Pregnancy outcomes of women whom spouse fathered children after tyrosine kinase inhibitor therapy for chronic myeloid leukemia : A systematic review

The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML). Although the efficacy of TKIs is beyond dispute, conception-related safety issues are still waiting to be explored, particularly in males. This systematic review aimed to summarize all available evidence on pregnancy outcomes of female spouses of male CML patients who fathered children after TKI treatment for CML.We performed a systematic search in seven electronic databases for studies that reported on male CML patients who did or did not discontinue TKI treatment before conceiving, and the pregnancy outcomes of their female spouse are available. The search centered on the TKI era (from 2001 onward) without any other language or study design restrictions.Out of a total of 38 potentially eligible papers, 27 non-overlapping study cohorts were analyzed. All were descriptive studies (case or case series studies). Altogether, 428 pregnancies from 374 fathers conceived without treatment discontinuation, 400 of which (93.5%) ended up in a live birth. A total of ten offspring with a malformation (2.5%) were reported: six with imatinib (of 313 live births, 1.9%), two with nilotinib (of 26 live births, 7.7%), one with dasatinib (of 43 live births, 2.3%), and none with bosutinib (of 12 live births). Data on CML status were scarcely reported. Only nine pregnancies (from nine males) and no malformation were reported in males who discontinued TKI treatment before conception.Malformations affected, on average 2.5% of live births from fathers who did not discontinue TKI treatment before conception, which is comparable with the rate of malformations in the general population. Large-scale studies with representative samples are awaited to confirm our results

Súlyos epilepsziás encephalopathia hátterében azonosított MECP2-gén-mutáció fiúbetegben = MECP2 mutation in a male patient identified in the background of severe epileptic encephalopathy

Absztrakt: A szerzők egy negatív családi anamnézisű, súlyos, neonatalis kezdetű epilepsziás encephalopathiában szenvedő, jelenleg kétéves fiúgyermek esetét mutatják be. A terápiarezisztens epilepszia és az igen súlyos fejlődésbeli elmaradás etiológiáját kiterjedt klinikai vizsgálatokkal sem sikerült tisztázni. Genetikai okot feltételezve, külföldi genetikai laboratóriumban 128 gént tartalmazó újgenerációs szekvenálási (NGS-) panelvizsgálatot indikáltak epilepsziás encephalopathiát okozó betegségek irányában. A vizsgálat egy eddig ismeretlen hemizigóta misszensz mutációt igazolt a MECP2-génben. A szerzők az esetbemutatás kapcsán áttekintik a lányokban klasszikusan Rett-szindrómát okozó, a MECP2-gén mutációi által előidézett idegfejlődési rendellenességek spektrumát fiúkban. Más, X-hez kötött domináns öröklődésű betegségekhez hasonlóan sokáig úgy gondolták, hogy a MECP2-gén-mutációt hordozó fiúmagzatok életképtelenek, napjainkra azonban ez a nézet megváltozott. A szerzők úgy tudják, hogy betegük az első magyar fiúgyermek, akinél a MECP2-gén mutációja igazolódott. Orv Hetil. 2019; 160(51): 2036–2039. | Abstract: Here we report on a severe, neonatal onset epileptic encephalopathy manifested in a currently 2-year-old boy with no family history of neurological disease. Extensive clinical investigations were unable to clarify the etiology of the infant’s condition characterized by drug-resistant seizures and markedly delayed developmental skills. As in this class of disorders a genetic cause might be identified, a next-generation sequencing (NGS) epilepsy panel examination consisting of 128 genes was initiated for a correct diagnosis. The genetic analysis identified a previously undescribed hemizygous missense mutation in the MECP2 gene. Similarly to other, X-linked dominant disorders, Rett syndrome was originally hypothesized to be lethal in males. This theory, however, has been revised. The aim of this report is to review the wide spectrum of neurodevelopmental diseases observed in male patients carrying mutations in the MECP2 gene classically associated with Rett syndrome in girls. To the author’s knowledge, this is the first report in Hungary to document MECP2 mutation of a male patient diagnosed by molecular genetic testing. Orv Hetil. 2019; 160(51): 2036–2039

Nagy dózisú methotrexatkezelések farmakokinetikai vizsgálata gyermekkori hematológiai malignitásokban

Monitoring the pharmacokinetic parameters of different anticancer drugs is necessary because they might have several side effects. Aim: Pharmacokinetic and toxicity evaluation of high-dose methotrexate treatments in children with acute lymphoblastic leukemia. Patients and methods: 43 children (28 boys, 15 girls, mean age: 7.03 years) in 147 cases were treated with 5 g/m2/24h MTX according to ALL-BFM 1995 and 2002 protocols. Methotrexate and 7-hydroxi-methotrexate levels were measured with high pressure liquid chromatography at 24, 36, 48 hours. Authors registered the development of hepatotoxicity, nephrotoxicity, grade III/IV oral mucositis. Results: Therapeutic methotrexate serum concentrations (30-100micromol/l) were achieved in 72.5% of the cases. Repeated treatments resulted similar serum levels. Hepatotoxicity and hypoproteinemia occurred in 17% and in 48.9% of the cases. There was significant correlation between serum 7-hydroxi-methotrexate and creatinine levels (p<0.05). Conclusion: 5 g/m2 methotrexate resulted reliable therapeutic serum levels with mild and reversible toxicity. 7-hydroxi-methotexate measurements might be more useful than methotrexate levels to detect toxicity. Orv. Hetil., 2011, 152, 1609-1617

Maternal overnutrition impairs offspring's insulin sensitivity: A systematic review and meta-analysis

This systematic review and meta-analysis aimed to investigate the association between maternal overnutrition and offspring's insulin sensitivity-following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Studies published in English before April 22, 2019, were identified through searches of four medical databases. After selection, 15 studies aiming to explore the association between prepregnancy body mass index (ppBMI) or gestational weight gain (GWG) of non-diabetic mothers and their offspring's insulin sensitivity (fasting insulin or glucose level and Homeostatic Measurement Assessment for Insulin Resistance [HOMA-IR]) were included in the meta-analysis. Associations of ppBMI and GWG with offspring's insulin sensitivity were analysed by pooling regression coefficients or standardized differences in means with 95% confidence intervals (CIs). Maternal ppBMI showed significant positive correlations with the level of both fasting insulin and HOMA-IR in offspring (standardized regression coefficient for fasting insulin: 0.107, CI [0.053, 0.160], p < 0.001 and that for HOMA-IR: 0.063, CI [0.006, 0.121], p = 0.031). However, the result of the analysis on coefficients adjusted for offspring's actual anthropometry (BMI and adiposity) was not significant. Independent from ppBMI, GWG tended to show a positive correlation with insulin level, but not after adjustment for offspring's anthropometry. Offspring of mothers with excessive GWG showed significantly higher HOMA-IR than those of mothers with optimal GWG (p = 0.004). Our results demonstrate that both higher ppBMI and GWG increase the risk of offspring's insulin resistance, but the effect of ppBMI on insulin sensitivity in offspring may develop as consequence of their adiposity

Hygromycin B, carboxin and nourseothricin susceptibility of polyunsaturated fatty acid producing Mortierella and Umbelopsis strains

Mortierella and Umbelopsis species are particularly active in polyunsaturated fatty acid (PUFA) synthesis as they are able to produce many ω-3 and ω-6 PUFAs. Genetic manipulation of the lipid production to generate PUFA overproducing strains and strains with altered PUFA profile requires well-established transformation systems and reliable selectable markers. Therefore, we screened different antifungal agents, which can be used for selection in further transformation experiments. Hygromycin B, carboxin, pyrithiamine and nourseothricin susceptibility of several Mortierella and Umbelopsis isolates was investigated using a broth microdilution method. Pyrithiamine was totally ineffective against all isolates while the other three antifungal agents were active against Mortierella and Umbelopsis strains. Several Mortierella isolates represented high sensitivity to hygromycin B whilst nourseothricin was rather active against Umbelopsis species. Carboxin inhibited the hyphal growth and the spore germination of all isolates completely in low concentrations

Probiotics have beneficial metabolic effects in patients with type 2 diabetes mellitus : a meta-analysis of randomized clinical trials

Probiotics have been reported to have a positive impact on the metabolic control of patients with type 2 diabetes. We aimed to systematically evaluate the effects of probiotics on cardiometabolic parameters in type 2 diabetes based on randomized controlled studies. MEDLINE, Embase, and CENTRAL databases were reviewed to search for randomized controlled trials that examined the effects of probiotic supplementation on cardiometabolic parameters in patients with type 2 diabetes. 32 trials provided results suitable to be included in the analysis. The effects of probiotics were calculated for the following parameters: BMI, total cholesterol levels, LDL, triglycerides, HDL, CRP, HbA1c levels, fasting plasma glucose, fasting insulin levels, systolic and diastolic blood pressure values. Data analysis showed a significant effect of probiotics on reducing total cholesterol, triglyceride levels, CRP, HbA1c, fasting plasma glucose, fasting insulin levels, and both systolic and diastolic blood pressure values. Supplementation with probiotics increased HDL levels however did not have a significant effect on BMI or LDL levels. Our data clearly suggest that probiotics could be a supplementary therapeutic approach in type 2 diabetes mellitus patients to improve dyslipidemia and to promote better metabolic control. According to our analysis, probiotic supplementation is beneficial in type 2 diabetes mellitus

Generalizált epilepszia hátterében azonosított ioncsatorna-génmutáció ritka formája = A rare form of ion channel gene mutation identified as underlying cause of generalized epilepsy

Absztrakt: A molekuláris genetikai technológiák fejlődése következtében egyre több, korábban idiopátiásnak tartott betegség hátterében ismerjük meg a genetikai eltérést. A generalizált epilepsziában szenvedő, a betegség lefolyása során epilepsziaszindrómát váltó, jó intellektusú, kiterjedt hipopigmentált folttal rendelkező fiúgyermek célzott genetikai vizsgálata neurocutan szindróma irányába nem hozott eredményt. Teljesexom-szekvenálás során egy kálium-klorid-kotranszporter génjének heterozigóta misszensz mutációja igazolódott, ami a fenotípussal összevetve, az irodalomban az idiopátiás generalizált epilepszia 14-es típusaként ismert epilepsziaszindróma diagnózisát támasztja alá. Orv Hetil. 2019; 160(21): 835–838. | Abstract: The advances in molecular genetic methods has lead to the discovery of the genetic alterations that underlie the etiology of most diseases previously held to be idiopathic. Targeted genetic examination of a pediatric male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy displaying a switch in epilepsy syndrome during the course of the disease towards a neurocutaneous syndrome was unsuccessful. Whole-exome sequencing identified a heterozygous missense mutation in a potassium chloride cotransporter gene, which together with the phenotype underscores the diagnosis of an epilepsy syndrome known in the literature as idiopathic generalized epilepsy type 14. Orv Hetil. 2019; 160(21): 835–838