Short stature and combined immunodeficiency associated with mutations in RGS10.

We report the clinical and molecular phenotype of three siblings from one family, who presented with short stature and immunodeficiency and carried uncharacterized variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). This gene encodes regulator of G protein signaling 10 (RGS10), a member of a large family of GTPase-activating proteins (GAPs) that targets heterotrimeric G proteins to constrain the activity of G protein-coupled receptors, including receptors for chemoattractants. The affected individuals exhibited systemic abnormalities directly related to the RGS10 mutations, including recurrent infections, hypergammaglobulinemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Although the GAP activity of each RGS10 variant was intact, each protein exhibited aberrant patterns of PKA-mediated phosphorylation and increased cytosolic and cell membrane localization and activity compared to the wild-type protein. We propose that the RGS10 p.E163del and p.A171S mutations lead to mislocalization of the RGS10 protein in the cytosol, thereby resulting in attenuated chemokine signaling. This study suggests that RGS10 is critical for both immune competence and normal hormonal metabolism in humans and that rare RGS10 variants may contribute to distinct systemic genetic disorders.

Profile of incidental exposures to e-cigarette liquids in Europe, 2018-2019.

BACKGROUND: Following the implementation of the European Union Tobacco Product Directive (EU TPD) regulations on e-cigarette products in 2016, we assessed the current profile of e-cigarette liquid exposure incidents and their associated health outcomes. METHODS: De-identified data were received from poison centers in eight EU Member States (Sweden, the Netherlands, Italy, Hungary Austria, Finland, Spain and Croatia) reporting on e-cigarette liquid exposure incidents between August 2018 to December 2019. Descriptive analysis was conducted to present incident characteristics and health outcomes. Chi-square tests and multivariable logistic regression analysis were used to test associations. RESULTS: Of the 223 e-liquid exposure incidents recorded by poison centers in multiple EU MS, 64.7% of the cases were unintentional exposures, ranging from 48.4% among adults aged ≥19 years to 100.0% among children aged 0-5 years (p < 0.05). The most frequent route of exposure was ingestion (73.5%) while55.2% experienced any clinical symptoms, including nausea (16.6%), vomiting (11.1%), and dizziness (9.0%). 57.8% of the cases were treated at the residence or on-site. CONCLUSION: Further monitoring is warranted, using uniform reporting requirements, to ensure the continued compliance to the EU TPD and assess its long-term impact on related incident characteristics.

Catecholamine-Secreting Tumors in Pediatric Patients With Cyanotic Congenital Heart Disease.

Catecholamine-secreting tumors are rare among the pediatric population but are increasingly being reported in children with sustained hypoxia secondary to cyanotic congenital heart disease (CCHD). With this review, we report the clinical characteristics of these tumors in children with CCHD. The articles included in the present review were identified using PubMed through February 2019. A manual search of the references retrieved from relevant articles was also performed. Pheochromocytomas and paragangliomas (PPGL) in children are commonly associated with high-risk germline or somatic mutations. There is evidently a higher risk of tumorigenesis in children with CCHD as compared with the general pediatric population, even in the absence of susceptible gene mutations. This is due to molecular mechanisms involving the aberrant activation of hypoxia-response elements, likely secondary to sustained hypoxemia, resulting in tumorigenesis. Due to overlapping symptoms with CCHD, the diagnosis of PPGL may be delayed or missed in these patients. We studied all previously reported PPGL cases in children with CCHD and reviewed phenotypic and biochemical features to assess for contributing factors in tumorigenesis. Larger studies are needed to help determine other potential predisposing factors and to establish screening guidelines in this high-risk population. A delay in diagnosis of the PPGL tumors can lead to exacerbation of cardiac failure, and therefore early diagnosis and intervention may provide better outcomes in these patients, necessitating the need for regular surveillance. We recommend routine biochemical screening in patients with sustained hypoxia secondary to CCHD.

McCune-Albright Syndrome With Unremitting Hyperthyroidism at Early Age: Management Perspective for Early Thyroidectomy.

Background. McCune-Albright syndrome (MAS) is characterized by hyperpigmented macules, endocrinopathies, and fibrous dysplasia. Hyperthyroidism is the second most common endocrinopathy in MAS and its management is challenging, particularly among infants and toddlers. Traditionally, young infants have been treated with antithyroid medications, but remission is likely and these medications have severe side effects and affect the control of other endocrinopathies. Thus, it is reasonable to consider permanent treatment options at an earlier age. In this article, we performed a retrospective chart review and describe 3 children who underwent thyroidectomy at an early age due to complex presentation. Case Descriptions. Case 1 was a female patient who underwent bilateral adrenalectomy due to adrenal hyperplasia and subsequently underwent thyroidectomy at 5 months of age due to unremitting hyperthyroidism with fibrous dysplasia, multiple fractures, and ovarian cysts with vaginal bleeding. Case 2 was a 20-month-old female on methimazole who acquired influenza A, precipitating a thyroid storm, and subsequently developed central precocious puberty. Case 3 was a 4-year-old female who underwent thyroidectomy because of unremitting hyperthyroidism after methimazole cessation due to declining neutrophils. All 3 children experienced no complications from thyroidectomy. Conclusions. Early thyroidectomy by an experienced surgeon is an option for managing MAS-associated hyperthyroidism, even in very young patients, with excellent results.

Characteristics and outcomes of e-cigarette exposure incidents reported to 10 European Poison Centers: a retrospective data analysis.

BACKGROUND: The use of e-cigarettes has increased during the past few years. Exposure to e-cigarette liquids, whether intentional or accidental, may lead to adverse events our aim was to assess factors associated with e-cigarette exposures across European Union Member States (EU MS). METHODS: A retrospective analysis of exposures associated with e-cigarettes reported to national poison centers was performed covering incidents from 2012 to March 2015 from 10 EU MS. De-identified and anonymous raw data was acquired. RESULTS: In total, 277 incidents were reported. Unintentional exposure was the most frequently cited type of exposure (71.3%), while e-cigarette refill vials were responsible for the majority of the reported incidents (87.3%). Two-thirds of all exposures (67.5%) occurred as ingestion of e-liquids, which was more frequent among children (≤ 5 years, 6-18 years) compared to adults (87.0% vs. 59.3% vs. 57.6%, p < 0.001 respectively), exposure via the respiratory (5.4% vs. 22.2% vs. 22.2%, p < 0.001) were more frequent among paediatric patients while ocular routes (2.2% vs. 3.7% vs. 11.4%, p = 0.021) were more frequent among adults. Logistic regression analyses indicated that paediatric incidents (≤ 5 years) were more likely to be through ingestion (adjusted Odds Ratio [aOR] = 4.36, 95% Confidence Interval [C.I.]: 1.87-10.18), but less likely to have a reported clinical effect (aOR = 0.41, 95% C.I.: 0.21-0.82). CONCLUSIONS: Our study highlighted parameters related to e-cigarette exposure incidents in 10 EU MS, the results of which indicate that consideration should be given to the design features which may mitigate risks, thereby protecting users, non-users and especially children.

Distribution of Chlamydia trachomatis genotypes in neonatal conjunctivitis in Hungary.

The objective of the present study was to determine the frequency and age distribution of different Chlamydia trachomatis (CT) genotypes causing ophthalmia neonatorum (ON) in Hungary. Using CT specific PCR, we tested 76 conjunctival samples from symptomatic infants up to 3 months old in the National Centre for Epidemiology, Budapest between 2008 and 2016. CT tested positive in 30 of 76 conjunctival samples (39.5 %). The sequencing of the positive samples was successful in every case but one, and resulted in 48 % dominance for genotype E (14/29), followed by 24 % for genotype G (7/29), 10 % for J (3/29), 6.9 % for K and F (2/29), and 3.4 % for H (1/29). CT must still be regarded as a common pathogen causing ON in Hungary. Routine screening and treatment of pregnant women can be recommended to prevent these conditions. Chronic ON cases can be reduced by early diagnosis. Further research is needed to explain the dominance of genotypes E and G.

Chlamydial conjunctivitis: prevalence and serovar distribution of Chlamydia trachomatis in adults.

The extragenital manifestation of Chlamydia trachomatis infection frequently results in non-specific conjunctivitis among sexually active adults. The aims of the present study were to determine the prevalence of C. trachomatis, to describe the distribution of serovars among patients with conjunctivitis and to characterize the relationship between the prevalence and patient demographics such as age and gender. A total of 245 conjunctival specimens were screened for C. trachomatis DNA targeting the plasmid gene. Serovar determination of the C. trachomatis-positive specimens was carried out by an omp1 PCR-based RFLP analysis method. Statistical analysis was done using a generalized linear model. C. trachomatis was detected in 53 cases (21.6 %) of adult conjunctivitis. Molecular genotyping differentiated seven distinct urogenital serovars, the most prevalent being serovar E (16/53), followed by F (15/53), D (6/53), K (6/53), G (4/53), H (4/53) and J (2/53). Statistical analysis showed higher C. trachomatis prevalence in the younger age groups, and this peaked at younger age in women than in men. The high prevalence of this pathogen found in ocular samples should alert ophthalmologists to focus on the role of C. trachomatis in adult conjunctivitis. The serovar distribution indicated that ocular chlamydial infections usually have a genital source. Nevertheless, conjunctivitis might be the only sign of this sexually transmitted infection. Further comparative genotyping of C. trachomatis in ocular and genital specimens might give more detailed epidemiological information about the aetiology of the disease.

Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it.

CONTEXT: Ectopic ACTH/CRH syndrome is a rare cause of Cushing syndrome (CS), especially in children. The localization, work-up, and management of ACTH/CRH-secreting tumors are discussed. SETTING: A retrospective study was conducted of patients under 21 years of age evaluated at the National Institutes of Health (NIH) for CS and diagnosed with ectopic ACTH/CRH-secreting tumors during the period 2009-2014. PATIENTS: Seven patients with ectopic ACTH/CRH CS are included in this study with a median age 13.6 years (range 1-21), and 3 are female. MEASUREMENTS: Clinical, biochemical, radiological features, treatment, and histological findings are described. RESULTS: Seven patients were found to have ACTH/CRH-secreting tumors, all with neuroendocrine features. The site of the primary lesion varied: pancreas (3), thymus (2), liver (1), right lower pulmonary lobe (1). PATIENTS underwent biochemical evaluation for CS, including diurnal serum cortisol and ACTH levels, urinary free cortisol levels (UFC), and CRH stimulation tests. All patients underwent radiological investigations including MRI, CT, and PET scan; imaging with octreotide and 68 gallium DOTATATE scans were performed in individual cases. Five patients underwent inferior petrosal sinus sampling; 4 patients had sampling for ACTH and CRH levels from additional sites. Three patients underwent trans-sphenoidal surgery (TSS), and 3 patients required bilateral adrenalectomy. Three patients (43%) died due to metastatic disease, demonstrating the high mortality rate. One of the unique findings in these seven patients is that in each case, their neuroendocrine tumors were ultimately proven to be co-secreting ACTH and CRH. This explains the enigmatic presentation, in which 3 patients initially thought to have Cushing's disease (CD) with corresponding pituitary hyperplasia underwent TSS prior to the correct localization of the causative tumor. CONCLUSIONS: Ectopic ACTH/CRH co-secreting tumors are extremely rare in children and adolescents. The diagnosis of this condition is frequently missed and is sometimes confused with CD due to the effect of CRH on the pituitary.

Growth regulator requirement for in vitro embryogenic cultures of snowdrop (Galanthus nivalis L.) suitable for germplasm preservation.

In this study, we report on the production of bulb scale-derived tissue cultures capable of efficient shoot and plant regeneration in three genotypes of snowdrop (Galanthus nivalis L., Amaryllidaceae), a protected ornamental plant. For culture line A, high auxin and low cytokinin concentration is required for callus production and plant regeneration. The type of auxin is of key importance: α-naphthaleneacetic acid (NAA) in combination with indole-3-acetic acid (IAA) at concentrations of 2 mg L-1 or 2-10 mg L-1 NAA with 1 mg L-1 N6-benzyladenine (BA), a cytokinin on full-strength media are required for regeneration. Cultures showing regeneration were embryogenic. When lines B and C were induced and maintained with 2 mg L-1 NAA and 1 mg L-1 BA, they produced mature bulblets with shoots, without roots. Line A produced immature bulblets with shoots under the above culture condition. Amplified Fragment Length Polymorphism (AFLP) analysis showed that (i) genetic differences between line A and its bulb explants were not significant, therefore these tissue cultures are suitable for germplasm preservation, and (ii) different morphogenetic responses of lines A, B and C originated from genetic differences. Culture line A is suitable for field-growing, cultivation and germplasm preservation of G. nivalis and for the production of Amaryllidaceae alkaloids.

Investigation of dietary important components in selected red fleshed apples by GC-MS and LC-MS.

Three red-fleshed apple cultivars (Malus 'Geneva': GFV-03, Hungarian hybrid: GFV-04, Malus pumila Niedwetzkyana: GFV-05) were investigated for their chemical composition by sHS-SPME-GC-MS and HPLC-DAD-MS/MS analytical techniques. In cultivars GFV-03 and GFV-05 sesquiterpene α-farnesene were dominant while the alphatic esters were present mostly in traces. In GFV-04 - the new disease resistant advanced selection of the Hungarian apple breeding program - hexanol and hexyl 2-methylbutanoate were present in larger amounts while the amount of α-farnesene was lower than the other two cultivars. Using HPLC-DAD-MS/MS four phenolic acid derivatives, four anthocyanins, six flavonoids of quercetin derivatives and two dihydrochalcone phloretin glycosides were identified or characterized among the detected sixteen phenolic compounds.

Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation.

Isolated hypocortisolism due to ACTH deficiency is a rare condition that can be caused by homozygous or compound heterozygous mutations in the gene encoding proopiomelanocortin (POMC). Loss of function mutations of POMC gene typically results in adrenal insufficiency, obesity and red hair. We describe an 18 month old Hispanic female with congenital adrenal insufficiency, a novel POMC mutation and atypical clinical features. The patient presented at the age of 9 months with hypoglycemia and the endocrine evaluation resulted in a diagnosis of ACTH deficiency. She developed extreme weight gain prompting sequence analysis of POMC, which revealed a homozygous c.231C > A change which is predicted to result in a premature termination codon. The case we report had obesity, hypocortisolism but lacked red hair which is typical for subjects with POMC mutations. Mutations of POMC should be considered in individuals with severe early onset obesity and adrenal insufficiency even when they lack the typical pigmentary phenotype.

Molecular epidemiological analysis of env and pol sequences in newly diagnosed HIV type 1-infected, untreated patients in Hungary.

The aim of our study was to monitor the diversity of HIV-1 strains circulating in Hungary and investigate the prevalence of resistance-associated mutations to reverse transcriptase (RT) and protease (PR) inhibitors in newly diagnosed, drug-naive patients. A total of 30 HIV-1-infected patients without prior antiretroviral treatment diagnosed during the period 2008-2010 were included into this study. Viral subtypes and the presence of RT, PR resistance-associated mutations were established by sequencing. Classification of HIV-1 strains showed that 29 (96.6%) patients were infected with subtype B viruses and one patient (3.3%) with subtype A virus. The prevalence of HIV-1 strains with transmitted drug resistance mutations in newly diagnosed individuals was 16.6% (5/30). This study showed that HIV-1 subtype B is still highly predominant in Hungary and documented a relatively high transmission rate of drug resistance in our country.

[Role of phytotherapy in the prevention and treatment of obesity]. / Gyógynövények szerepe az elhízás megelozésében és kezelésében.

The rapidly increasing prevalence of overweight and diabetes mellitus is a serious global threat to healthcare. Nowadays, medicinal plants and natural treatments are becoming more and more popular. Diabetes has historically been treated with plants or plant derived formulations in different cultures, mainly in China, Asia and India. Different mechanisms for the antidiabetic effect of plants have been proposed: increased release of insulin, reduction of intestinal glucose absorption, enhancement of glycogen synthesis. The scientific evidences for most of these plants are still incomplete. The large market for plant remedies has resulted in an array of unauthorized products or marketed as dietary supplements and, at the same time, no reliable pharmaceutical-grade products are registered for this purpose.

X-linked hypophosphatemic rickets associated with respiratory failure.

We report a 5-year-old girl who presented to our emergency room with respiratory arrest and limb deformities and was subsequently diagnosed with X-linked hypophosphatemic rickets. On normalization of the serum phosphorus concentration, her respiratory distress resolved, illustrating that untreated X-linked hypophosphatemic rickets can lead to life-threatening respiratory distress.

Rapid resolution of consumptive hypothyroidism in a child with hepatic hemangioendothelioma following liver transplantation.

We report a unique case of a 3-mo-old female with consumptive hypothyroidism and liver hemangioendothelioma who required pharmacological doses of thyroid hormones and was cured following liver transplantation. Liver hemangioendotheliomas are capable of producing an excess of the thyroid hormone inactivating enzyme, type-3 iodothyronine deiodinase. The increased tumoral enzyme activity leads to rapid degradation of thyroid hormones, resulting in consumptive hypothyroidism. Review of similar cases indicated variable outcomes. We focus on our patient's clinical course and describe in detail the thyroid hormone replacement therapy and a unique outcome of this rare type of hypothyroidism. This first example of a prompt and complete resolution of consumptive hypothyroidism in an infant after liver transplantation confirms the concept and the reversibility of consumptive hypothyroidism and provides novel insights into the rapidity of response of the infant's hypothalamic-pituitary-thyroid axis to thyroid hormone replacement.

[Gas chromatography for analysis of essential oils. Characteristics of essential oil of Dracocephalum species and the influence of extraction method on its composition]. / Gáizkromatográfia alkalmazása illóolajok analízisére Dracocephalum fajok illóolaj jellemzoi és az extrakciós mód illóolajösszetételt befolyásoló hatása.

In this work the essential oil composition of some less known Dracocephalum species was studied and compared the effectiveness, selectivity and influence of different extraction methods (hydrodistillation, Soxhlet extraction with organic solvents and supercritical fluid extraction) on essential oils. For investigations in Hungary and Transylvania cultivated plant material was used. The analysis of essential oils was carried out by GC and GC-MS methods. The components were identified by standard addition, retention factors and mass spectra. The percentile evaluation of each volatile constituents was made on basis of GC-FID chromatograms. The accuracy of measurements was characterized by relative standard deviation. In the essential oil of D. renati Emb. (studied firstly by us) 18.3% of limonene was measured and carvone, citrals and linalyl acetate monoterpenes, methyl chavicol and some sesquiterpene (e.g. bicyclovetivenol) determined in lower quantities. We established that more than 50% of essential oil of D. grandiflorum L. was formed by sesquiterpenes (beta-caryophyllene and- oxide, beta-bourbonene, beta-cubebene, aromadendrene) and the essential oil of D. ruyschiana L. contained pinocamphone isomers in more than 60%. The oxygenated acyclic monoterpenes, the characteristic constituents of Moldavian dragonhead were present in some tenth percent only in D. renati oil. We found significant differences in the composition of the SFE extract and traditional essential oil of D. moldavica L. The supercritical fractions collected at the beginning of the extraction process were richer in valuable ester component (geranyl acetate) than the essential oil obtained by hydrodistillation. The fractions collected at the end of supercritical were poor in oxygenated monoterpenes but rich in minor compounds of traditional oil, e.g. palmitic acid.

[Free radical scavenger and lipid peroxidation inhibiting effects of medicinal plants used in phytotherapy]. / Fitoterápiában jelentos gyógynövények szabadgyökfogó es lipidperoxidációt gátló hatása.

Epidemiological and clinical studies have proved the beneficial effect of bioactive compounds of vegetables and medicinal plants used in phytotherapy on prevention of several diseases. Beyond the well-known natural antioxidants, such as vitamins, other natural substances can function as antioxidants. In 1992 the Saas Fee Declaration was published by leader nutritionist and biochemists underlining the importance of prevention in health maintenance based on scientific studies with natural compounds. According to the declaration the antioxidants are the main active and beneficial components. Authors joining with the spirit of Saas Fee Declaration have worked out a complex examination system to study the antioxidant, free radical scavenging and inhibitory effects on lipid peroxidation of isolated components, natural plant extracts and herbal preparations. The members of the system are the followings: hydrogendonating ability, reducing power, chelating activity, free radical scavenging activities measured by chemiluminescence techniques, electron paramagnetic resonance / spin trapping studies, inhibition of lipid peroxidation induced in rat brain / liver microsomes, consequencies and treatment of experimental hyperlipidemia, morphological and histological studies. Only one measurement cannot give enough information about the antioxidant properties of the products. Complex in vitro examination of a novel antioxidant can draw pictures of correlation between the chemical structure and antioxidant effect, the mechanism of its favourable effect and its presumable role in prevention of lipid peroxidation. With the use of these results planning and execution of in vivo examinations should be more precise, practical and essential.

[Influence of extraction methods on the composition of essential oils]. / Extrakciós módszerek hatása az illóolajok osszetételére.

The aim of this work is to demonstrate our results on comparison of composition of essential oil fractions obtained by traditional steam distillation and supercritical fluid extraction. The plant materials for the various extraction methods were selected from the Lamiaceae, Apiaceae and Asteraceae families. For the supercritical fluid extraction (SFE) carbon dioxide was used as supercritical solvent. The extracts were collected by stage wise precipitation in two separators. The waxy product and extract rich in essential oil were collected in the 1st and in the 2nd separator respectively. The traditional water steam distillation (SD) was carried out in the special apparatus of the Hungarian Pharmacopoea (7th ed.). GC analysis was carried out on capillary silica fused columns coated with DB-1701 and the specific chiral columns coated with Rt-beta DEX m or Rt-beta DEX sm. Comparing the composition of steam distilled oils with that of volatile SFE fractions the following general characteristics were established. The SFE fractions were richer in monoterpene-esters and poorer in alcohols than the traditional essential oils (clary sage, lavander, moldavian dragonhead). Regarding the distribution of the monoterpene and sesquiterpene compounds, the SFE fractions contained sesquiterpenes in higher percentage than the distilled oils (Salvia fruticosa). Furthermore, the proportion of sesquiterpenes increased in SFE fractions collected successively with time (Salvia officinalis) similar to the ratio of oxygenated monoterpenes to monoterpene hydrocarbons (Rosmarinus officinalis). The phtalides of lovage (Satureja hortensis) did not show regular change during the supercritical extraction. In other cases it was verified that part of the mono- and sesquiterpenes were present originally in bound form (glycosides) in plants. Thus they appeared only in essential oil fractions after previous acidic treatment (Thymus, Origanum, Satureja species). During the super-critical extraction the azulenogene sesquiterpene lactones did not transform to azulenes (chamomile, yarrow), but SFE fractions of some Asteraceae plants contained sesquiterpene-gamma-lactones of unchanged structure.