoj astmi. U njih slijedi, kroz određivanje fenotipskih obilježja, izbor biološkog liječenja temeljnog na pretpostavljenom endotipu.Severe asthma is considered a complex and heterogeneous disease, which includes different phenotypes, defined in terms of both clinical and molecular characteristics and underlining endotypes. It is estimated that severe asthma affects 2-5% of all children with asthma. It occurs more frequently in children older than ten years of age, with a slight prevalence among the male sex. Although severe asthma is uncommon, this group of children has an increased risk of drug side effects and life-threatening exacerbations that impair quality of life. Also, the financial burden from medication, scheduled and unscheduled doctor visits, hospitalizations and absence from school and work by parents have to be considered. There is no uniform definition of severe asthma, but the common characteristic is the need for maximal maintenance therapy, including high-dose inhaled steroids, long-acting beta-agonists, and/ or leukotriene receptor antagonists/theophylline. Despite the highest doses of maintenance therapy, patients with severe asthma fail to control the disease. Uncontrolled asthma has to be re-evaluated by confirming the diagnosis and modifying factors contribut- ing to symptoms and exacerbations like poor adherence, environmental risks (persistent allergen and pollutant exposure) and co- morbidities (upper airway disease, gastroesophageal reflux, obesity, anxiety). Children with poor asthma control due to misdiagnosed asthma, poor adherence or environmental risks have difficult-to-treat asthma, whereas children who still have poor control despite re-education to improve adherence and modification of environmen- tal risks have severe, therapy-resistant asthma. The approach to children with difficult-to-treat-asthma, which includes systematic evaluation and acting on modifying factors, enables achieving the long-term goals of asthma treatment in approximately two-thirds of patients. The remaining children, whose asthma is still uncontrolled despite optimized therapy, have severe, therapy-resistant asthma. Those children are candidates for bio- logical treatment based on the determination of phenotypic features

From phenotype to biological treatment of severe asthma

Teška astma je složena i heterogena bolest koja kliničara stavlja pred težak zadatak razlikovanja bolesnika prema rizičnim manife- stacijama bolesti (fenotipovi) i specifičnim patofiziološkim mehanizmima u podlozi bolesti (endotipovi), a sve u cilju odabira što učinkovitijeg liječenja prilagođenog potrebama pojedinog bolesnika. Dosadašnja istraživanja i pokušaji fenotipiziranja bolesnika s astmom, pa tako i teškom astmom, kod djece nisu dovela do jedno- značnog zaključka, osim već otprije poznatih činjenica da najveći dio djece ima atopiju s višestrukim preosjetljivostima (nerijetko kombinacija nutritivnih i aeroalergena, uloga plijesni), reverzibilnu bronhoopstrukciju i rane znakove remodelacije bronha. Samo mali broj djece ima trajnu bronhoopstrukciju (FEV1< 80%). Endotipovi teške astme ne razlikuju se od onih opisanih u astmi općenito: tip 2 (visoki Th2; eozinofili u serumu i sputumu, visoki IgE, FeNO; ključni citokini IL-4, IL-5, IL-13) i ne-tip 2 (niski Th2, neutrofilna, pau- cigranulocitna ili miješana upala; ključni citokini IL-8, IL-17, IL-22). Tip 2 je češći endotip kod djece i za njega postoji dostupna i odo- brena biološka terapija (anti-IgE i anti-IL-5). Ne-tip 2 je rjeđi endotip, obilježen općenito ograničenim terapijskim opcijama, među kojima se razmatra primjena azitromicina. Teška astma, iako kod djece rijetko zastupljena, predstavlja rizični fenotip koji ozbiljno narušava kvalitetu života. Pažljivo praćenje bolesnika i određivanje temeljnog endotipa omogućuje izbor i primjenu ciljanog i personaliziranog liječenja.Severe asthma is considered a complex and heterogeneous disease, which includes different phenotypes, defined in terms of both clinical and molecular characteristics and different underlining endotypes. According to different studies, there are several clinical phenotypes of severe asthma in children. Most children are allergic to multiple aeroallergen sensitization (house dust mites, pollen, molds) and have high levels of total and specific IgE, reversible airflow obstruc- tion and early signs of remodelation. A small subgroup of children has persistent airflow limitation (FEV1 <80% predicted). There are two major underlining functional or pathophysiologic mechanisms for different phenotypes of asthma and severe asthma accord- ing to the immune mechanism: Type 2 asthma (Th2-high asthma, eosinophils in serum and sputum, high IgE levels, high FeNO; key cytokines IL-4, IL-5, IL-13) and non-Type 2 asthma (Th2-low asthma, neutrophilic, paucigranulocytic and mixed granulocytic inflam- mation; key cytokines IL-8, IL-17, IL-22). The type 2 asthma endotype is more common in children, while biomarkers involved in the pathogenesis, such as IgE and IL-5 have become targets for biological therapy. The non-type 2 asthma endotype, less frequent in children with severe asthma, has fewer therapeutic options. The effect of azithromycin is still under investigation. Severe asthma, although uncommon, is a complex and high-risk phenotype of childhood asthma. Close monitoring of the patient and precise definition of underlying endotype during evaluation enables identification and use of personalized, endotype-targeted treatment

NASOPHARYNGEAL COLONISATION AND RESISTANCE OF STREPTOCOCCUS PNEUMONIAE, MORAXELLA CATARRHALIS AND HAEMOPHILUS INFLUENZAE IN PRE-SCHOOL CHILDREN WITH DIAGNOSIS OTITIS MEDIA ACUTA

Nazofaringealna kolonizacija humanopatogenim bakterijama preduvjet je za razvoj akutnog otitisa media (AOM). Većina autora danas se slaže s mišljenjem da pozitivan bakteriološki nalaz iz obriska nazofarinksa (NF) ima klinički značaj. Ubrzani porast rezistencije ovih bakterija na antibiotike komplicira dosadašnju empirijsku terapiju ovih infekcija u mnogim zemljama. Cilj ovog istraživanja bio je odrediti učestalost i rezistenciju pojedinih patogenih izolata iz obriska NF-a djece predškolske dobi s uputnom dijagnozom rhinopharyngitis acuta i AOM. Cilj istraživanja bio je i pokazati da dosadašnja preporučena empirijska terapija ovih infekcija amoksicilinom nije bakteriološki opravdana. Od ukupnog broja obrisaka NF-a (1229), 468 uzoraka bilo je bakteriološki pozitivno (38,08%). Od ukupnog broja pozitivnih nalaza u 40,60% izoliran je pneumokok, u 40,17% M. catarrhalis, u 15,17% H. influenzae, a u 4,06% izolirani su BHS-A, C ili G. Rezultati našeg istraživanja pokazuju da je najviša rezistencija najčešćeg izolata - pneumokoka bila na penicilin i amoksicilin ( 37,37%). Empirijska terapija određene infekcije određenim antibiotikom moguća je samo ako rezistencija najčešćeg uzročnika na taj antibiotik u određenoj populaciji ne prelazi 15%. Zaključak ovog istraživanja je da u empirijskoj terapiji navedenih infekcija u našoj regiji više nije mjesto penicilinu ni amoksicilinu.Nasopharyngeal colonisation with human pathogenic bacteria is a prerequisite for the development of otitis media acute (OAM). Most authors agree that bacterial isolation from nasopharyngeal secretion has clinical signficance. The continuing increase in resistance to commonly used antibiotics makes treatment of these infections difficult in many countries. The purpose of this report was to determine the incidence and resistance in nasopharyngeal isolates in pre-school children with the diagnosis of Rhinopharyngitis acuta and Otitis media acuta. The objective of this study was to show that usually empiric antibiotic therapy with amoxicillin is not justified. From the total number of nasopharyngeal samples (1229), 468 had a positive bacteriological result (38.08%). Pneumococcus was isolated from 40.60% samples, Moraxella catarrhalis from 40.17%, Haemophilus influenzae from 15.17% samples and from 4.06% samples was isolated BHS-A, C or G. Our results show highly resistance of first isolate - Pneumococcus on penicillin and amoxicillin ( 37.37% ). Empiric therapy of a particular infection with a particular antibiotic is possible only if the antibiotic resistance to the common cause is under 15 % in a particular population. The conclusion of this paper is that there is no reason for using penicillin and amoxicillin in empiric therapy for specified infections in our region

Allergen immunotherapy in allergic diseases

Alergenska imunoterapija (AIT) još uvijek je jedina dostupna terapija alergijskih bolesti koja djeluje na imunosnu disfunkciju u podlozi alergije te može modificirati tijek i napredovanje bolesti. Suvremeno načelo imunoterapije ne razlikuje se znatnije od ideje koju je imao Leonard Noon 1911. godine, kad je prvi puta AIT primijenjena za liječenje alergijskog rinitisa. AIT podrazumijeva ponavljanu primjenu rastućih doza alergena supkutanim injekcijama do doze održavanja koja se primjenjuje tijekom najmanje tri godine, čime se postiže specifična tolerancija na alergen s dugoročnom učinkovitošću i nakon prekida liječenja. U novije vrijeme sublingvalni put primjene, provediv i u kućnim uvjetima, pokazao se učinkovitom i sigurnom alternativom supkutanom putu. Oralna se imunoterapija sve više primjenjuje u liječenju IgE posredovane alergije na hranu i omogućava postizanje učinkovite ograničene desenzitizacije, ali ne i dugotrajne tolerancije. Imunosni mehanizmi pojave tolerancije uključuju povećano stvaranje interleukina 10 (IL-10) i transformirajućeg faktora rasta beta (TGF-β), smanjenje broja alergenski specifičnih T-pomoćničkih stanica tipa 2 (Th2), indukciju alergenski specifičnih regulacijskih limfocita T i B (Tregs i Bregs) i proizvodnju alergenski specifičnih IgG 4 i IgA blokirajućih protutijela. S obzirom na stalan porast prevalencije alergijskih bolesti, od velikog je interesa u liječenju alergija istražiti nove metode za postizanje imunotolerancije sa sigurnijim, učinkovitijim i dugotrajnijim učinkom; to uključuje alternativne putove primjene alergena za imunoterapiju, nove adjuvanse, rekombinantne alergene (uključujući hipoalergene varijante) i kombinaciju alergena s imunološkim modifikatorima ili monoklonskim protutijelima koji potiskuju Th2 stanični put.Allergen immunotherapy (AIT) is still the only available therapy for allergic diseases that acts on the immune dysfunction underlying the allergy and can modify the course and progression of the disease. The modern principle of immunotherapy is not significantly different from the idea that Leonard Noon had in 1911, when AIT was first used for the treatment of allergic rhinitis. AIT implies repeated application of increasing doses of allergen by subcutaneous injections up to a maintenance dose that is administered for at least three years, which achieves specific tolerance to the allergen with long-term efficacy even after treatment discontinuation. More recently, the sublingual route of administration, which can be carried out at home, has proven to be an effective and safe alternative to the subcutaneous route. Oral immunotherapy is increasingly used in the treatment of IgE-mediated food allergy and enables the achievement of effective limited desensitization, but not long-term tolerance. Immunological mechanisms of tolerance include increased production of interleukin 10 (IL-10) and transforming growth factor beta (TGF-β), reduction in the number of allergen-specific T helper cells type 2 (Th2), induction of allergen-specific regulatory T and B lymphocytes (Tregs and Bregs) and the production of allergenspecific IgG4 and IgA blocking antibodies. Considering the continuous increase in the prevalence of allergic diseases, it is of great interest in the treatment of allergies to investigate new methods for achieving immunotolerance with a safer, more effective and long-lasting effect; these include alternative routes of administration of allergens for immunotherapy, new adjuvants, recombinant allergens (including hypoallergenic variants), and the combination of allergens with immune modifiers or monoclonal antibodies that suppress the Th2 cell pathway