Utjecaj ekstrakta cvijeta trnine na homeostazu glukoze u normoglikemijskom i aloksanom induciranom hiperglikemijskom C57BL/6 mišu

Research background. The use of plants and their extracts in treatments of chronic diseases is widely known in traditional medicine. The aim of this study is to determine the effects of 10-day consumption of blackthorn (Prunus spinosa L.) flower extract on blood glucose, glycaemic load, serum α-amlyase activity and insulin concentration in normoglycaemic and hyperglycaemic (alloxan-induced) mice model. Experimental approach. Normoglycaemic and hyperglycaemic (treated with alloxan, 150 mg per kg body mass) C57BL/6 mice were administered daily, during 10 days, blackthorn flower extract by gavage. The sugar mass concentration within the extract was determined by HPLC analysis. In mice, blood and serum blood glucose concentrations, and oral glucose tolerance test were determined by blood glucometer. Serum insulin concentration was determined by ELISA assay and α-amylase activity by colourimetric assay. Results and conclusions. The blackthorn flower extract increased glucose concentrations in normoglycaemic mice by 30% after the 1st and 5th day and by 17% after the 10th day of consumption. It is a consequence of released sugars because sugar analysis revealed 59.8 mg/L monosaccharides, mainly fructose (55.7 mg/L) and glucose (24.3 mg/L) in the extract. On the contrary, the extract consumption reduced serum blood glucose in hyperglycaemic mice by 29% after 10 days of treatment. Oral glucose tolerance test also confirmed that in the hyperglycaemic group treated with blackthorn flower extract glucose homeostasis was improved and showed decrease in blood glucose. Serum insulin concentration increased by 49% and serum α-amylase activity by 46% after 10 days of treatment with blackthorn flower extract in hyperglycaemic group. Thus, it can be concluded that blackthorn flower extract improved glucose tolerance, enhanced insulin secretion and lowered serum α-amylase activity. Novelty and scientific contribution. The obtained results show for the first time the potential of blackthorn (Prunus spinosa L.) flower extract in hyperglycaemia management.Pozadina istraživanja. Primjena biljaka i njihovih ekstrakata u liječenju kroničnih bolesti nadaleko je poznata u tradicionalnoj medicini. Svrha je ovoga rada bila utvrditi utjecaj desetodnevne konzumacije ekstrakta cvijeta trnine na koncentraciju glukoze u krvi, glikemijsko opterećenje, aktivnost α-amilaze i koncentraciju inzulina u serumu normoglikemijskih i hiperglikemijskih (induciranih aloksanom) miševa. Eksperimentalni pristup. Normoglikemijski i hiperglikemijski (inducirani s 150 mg aloksana po kg tjelesne mase) C57BL/6 miševi tretirani su tijekom 10 dana ekstraktom cvijeta trnine. Koncentracija šećera u ekstraktu određena je HPLC analizom, a koncentracija glukoze u krvi i oralna podnošljivost glukoze (oralni glukoza tolerans test) ispitane su glukometrom. Koncentracija inzulina u serumu određena je ELISA testom, a aktivnost α-amilaze kolorimetrijskom metodom. Rezultati i zaključci. Ekstrakt cvijeta trnine povećao je koncentraciju glukoze u krvi u normoglikemijskom mišu za 30 % nakon prvog i petog dana, te za 17 % nakon desetog dana konzumacije. To je bila posljedica prisustva slobodnih šećera, što je potvrđeno analizom njihovog sastava, kojom je utvrđeno da ekstrakt sadržava 59,8 mg/L monosaharida, uglavnom fruktoze (55,7 mg/L) i glukoze (24,3 mg/L). Suprotno tome, tretman ekstraktom cvijeta trnine je nakon 10 dana smanjio koncentraciju glukoze u krvi hiperglikemijskog miša za 29 %. Oralni glukoza tolerans test potvrdio je da se u hiperglikemijskoj skupini tretiranoj ekstraktom poboljšala podnošljivost glukoze te da je brže uspostavljena njezina homeostaza. Koncentracija inzulina u serumu povećala se za 49 %, a aktivnost α-amilaze za 46 % nakon desetodnevnog tretmana hiperglikemijske skupine ekstraktom cvijeta trnine. Može se zaključiti da ekstrakt cvijeta trnine poboljšava podnošljivost glukoze, potiče lučenje inzulina te smanjuje aktivnost serumske α-amilaze. Novina i znanstveni doprinos. Dobiveni rezultati prvi put pokazuju mogućnost primjene ekstrakta cvijeta trnine u regulaciji hiperglikemije

Upotreba standardnih si jedinica i termodinamike pri određivanju uticaja herbicida na samooplodne linije kukuruza - 2. status slobodne energije

The two herbicides and their combined treatment influenced the change of water input in each of 15 investigated maize inbreds. The water volume (ml) fluctuated between 11 to 110% in shoot and 23 to 275% in root, what introduced the change of free energy (G) from -254.6 to -151.6 KJ in shoot and from -248.0 to -172.3 KJ in root. The difference in free, potential energy between non- and treatment (oΔtreatG) was in shoot from 11.1 to 90.2 KJ and in root from 16.8 to 75.7 KJ. Further, the lower magnitude of oΔtreatG amplitude between root and shoot implicated the tolerance of genotypes to applied herbicides. The energy, spent in biosynthesis of 1mg dry substance was amounted from 75.6 to 16.8 KJ mg-1; the applied herbicide treatments assembled the group of genotypes with lowered necessity of this energy, what has the positive implications in the sense of thermodynamics.Primena dva herbicida i njihove kombinacje kod klijanaca 15 samooplodnih linija kukuruza uticala je na primenjenu apsorpciju vode. Zapremina vode (ml) je varirala između 11 i 100% u izdanku i 23 i 275% u korenu, što utiče na promenu slobodne energije (G) od 254.6 do -151.6 KJ u izdanku i od -248.0 to -172.3 KJ u korenu. Razlika u slobodnoj energiji između netretiranih i tretiranih biljaka (oΔtreatG) iznosila je u izdanku od 11.1 do 90.2 KJ i u korenu od 16.8 do 75.7 KJ. Takođe manja magnituda oΔtreatG amplitude između korena i izdanka može da ukaže na tolerantnost genotipova prema primenjenom herbicidu. Energija, utrošena za sintezu 1 mg suve supstance je iznosila 75.6 do 16.8 KJ mg-1. Primenjeni herbicidi su istakli grupu genotipova koja je imala manje energetske potrebe za procese biosinteze, što predstavlja pozitivnu tendenciju, sa termodinamičke tačke gledišta

Upotreba standardnih SI jedinica i termodinamike pri određivanju uticaja herbicida na samooplodne linije kukuruza - 1. rast

From 15 maize inbreds, submitted to alachlor and atrazine treatment in controlled conditions, after 14 days growing in sand under distilled water, fresh and dry weight and length of root and shoot were determined. The parameters derived of those measurements: concentration (gL-1), root: shoot relation and pseudospecific density (d, d-1, µmol mg-1) classified the mechanisms of herbicide influence in whole plants and roots or shoots. Thus, alachlor lowered weights, lengths, root: shoot relation and elevated concentration in all inbreeds, underlining the suppression of water input and root as the target. The atrazine, on the contrary, downed concentration, promoting the water-induced growth. The applications of diluted or combined herbicides’ forms segregated the genotypes to tolerant or sensitive as whole plant or partially root or shoot, only. The pseudo-specific density separated the genotypes to non- or stable system to hold up the induced change.Klijanci 15 samooplodnih linija kukuruza bili su izloženi tretmanu alahlora i atrazina, u kontrolisanim uslovima klijališta (gajeni su 14 dana na peščanoj podlozi, uz zalivanje sa destilovanom vodom). Bila su izvršena merenja sveže i suve mase, dužine korena i izdanka. Dobijeni parametri su poslužili za izračunavanje: koncentracije (gL-1), koren: izdanak relacije i pseudospecifične gustine (d, d-1, µmol mg-1). Navedene veličine su primenjene za definisanje uticaja herbicida, kako na cele klijance, tako i na njihove pojedine delove: koren i izdanak. Tako je alahlor uticao na smanjenje sveže i suve mase, dužine i relacije korena i izdanka, uz povećanje koncentracije, kod svih linija. Potrebno je naglasiti i smanjenu apsorpciju vode u koren, kao mesto sa najintenzivnijom reakcijom na alahlor. Sa druge strane, atrazin je smanjio koncentraciju, vodeći tzv. vodom indukovanom porastu. Tretmani sa većim razblaženjem ili kombinacijom herbicida definisali su linije kukuruza na tolerantne i osetljive, preko celih klijanca ili njihovih delova, tj. korena i izdanka. Pseudospecifična gustina je poslužila za determinisanje linija prema stabilnosti sistema da izdrži indukovanu promenu

Upotreba standardnih si jedinica i termodinamike pri određivanju uticaja herbicida na samooplodne linije kukuruza - 3. efekat niske temperature

The five maize inbred lines were subjected to concomitant treatments of herbicides: EPTC, alachlor and S-metolachlor and extended low temperature (22°C during 6 days and 10°C during 15 days). The fresh and dry substance and water content were determined. The calculated parameters fluctuated: concentration between 72 and 219 g L- 1; then, pseudo-specific density between 47 and 51 µmol mg -1. The free energy, spend for 1 mg of dry substance biosynthesis was higher in low temperature conditions and in alachlor treatment at both temperature conditions. Meanwhile, the changes of differential free energy, enthalpy and entropy, as thermodynamical parameters, followed the changes of fresh, dry substance and water volume in root and shoot of examined inbreeds, therefore the inbreeds with lower values of differential free energy, enthalpy and entropy had the higher tolerance to herbicide treatments.Pet samooplodnih linija kukuruza bilo je izloženo kombiniovanom tretmanu herbicida: EPTC, alachlora i S-metolachlora u kombinaciji sa produženom niskom temperaturom (22°C tokom 6 dana i 10°C tokom 15 dana). Određivan je sadržaj sveže i suve supstence i sadržaj vode. Obračunski parametari su varirali: između 72 i 219 g L-1, zatim, pseudo-specific density između 47 I 51 µmol mg -1. Slobodna energija, utrošena za biosintezu 1 mg suve supstance imala je niže vrednosti pri nižoj temperature i u tretmanu sa alahlorom, u oba temperaturna režima. Takođe, promene diferencijalne slobodne energije, entalpije i entropije, kao termodinamičkih parametara, pratile su promene sveže i suve supstance i sadržaj vode u korenu i izdanku svih ispitivanih linija. Sa druge strane, linije koje su imale niže vrednosti diferencijalne slobodne energije, entalpije i entropije, imale su i veću tolerantnost prema upotrebljenim herbicidima

Interakcija naringina s valproatom u regulaciji dislipidemije u C57BL/6 miševa

Valproate is a common antiepileptic drug whose adverse effects include liver steatosis and dyslipidaemia. The aim of our study was to see how natural flavonoid antioxidant naringin would interact with valproate and attenuate these adverse effects. For this reason we treated male C57BL/6 mice with a combination of 150 mg/kg of valproate and 25 mg/kg naringin every day for 10 days and compared their serum triglycerides, cholesterol, LDL, HDL, VLDL, and liver PPAR-alpha, PGC-1 alpha, ACOX1, Nrf2, SOD, CAT, GSH, and histological signs of steatosis. Valproate increased lipid peroxidation parameters and caused pronounced microvesicular steatosis throughout the hepatic lobule in all acinar zones, but naringin co-administration limited steatosis to the lobule periphery. In addition, it nearly restored total serum cholesterol, LDL, and triglycerides and liver ACOX1 and MDA to control levels. and upregulated PPAR-alpha and PGC-1 alpha, otherwise severely downregulated by valproate. It also increased SOD activity. All these findings suggest that naringin modulates key lipid metabolism regulators and should further be investigated in this model, either alone or combined with other lipid regulating drugs or molecules.Valproat je najčešće korišten antiepileptik, čiji štetni učinci uključuju masnu jetru (steatozu) i dislipidemiju. Cilj istraživanja bio je utvrditi kako će prirodni flavonoid i antioksidans naringin u interakciji s valproatom ublažiti navedene štetne učinke. Mužjaci miševa C57BL/6 bili su svakodnevno tijekom 10 dana izloženi valproatu u dozi od 150 mg/kg i naringinu u dozi od 25 mg/kg te njihovim međusobnim kombinacijama u istim dozama. Nakon pokusnog razdoblja usporedili smo razinu serumskih triglicerida, kolesterola, LDL, HDL i VLDL, jetrene markere PPAR-alfa, PGC-1 alfa, ACOX1 i Nrf2 te antioksidacijske markere SOD, CAT i GSH u jetri. Svaka je jetra analizirana histološki. Valproat je povećao parametre peroksidacije lipida i izazvao izraženu mikrovezikularnu steatozu u cijelom jetrenom lobulu u svim acinarnim zonama, ali je istodobna primjena naringina ograničila steatozu na periferiju lobula. Osim toga, naringin je uspostavio normalnu ravnotežu serumskoga kolesterola, LDL i triglicerida te jetrenih markera PPAR-alfa i PGC-1 alfa, ACOX1 i MDA. Također je povećao aktivnost SOD-a. Svi ovi nalazi upućuju na to da naringin modulira ključne regulatore metabolizma lipida i da ga treba dalje istražiti u ovome modelu, bilo samog ili u kombinaciji s drugim lijekovima ili molekulama za regulaciju lipida

Neuroendocrine tumors of the gastrointestinal tract

Neuroendokrini tumori (NET - engl. Neuroendocrine tumors) gastrointestinalnog (GI - engl. Gastrointestinal) sustava su rijetka i heterogena skupina novotvorina koje imaju određene zajedničke stanične osobine te jedinstvene osobine s obzirom na smještaj u gastrointestinalnom traktu. Očituju se širokim rasponom simptoma poput: abdominalnih bolova, mučnine, povraćanja, konstipacije, crvenom ili tamnom stolicom, crvenilom kože, umorom, neobjašnjivim smanjenjem tjelesne težine, žuticom, krastama kože i duševnim smetnjama. Klinička prezentacija neuroendokrinih tumora gastrointestinalnog sustava se razlikuje prema dijelu gastrointestinalnog sustava u kojem nastanu i koliko je opsežan njihov lokalni rast na lokaciji nastanka, prema tome da li izlučuju hormone u organizam oboljele osobe i ako da, koje hormone te da li postoji metastatski rasap bolesti. Rana dijagnoza svih novotvorina, tako i neuroendokrinih tumora gastrointestinalnog sustava, je od izričite važnosti u smanjenju nepovoljnih zdravstvenih ishoda kod oboljelih. Uz korištenje kliničkog pregleda i uzimanja anamneze, za dijagnozu neuroendokrinih tumora gastrointestinalnog sustava se koriste laboratorijske analize razina kemijskih spojeva koje ove novotvorine mogu izlučivati te radiološke slikovne metode i patohistološka analiza novotvorine nakon biopsije. Prognoza i liječenje neuroendokrinih tumora gastorintestinalnog sustava ovisi o tome u kojem stadiju je bolest što se određuje prema smjernicama Svjetske zdravstvene organizacije iz 2019. godine. Metode liječenja uključuju kiruršku resekciju dijela gastrointestinalnog trakta u kojemu se novotvorina nalazi, kemotrapiju i radioterapiju, primjenu somatostatinskih analoga, imunoterapiju i primjenu radionuklidne terapije peptidnih receptora.Neuroendocrine tumors of the gastrointestinal tract are a rare and heterogenous group of neoplasms that posses certain common cellular characteristics and unique characteristics depending on their location within the gastrointestinal tract. They present with a wide variety of symptoms including abdominal pain, nausea, vomiting, constipation, red or black discoloration of the stool, skin redness, fatigue, inexplicable weight loss, jaundice, skin scabbing and mental disturbances. The clinical presentation of neuroendocrine tumors of the gastrointestinal tract differs depending on the location of the gastrointestinal tract where the tumor forms, how expansive their local growth is at the site of formation, if they secrete hormones into the organism of the patient and if they do, which particular hormone they secrete and whether there are distant meastases present. The early diagnosis of all neoplasms, including neuroendocrine tumors of the gastrointestinal tract is paramount since it decreases unfavorable outcomes for the patient. Along with a clinical exam and history taking, the diagnosis of neuroendocrine tumors of the gastrointestinal tract is comprised of laboratory examinations of the levels of chemical compunds which these neoplasms may secrete along with radiological imaging and pathohistological analysis of the neoplasm following a biopsy. The prognosis and treatment of neuroendocrine tumors of the gastrointestinal tract depends on which stage the disease is in, which in turn is determined using the World Health Organization guidelines from 2019. Methods of treatment include surgical resection of the part of the gastrointestinal tract where the neoplasm is located, chemotherapy and radiotherapy, somatostatin analogues, imunotherapy and radionuclide therapy of peptide receptors

Neuroendocrine tumors of the gastrointestinal tract

Neuroendokrini tumori (NET - engl. Neuroendocrine tumors) gastrointestinalnog (GI - engl. Gastrointestinal) sustava su rijetka i heterogena skupina novotvorina koje imaju određene zajedničke stanične osobine te jedinstvene osobine s obzirom na smještaj u gastrointestinalnom traktu. Očituju se širokim rasponom simptoma poput: abdominalnih bolova, mučnine, povraćanja, konstipacije, crvenom ili tamnom stolicom, crvenilom kože, umorom, neobjašnjivim smanjenjem tjelesne težine, žuticom, krastama kože i duševnim smetnjama. Klinička prezentacija neuroendokrinih tumora gastrointestinalnog sustava se razlikuje prema dijelu gastrointestinalnog sustava u kojem nastanu i koliko je opsežan njihov lokalni rast na lokaciji nastanka, prema tome da li izlučuju hormone u organizam oboljele osobe i ako da, koje hormone te da li postoji metastatski rasap bolesti. Rana dijagnoza svih novotvorina, tako i neuroendokrinih tumora gastrointestinalnog sustava, je od izričite važnosti u smanjenju nepovoljnih zdravstvenih ishoda kod oboljelih. Uz korištenje kliničkog pregleda i uzimanja anamneze, za dijagnozu neuroendokrinih tumora gastrointestinalnog sustava se koriste laboratorijske analize razina kemijskih spojeva koje ove novotvorine mogu izlučivati te radiološke slikovne metode i patohistološka analiza novotvorine nakon biopsije. Prognoza i liječenje neuroendokrinih tumora gastorintestinalnog sustava ovisi o tome u kojem stadiju je bolest što se određuje prema smjernicama Svjetske zdravstvene organizacije iz 2019. godine. Metode liječenja uključuju kiruršku resekciju dijela gastrointestinalnog trakta u kojemu se novotvorina nalazi, kemotrapiju i radioterapiju, primjenu somatostatinskih analoga, imunoterapiju i primjenu radionuklidne terapije peptidnih receptora.Neuroendocrine tumors of the gastrointestinal tract are a rare and heterogenous group of neoplasms that posses certain common cellular characteristics and unique characteristics depending on their location within the gastrointestinal tract. They present with a wide variety of symptoms including abdominal pain, nausea, vomiting, constipation, red or black discoloration of the stool, skin redness, fatigue, inexplicable weight loss, jaundice, skin scabbing and mental disturbances. The clinical presentation of neuroendocrine tumors of the gastrointestinal tract differs depending on the location of the gastrointestinal tract where the tumor forms, how expansive their local growth is at the site of formation, if they secrete hormones into the organism of the patient and if they do, which particular hormone they secrete and whether there are distant meastases present. The early diagnosis of all neoplasms, including neuroendocrine tumors of the gastrointestinal tract is paramount since it decreases unfavorable outcomes for the patient. Along with a clinical exam and history taking, the diagnosis of neuroendocrine tumors of the gastrointestinal tract is comprised of laboratory examinations of the levels of chemical compunds which these neoplasms may secrete along with radiological imaging and pathohistological analysis of the neoplasm following a biopsy. The prognosis and treatment of neuroendocrine tumors of the gastrointestinal tract depends on which stage the disease is in, which in turn is determined using the World Health Organization guidelines from 2019. Methods of treatment include surgical resection of the part of the gastrointestinal tract where the neoplasm is located, chemotherapy and radiotherapy, somatostatin analogues, imunotherapy and radionuclide therapy of peptide receptors

Neuroendocrine tumors of the gastrointestinal tract

Neuroendokrini tumori (NET - engl. Neuroendocrine tumors) gastrointestinalnog (GI - engl. Gastrointestinal) sustava su rijetka i heterogena skupina novotvorina koje imaju određene zajedničke stanične osobine te jedinstvene osobine s obzirom na smještaj u gastrointestinalnom traktu. Očituju se širokim rasponom simptoma poput: abdominalnih bolova, mučnine, povraćanja, konstipacije, crvenom ili tamnom stolicom, crvenilom kože, umorom, neobjašnjivim smanjenjem tjelesne težine, žuticom, krastama kože i duševnim smetnjama. Klinička prezentacija neuroendokrinih tumora gastrointestinalnog sustava se razlikuje prema dijelu gastrointestinalnog sustava u kojem nastanu i koliko je opsežan njihov lokalni rast na lokaciji nastanka, prema tome da li izlučuju hormone u organizam oboljele osobe i ako da, koje hormone te da li postoji metastatski rasap bolesti. Rana dijagnoza svih novotvorina, tako i neuroendokrinih tumora gastrointestinalnog sustava, je od izričite važnosti u smanjenju nepovoljnih zdravstvenih ishoda kod oboljelih. Uz korištenje kliničkog pregleda i uzimanja anamneze, za dijagnozu neuroendokrinih tumora gastrointestinalnog sustava se koriste laboratorijske analize razina kemijskih spojeva koje ove novotvorine mogu izlučivati te radiološke slikovne metode i patohistološka analiza novotvorine nakon biopsije. Prognoza i liječenje neuroendokrinih tumora gastorintestinalnog sustava ovisi o tome u kojem stadiju je bolest što se određuje prema smjernicama Svjetske zdravstvene organizacije iz 2019. godine. Metode liječenja uključuju kiruršku resekciju dijela gastrointestinalnog trakta u kojemu se novotvorina nalazi, kemotrapiju i radioterapiju, primjenu somatostatinskih analoga, imunoterapiju i primjenu radionuklidne terapije peptidnih receptora.Neuroendocrine tumors of the gastrointestinal tract are a rare and heterogenous group of neoplasms that posses certain common cellular characteristics and unique characteristics depending on their location within the gastrointestinal tract. They present with a wide variety of symptoms including abdominal pain, nausea, vomiting, constipation, red or black discoloration of the stool, skin redness, fatigue, inexplicable weight loss, jaundice, skin scabbing and mental disturbances. The clinical presentation of neuroendocrine tumors of the gastrointestinal tract differs depending on the location of the gastrointestinal tract where the tumor forms, how expansive their local growth is at the site of formation, if they secrete hormones into the organism of the patient and if they do, which particular hormone they secrete and whether there are distant meastases present. The early diagnosis of all neoplasms, including neuroendocrine tumors of the gastrointestinal tract is paramount since it decreases unfavorable outcomes for the patient. Along with a clinical exam and history taking, the diagnosis of neuroendocrine tumors of the gastrointestinal tract is comprised of laboratory examinations of the levels of chemical compunds which these neoplasms may secrete along with radiological imaging and pathohistological analysis of the neoplasm following a biopsy. The prognosis and treatment of neuroendocrine tumors of the gastrointestinal tract depends on which stage the disease is in, which in turn is determined using the World Health Organization guidelines from 2019. Methods of treatment include surgical resection of the part of the gastrointestinal tract where the neoplasm is located, chemotherapy and radiotherapy, somatostatin analogues, imunotherapy and radionuclide therapy of peptide receptors

Endoscopic repair of cerebrospinal fluid rhinorrhea

Abstract Introduction: Nasal liquorrhea indicates a cerebrospinal fluid fistula, an open communication between the intracranial cerebrospinal fluid and the nasal cavity. It can be traumatic and spontaneous. Objective: The aim of this study was to assess the outcome of endoscopic repair of cerebrospinal fluid fistula using fluorescein. Methods: This retrospective study included 30 patients of both sexes, with a mean age of 48.7 years, treated in the period from 2007 to 2015. All patients underwent lumbar administration of 5% sodium fluorescein solution preoperatively. Fistula was closed using three-layer graft and fibrin glue. Results: Cerebrospinal fluid fistulas were commonly located in the ethmoid (37%) and sphenoid sinus (33%). Most patients presented with traumatic cerebrospinal fluid fistulas (2/3 of patients). The reported success rate for the first repair attempt was 97%. Complications occurred in three patients: one patient presented with acute hydrocephalus, one with reversible encephalopathy syndrome on the fifth postoperative day with bilateral loss of vision, and one patient was diagnosed with hydrocephalus two years after the repair of cerebrospinal fluid fistula. Conclusion: Endoscopic diagnosis and repair of cerebrospinal fluid fistulas using fluorescein intrathecally has high success rate and low complication rate