Neurotoxicity due to acute prenatal exposure to high-dose of mercury (Hg) is well documented. However, the effect of prenatal exposure to low Hg levels on child neurodevelopment and the question ...about “safety” of fish-eating during pregnancy remain controversial. International comparisons of Hg concentrations in mother-child biological samples and neurodevelopmental scores embedded in birth cohort studies may provide useful evidence to explore this issue.
The Mediterranean (Italy, Slovenia, Croatia, and Greece) cohort study included 1308 mother-child pairs enrolled in the Public Health Impact of long-term, low-level, Mixed Element exposure in a susceptible population EU Sixth Framework Programme (PHIME). Maternal hair and venous blood, cord blood and breast milk samples were collected, and total Hg (THg) levels were measured. Demographic and socioeconomic information, lifestyles and nutritional habits were collected through questionnaires at different phases of follow-up. Children at 18 months of age underwent neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Multivariate linear and logistic regressions were performed, for each country, to assess the association between THg and BSID-III scores, obtaining adjusted β coefficients and odds ratios (ORs). These values were used to conduct a meta-analysis, to explore possible heterogeneity among countries and to obtain combined estimates of the association between THg exposure and BSID-III scores.
Median THg (ng/g) was: 704 in maternal hair, 2.4 in maternal blood, 3.6 in cord blood, and 0.6 in breast milk. THg concentrations were highest in Greece and lowest in Slovenia. BSID-III neurodevelopmental scores were higher in Croatia and Slovenia. The meta-analysis of multivariate linear models found an overall positive association between language composite score and receptive communication scaled score and increasing THg in maternal hair (n = 1086; β = 0.55; 95%CI: 0.05–1.05 and n = 1075; β = 0.12; 95%CI: 0.02–0.22, respectively). The meta-analysis of logistic regression models showed that the overall adjusted OR between THg in cord blood and suboptimal gross motor score was borderline significant (n = 882; OR = 1.03; 95%CI: 1.00–1.07). Heterogeneity was found across the four sub-cohorts for language composite score in maternal blood, and for fine motor scaled score in cord blood and breast milk. Language composite score and THg concentrations in maternal venous blood were positively related (n = 58; β = 4.29; CI95% (−0.02, 8.60)) in Croatia and an increase of 1 ng/g of THg in maternal venous blood was associated with a reduced risk for children to fall in the lowest quintile of language score by 31% (n = 58; OR = 0.69; CI 95%: 0.37, 1.01). The comparison of β coefficients obtained by multiple linear regression model showed an inverse association between fine motor score and THg concentrations in cord blood for Croatia (n = 54; β = −0.53; CI 95%: −1.10, 0.04) and Slovenia (n = 225; β = −0.25; CI 95%: −0.49, −0.01). In Slovenia THg level in breast milk was associated with suboptimal fine motor performance (n = 195; OR = 5.25; CI 95%: 1.36, 21.10).
This study showed an inverse relation between THg levels and developmental motor scores at 18 months, although the evidence was weak and partially internally and externally inconsistent. No evidence of detrimental effects of THg was found for cognitive and language outcomes at these concentrations and age.
Febrilne konvulzije najčešći su konvulzivni poremećaj u djetinjstvu, zbog čega bi liječnici trebali biti upoznati s pravilnom procjenom i liječenjem ovoga uobičajenog stanja. Definira se kao bilo ...koji napadaj popraćen vrućicom, bez infekcije središnjega živčanog sustava, koji se javlja kod djece između šest mjeseci i pet godina. U upotrebi je pet kriterija prema kojima se klasificiraju kao jednostavne ili složene febrilne konvulzije. Ova klasifikacija nudi drugačije smjernice za kliničku praksu, poglavito odluku o provođenju lumbalne punkcije kako bi se isključila intrakranijalna infekcija. Hrvatsko društvo za dječju neurologiju izradilo je 2012. godine prve smjernice za racionalnu dijagnostiku i terapiju febrilnih konvulzija koje su trebale biti izvedive u svim bolničkim ustanovama u Republici Hrvatskoj. Iako su smjernice bile od velike pomoći mnogim kliničarima, dobivanjem novih medicinskih dokaza i razumijevanjem kliničkih entiteta koju se prezentiraju febrilnim konvulzijama, a variraju od samolimitirajućeg poremećaja bez dugoročnih posljedica preko samoograničavajućih i medikamentima kontroliranih entiteta pa sve do teških epileptičkih encefalopatija, nove smjernice pridonose postavljanju dijagnoze u hitnoj ambulanti, uključuju preporuke o hospitalizaciji, primjeni elektroencefalografije, neuroslikovnih pretraga, profilaksi diazepamom i antipireticima. Iako nove smjernice sadrže nove kliničke preporuke, ostavljaju neka neriješena pitanja na koja buduća klinička istraživanja trebaju ponuditi odgovore.
Rano suzbijanje, prekidanje epileptičkih napadaja središnji je stup u strategiji njihova liječenja. Većina epileptičkih napadaja događa se izvan medicinske ustanove, najčešće u kućnom okruženju. ...Stoga smo izradili i predložili ovaj algoritam zbrinjavanja motoričkih/konvulzivnih epileptičkih napadaja u izvanbolničkom okruženju, prvenstveno s ciljem pružanja uniformne informacije i edukacije roditelja/skrbnika te za olakšavanje snalaženja liječnicima primarne zdravstvene zaštite i timovima hitne medicinske pomoći. Za potrebe pisanja ovog rada analizirali smo i sintetizirali postojeće smjernice u cilju preporuke jednostavnog, razumljivog i racionalnog terapijskog algoritma koji savjetujemo i primjenjujemo kao službeni algoritam preporuka naše ustanove. U njegovoj izradi usmjerili smo se na svjetske i nacionalne preporučene algoritme kao i dostupne studije koje su, koliko je to moguće, temeljene na dokazima. Prema našim saznanjima ovo je prvi pisani nacionalni algoritam takve vrste te do sada nisu postajale pisane smjernice/upute za liječenje epileptičkih napadaja, produljenih epileptičkih napadaja i epileptičkog statusa u izvanbolničkom okruženju uzimajući u obzir dostupnost, racionalnost i primjenjivost pojedinih lijekova u izvanbolničkim uvjetima, uvažavajući kliničku praksu u Republici Hrvatskoj. Sukladno navedenom,
primjena benzodiazepina (BZD), vremenski jasno definirana, smatra se prvom linijom liječenja epileptičkog napadaja. Izvanbolnička primjena BZD-a, prvenstveno midazolama za orkomukuznu primjenu ili diazepama za rektalnu primjenu, povezana je s kraćim trajanjem generaliziranih konvulzivnih napadaja, smanjenjem vjerojatnosti ponavljajućih napadaja i smanjenjem broja posjeta hitnoj pomoći. Ukoliko napadaj potraje >3 minuta, svakako je potrebno žurno primijeniti jedan od BZD-a, pod pretpostavkom da ga se posjeduje (midazolam oromukozno – prednost! ili diazepam rektalno), te isto ponoviti u slučaju daljnjeg trajanja napadaja duljeg od pet minuta te pozvati/alarmirati sustav hitne medicinske pomoći. Uz provođenje mjera održavanja vitalnih funkcija potrebno je inzistirati na intravaskularnom pristupu za ponovljenu primjenu BZD-a, no doza BZD-a može se ponoviti intramuskularno. U rijetkim slučajevima može se primijeniti fenobarbiton intramuskularno, kao i levetiracetam intravenozno, a u slučaju izostanka njihova učinka započeti s primjenom midazolama u trajnoj infuziji. Dostupnost primjerenih oblika BZD-a, sukladno smjernicama, u izvanbolničkom okruženju kao i njihova pravilna uporaba – pravodobna primjena i odgovarajuće doziranje početkom napadaja – dva su ključna koraka prema poboljšanju
cjelokupne zdravstvene skrbi u djece s visokim rizikom za pojavu epileptičkih napadaja i djece s epilepsijom. Navedeno ujedno predstavlja i pravovremeno suzbijanje produljenih epileptičkih napadaja i prevenciju epileptičkog statusa.
Pravilan san nužan je za sazrijevanje temeljnih moždanih funkcija, a spavanje se sve više prepoznaje kao ključni proces u neurorazvojnim procesima. Osobe s poremećajima spavanja u ranom djetinjstvu, ...u kasnijoj dobi imaju poteškoća u kognitivnim funkcijama kao i veću pojavu psihijatrijskih poremećaja. U djece s poremećajima iz spektra autizma (PSA) patološki obrasci spavanja javljaju se od 30% do 80%. Najčešći patološki obrasci spavanja u djece sa PSA-om uključuju: poteškoće s uspavljivanjem, nemiran san, česta noćna i ranojutarnja buđenja, nisku učinkovitost spavanja, nesanicu tijekom dana te noćne more, jutarnje glavobolje, plač tijekom spavanja, apneju i hodanje u snu. Navedeno se povezuje s patološkim sazrijevanjem cirkadijalnog sustava koji dovode do promjena u obrascu spavanje - budnost. Jedan od ključnih čimbenika za regulaciju cirkadijalnog ritma i pravilnog sna je melatonin. U djece sa PSA-om dokazana je disregulacija sinteze i otpuštanja melatonina kao i promjena u ekspresiji gena odgovornih za njegovu fi ziološku funkciju. Istraživanja upućuju na to da djeca sa PSA-om imaju smanjenu razinu melatonina, što se povezuje s naglašenijim simptomima autističnog spektra. Stoga se posljednjih godina sugerira da desinkronizacija cirkadijalnog sustava ima važnu ulogu u razvoju PSA-a. Primjena egzogenog melatonina produljenog oslobađanja u djece sa PSA-om dokazano je učinkovita u skraćivanju latencije spavanja, produživanju učinkovitog trajanja spavanja te smanjivanju noćnih i ranojutarnjih buđenja. Rezultati upućuju i na dobrobit primjene melatonina produljenog oslobađanja u poboljšanju određenih simptoma autističnog ponašanja. Shodno navedenom, suzbijajući i liječeći poremećaje spavanja i cirkadijalnog ritma spavanja u djece sa PSA-om, možemo eventualno pridonijeti i smanjivanju određenih obrazaca ponašanja karakterističnih za djecu sa PSA-om.
Neuronska ceroidna lipofuscinoza-tip 2 (CLN2) najčešća je dječja progresivna neurodegenerativna bolest. Glavna obilježja bolesti CLN2 su usporen razvoj govora koji prethodi epileptičkim napadajima, ...motoričkim poremećajima, progresivnom propadanju vida i kognitivnih funkcija te smrti u dobi rane adolescencije. Prosječno vrijeme od pojave prvih simptoma do postavljenja dijagnoze iznosi oko dvije godine. Kašnjenje u postavljanju dijagnoze odgađa terapijski pristup koji uključuje multidisciplinsku zdravstvenu skrb i učinkovitu primjenu enzimske nadomjesne terapije cerliponazom alfa (Brineura®). Dostupnost liječenja enzimskom nadomjesnom terapijom cerliponazom alfa svrstava CLN2 u skupinu lječivih neurodegenerativnih bolesti. U svake lječive i/ili potencijalno izlječive progresivne neurodegenrativne bolesti pravodobna dijagnoza je ključna, jer omogućuje liječenje u ranom stadiju bolesti. Prepoznavanje ranih simptoma od bitnog je značenja za usmjeravanje kliničara na odgovarajuće pretrage ili traženje dodatnog stručnog mišljenja. U sve djece s prvim neprovociranim epileptičkim napadajem u dobi između druge i četvrte godine, a izričito u one djece koja dodatno u anamnezi imaju podatak o usporenom razvoju govora i/ili motoričke smetnje prvi korak u cilju rane i pravodobne dijagnoze je mjerenje aktivnosti enzima TTP1 putem suhe kapi krvi na fi ltarskom papiru, koji je dostupan u našoj sredini. Dodatna genska analiza i nalaz patogenih mutacija u genu CLN2 potvrđuje dijagnozu. Podizanje svjesnosti o bolesti CLN2 kao lječivoj i potencijalno izlječivoj, te poštivanje predloženih smjernica u kliničkom pristupu zasigurno će pridonijeti tome da rana dijagnoza bolesti CLN2 postane naša stvarnost, a sve manje bude mit. Pravovremena i ispravna dijagnoza prvi je korak u poboljšanju cjelokupne skrbi za djecu oboljelu od bolesti CLN2 i njihove roditelje.
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•17% and 20% APOE ε4 carriers were identified among mothers and new-borns.•Mothers carrying APOE ε4 had higher Hg, As in venous and cord blood.•Mothers carrying APOE ε4 allele had ...higher Se in venous blood and plasma.•Statistical models confirmed maternal APOE ε4 and venous plasma Se association.•Seafood, ever-smoking, and parity had strong influence on studied associations.
We investigated the relationship between lipid binding glycoprotein apolipoprotein E (apoE; gene APOE) polymorphisms (ε4 allele carriers versus no carriers = ε4+/ε4−) and trace elements (TEs) (e.g., (methyl)mercury, arsenic, lead, cadmium, selenium, manganese, copper, and zinc) in mothers (N = 223) and their new-borns (N = 213) exposed to potentially toxic metal(loid)s from seafood consumption. The apoE isoform encoded by the ε4 allele is believed to have beneficial effects in early life but represents a risk factor for age-associated diseases. Under certain conditions ε4 carriers are more susceptible to oxidative stress and metal(loid) toxicity. DNA from Croatian pregnant women (N = 223, third trimester) and their new-borns (N = 176), was genotyped for APOE by TaqMan® SNP assay – rs429358 and rs7412. Seafood intake data and TE levels in maternal urine, milk, hair, peripheral venous blood, mixed cord blood, and new-borns’ urine were available from previous studies. We compared TEs between ε4+ and ε4− carriers using Mann-Whitney U tests and applied multiple linear regression models to analyse the TE’s dependence on the presence of allele ε4 (genotypes ε3/ε4, ε4/ε4) in combination with other explanatory variables. We identified 17% (n = 37) and 20% (n = 35) ε4 allele carriers in mothers and new-borns, respectively. The Mann-Whitney U test showed that mothers with the ε4 allele had significantly higher mean levels of (methyl)mercury in peripheral venous blood, cord blood, and hair; arsenic in urine and cord blood; and selenium in peripheral venous blood and plasma. However, taking confounders into account, only the maternal plasma selenium remained statistically significant in the linear regression models (ε4 carriers vs non-carriers: 62.6 vs 54.9 ng/mL, p < 0.001). Literature suggestions of possible ε4 allele impact on Hg levels were not observed, while superior selenium status observed in healthy pregnant women carrying allele ε4 could be linked to the proposed APOE ε4 beneficial effects early in life.
Characterization of the exposome, the totality of all environmental factors that one is exposed to from conception onwards, has been recommended to better evaluate the role of environmental ...influences on developmental programming and life-course vulnerability to major chronic diseases. In the framework of the Health and Environment-wide Associations based on Large population Surveys (HEALS) project we considered the pregnancy exposome exploiting two databases (PHIME and REPRO_PL) that include birth cohorts from three EU countries (Croatia, Slovenia and Poland). The databases contained information on several chemical exposures, socio-demographic, lifestyle and health related factors from conception to child birth, and neuropsychological scores assessed by the Bayley Scales of Infant and Toddler Development in the first two years of life. Our main goal was to assess consistency of environmental influences on neurodevelopment, if any, across European countries differing for geographical, socio-demographic characteristics and levels of chemical exposures to metals such as lead (Pb), mercury (Hg), cadmium (Cd) and trace elements, including micronutrients such as zinc (Zn) and selenium (Se). To this aim, we first selected variables common to the different databases, then applied univariate and multivariate regression analyses to identify factors linked to neurodevelopment, and finally performed meta-analysis to detect potential heterogeneity among cohorts and pooled estimates. Significant differences in exposure levels among the three sub-cohorts were observed as for Hg and Se; exposure levels under study were relatively low and within the range described in existing EU biomonitoring studies. The univariate analyses did not show any common pattern of association as only in the Polish cohort chemical exposure had an impact on neuropsychological outcome. In the meta-analysis, some consistent trends were evident, relative to the adverse influence of Pb on children's language and cognition and the positive influence of Se on language abilities. The effects of the neurotoxic metal Hg positively influenced the motor scores in the Polish cohorts, while it decreased the motor scores in the Slovenia and Croatian sub-cohorts. The only socio-demographic factor consistently associated to the outcome among cohorts was child's sex, with females performing better than males on cognitive and language scores. These findings point to the need of harmonizing existing cohorts or creating prospective study designs that facilitate comparisons in the exposome over time, places and kind of environmental exposures.
•The exposome paradigm allows to evaluate the impact of multiple exposures on child neurodevelopment.•Statistical methods are needed to cope with heterogeneity in levels of exposure and outcome among different study populations.•Our results support complexity of early life exposome and identify both heterogeneous and consistent effects across cohorts.
Epilepsy is one of the most common chronic diseases in children, and cannot be controlled with conventional antiepileptic drugs in 30% of cases. Therefore, in these cases, alternative approach such ...as corticosteroid therapy (CT) is used. The aim of this study was to analyze different types of CT used to treat drug-resistant childhood epilepsies, treated at Rijeka University Hospital Centre during a 5-year period (2016-2020). This retrospective study included 32 patients. The following parameters were analyzed: number of patients with a particular diagnosis, average age (in months) at the onset of epilepsy, average epilepsy duration (in months) prior to CT, average number of antiepileptic drugs used prior to CT, presence of changes on magnetic resonance imaging (MRI), presence of comorbidities, and types of CT. The average age at the onset of epilepsy was 14 months and average epilepsy duration prior to CT was 16 months. On average, 5 antiepileptic drugs were used prior to CT. MRI changes were present in 53.13% and comorbidities in 81.25% of study patients. Prednisone therapy was used in 28.13%, combined therapy with prednisone and methylprednisolone in 65.63%, and methylprednisolone in 6.25% of patients. Study results revealed the use of CT for particular diagnosis to differ among the centers, as well as within the same center, so it is important to highlight the importance of reaching universal guidelines for CT therapy of childhood epilepsies.
The relationships between inorganic arsenic (iAs) metabolism, selenium (Se) status, and genetic polymorphisms of various genes, commonly studied in populations exposed to high levels of iAs from ...drinking water, were studied in a Croatian-Slovenian population from the wider PHIME-CROME project. Population consisted of 136 pregnant women in the 3rd trimester and 176 non-pregnant women with their children (n = 176, 8–9 years old). Their exposure to iAs, defined by As (speciation) analyses of biological samples, was low. The sums of biologically active metabolites (arsenite + arsenate + methylated As forms) for pregnant women, non-pregnant women, and children, respectively were: 3.23 (2.84–3.68), 1.83 (1.54–2.16) and 2.18 (1.86–2.54) ng/mLSG; GM (95 CI). Corresponding plasma Se levels were: 54.8 (52.8–56.9), 82.3 (80.4–84.0) and 65.8 (64.3–67.3) ng/mL; GM (95 CI). As methylation efficiency indexes confirmed the relationship between pregnancy/childhood and better methylation efficiency. Archived blood and/or saliva samples were used for single nucleotide polymorphism (SNP) genotyping of arsenic(3+) methyltransferase - AS3MT (rs7085104, rs3740400, rs3740393, rs3740390, rs11191439, rs10748835, rs1046778 and the corresponding AS3MT haplotype); methylene tetrahydrofolate reductase - MTHFR (rs1801131, rs1801133); aquaporin - AQP 4 and 9 (rs9951307 and rs2414539); selenoprotein P1 - SELENOP (rs7579, rs3877899); indolethylamine N-methyltransferase - INMT (rs6970396); and metallothionein 2A - MT2A (rs28366003). Associations of SNPs with As parameters and urine Se were determined through multiple regression analyses adjusted using appropriate confounders (blood As, plasma Se, ever smoking, etc.). SNPs’ influence on As methylation, defined particularly by the secondary methylation index (SMI), confirmed the ‘protective’ role of minor alleles of six AS3MT SNPs and their haplotype only among non-pregnant women. Among the other investigated genes, the carriers of AQP9 (rs2414539) were associated with more efficient As methylation and higher urine concentration of As and Se among non-pregnant women; poorer methylation was observed for carriers of AQP4 (rs9951307) among pregnant women and SELENOP (rs7579) among non-pregnant women; MT2A (rs28366003) was associated with higher urine concentration of AsIII regardless of the pregnancy status; and INMT (rs6970396) was associated with higher As and Se concentration in non-pregnant women. Among confounders, the strongest influence was observed for plasma Se; it reduced urine AsIII concentration during pregnancy and increased secondary methylation index among non-pregnant women. In the present study of populations with low As exposure, we observed a few new As–gene associations (particularly with AQPs). More reliable interpretations will be possible after their confirmation in larger populations with higher As exposure levels.
•AS3MT; AQP4,9; INMT; SELENOP and MT2A SNPs were related to low iAs (GM ≤ 3.32 ng/mL).•AS3MT SNPs/haplotype protective effect was confirmed in non-pregnant women.•AQP9 and INMT SNPs were related to U-As and U-Se levels in non-pregnant women.•AQP4 SNP was associated with higher AsIII urine levels in pregnant women.•Pregnancy/childhood overwhelmed (AS3MT) or emphasised (AQP4) SNPs’ effects.
Prenatal exposure of long chain polyunsaturated fatty acids (LCPUFA) are essential for normal fetal growth and neurodevelopment. Availability of LCPUFA depends mostly on maternal fish consumption. ...Fish consumption also exposes the fetus to mercury which is well known neurotoxicant. We analyzed the associations of combined LCPUFA and mercury from fish consumption during pregnancy on newborn's brain measures and child neurodevelopment in a northern Adriatic coastal area.
The prospective cohort study included 257 mother – infant pairs enrolled in a susceptible population of the Public Health Impact on long-term, low-level, Mixed Element exposure (PHIME) EU Sixth Framework Programme from 2 recruitment areas of the northern part of the Adriatic coast. Umbilical cord blood taken at delivery was used for measuring concentration of total mercury (THg) and specific LCPUFA - docosahexaenoic acid (DHA) and arachidonic acid (ARA). Neonatal cranial sonography was performed at the age of 3 days in 57 newborns. Neurodevelopmental assessment of cognitive, motor and language skills were conducted at 257 children at the age of 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition. The participants were divided into two groups depending on the THg concentration in the umbilical cord blood (exposed > 5.8 μg/L and unexposed < 5.8 μg/L). Dietary habits and exposures to environmental and social factors were assessed through questionnaires.
There is a statistically significant difference in the cerebellum length (p = 0.032) and the superior frontal gyrus width (p = 0.023) between the exposed and the unexposed group. In combined analysis, including possible protective variables as DHA and ARA (R2 = 0.22, p = 0.001), the negative contribution of THg on cerebellum length (beta = −0.16, p = 0.001) persisted. We found no correlation between THg concentration in umbilical cord blood and child neurodevelopment scores at the age of 18 months. Language score with receptive and expressive subscores was significantly associated with fish consumption (p < 0.05).
This analysis demonstrates the existence of morphological brain changes in newborns that are prenatally exposed at mercury concentrations what was diminished in combined analyse including LCPUFA. Our results emphasizes the importance of LCPUFA's and mercury common influence as a predictor of developmental outcome. Fish consumption, not solely LCPUFA contributes to better language development of children at the age of 18 months.
•Fish consumption enables the availability of LCPUFA but also exposes to neurotoxic mercury.•Results showed negative contribution of mercury on cerebellum length in combined analysis with LCPUFA.•No correlation between mercury concentration and child neurodevelopment scores at the age of 18 months.•Language score positively correlated with prenatally fish consumption.
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