Genome-wide meta-analysis identifies novel gender specific loci associated with thyroid antibodies level in Croatians

Autoimmune thyroid diseases (AITD) are multifactorial endocrine diseases most frequently accompanied by Tg and TPO autoantibodies. Both antibodies have a higher prevalence in females and act under a strong genetic influence.To identify novel variants underlying thyroid antibody levels, we performed GWAS meta-analysis on the plasma levels of TgAb and TPOAb in three Croatian cohorts, as well as gender specific GWAS and a bivariate analysis.No significant association was detected with the level of TgAb and TPOAb in the meta-analysis of GWAS or bivariate results for all individuals. The bivariate analysis in females only revealed a genome-wide significant association for the locus near GRIN3A (rs4457391, P = 7.76 × 10^?9). The same locus had borderline association with TPOAb levels in females (rs1935377, P = 8.58 × 10^?8).In conclusion, we identified a novel gender specific locus associated with TgAb and TPOAb levels. Our findings provide a novel insight into genetic and gender differences associated with thyroid antibodies.     

A 10-year experience in the treatment of intraabdominal cerebrospinal fluid pseudocysts

The aim of this retrospective study was to assess a ten-year experience in the treatment of rare complications of ventriculoperitoneal shunting--intraabdominal cerebrospinal fluid pseudocysts. At this time there are no data about incidence, clinical course and treatment of these complications in Croatia. Cerebrospinal fluid (CSF) abdominal pseudocyst is an uncommon but important complication of ventriculoperitoneal shunts. Retrospective data were obtained from 5 children with abdominal CSF pseudocysts, treated between 1996 and 2007. The incidence of intraabdominal CSF pseudocysts in our study is 2.9%. All patients were girls ranged in age from 4 to 12 years old (mean 8.8 years). In most cases etiology of hydrocephalus was congenital, idiopathic. Abdominal pain and distension were the most frequent clinical finding (4/5). Although infection has been reported as responsible for pseudocyst formation, we did not found it in our series. Laparotomy with cyst wall excision and catheter replacement was performed in 2/5 cases, and only cyst fluid aspiration with catheter replacement in 3/5 cases. Recurrence of the abdominal cyst was observed in one girl who was in terminal stadium of anaplastic ependymoma. It is our opinion that only catheter replacement and cyst fluid evacuation, as one of the treatment modalities, may be successful, even in large CSF intraperitoneal pseudocysts.     

The advantages of end-to-side arteriovenous anastomosis over the other two types of arteriovenous anastomosis in dialysis patients

The functional duration of vascular access in dialysis patients depends on the emergence of threatening complications. Discussions are constantly being held in an attempt to discover their causality and decrease their emergence. In 260 patients undergoing haemodialysis, we have studied the potential existence of a cause-and-effect relation between the emergence of complications in the vascular access and the applied type of arteriovenous (av.) anastomosis in the arteriovenous (AV) fistula. We have observed the incidence of all complications, both that of the thrombosis incidence as well as the primary and secondary fistula patency (survival). The complications--The examinees with the end-to-end anastomosis showed the incidence of 8.08%, 6.15% of the patients with the end-to-side anastomosis and 7.31% of the patients with the side-to-side anastomosis. The differences regarding incidences are statistically significant (chi2-test = 29.25; P = 0.0001). Thrombosis--it has been found that thrombosis was the most frequent complication developing in 30.00% patients with the end-to-end av. anastomosis, in 2.31% patients with end-to-side av. anastomosis and in 5.56% patients with side-to-side av. anastomosis. The difference between the highest and the lowest assessment is 27.69%, and it is statistically relevant (chi2-test = 33.920; P = 0.0001). The primary patency (primary survival): within a 6-month interval following the establishment of vascular access, the first complications arose in 62.50% of patients with end-to-end av. anastomosis, 10.76% in those with end-to-side av. anastomosis and 18.88% in those with side-to-side av. anastomosis. The difference between the highest and the lowest assessment is 51.74%, which is statistically significant (chi2-test = 49.009; P = 0.0001). The secondary patency: 24 months subsequent to the establishment of vascular access, the AV-fistula was still functional in 52.50% of the patients with end-to-end av. anastomosis, 89.23% in those with end-to-side av. anastomosis and 81.11% in those with side-to-side av. anastomosis. The difference between the highest and the lowest assessment is 36.73%, which is also statistically significant (chi2-test = 26.579; P = 0.0001). According to our research, the end--to-side type of av. anastomosis in vascular access provides better results both in relation to the duration as well as the maintenance of the functionality of the Av-fistula and in the lower incidence of the complications than the other types, and hence it shows a definite advantage.     

Impaired esophageal function in patients with irritable bowel syndrome

The aim of the study was to determine prevalence of the signs and symptoms related to esophageal dysfunction in irritable bowel syndrome (IBS) patients, and to investigate sensorimotor function impairment based on the esophageal manometry study, thus to determine the correlation between them. The study included 30 patients with IBS, 14 of them with diarrhea (IBSd) and 16 with constipation (IBSc) as a predominant discomfort. Control group consisted of 30 healthy subjects. The patients were included in the study on the basis of the Rome criteria for IBS. In addition to thorough history and physical examination patient underwent esophagogastroduodenoscopy and esophageal manometry. The values of esophageal manometry obtained in healthy subjects served as controls in manometry studies. The patients with IBS suffered a great number of both colonic and extracolonic signs and symptoms, however, there was no statistically significant difference in the prevalence of particular symptoms between the two patient subgroups. In comparison with healthy subjects, the patients suffering from IBS showed pathologically altered values in the majority of parameters of esophageal motility. Comparison of the two subgroups of IBS patients according to esophageal motility characteristics yielded differences in only few of them. The results obtained in the study could explain why the patients with IBS quite commonly complain of the symptoms related to upper gastrointestinal tract, such as heartburn and chest pain of noncardiac genesis. The results also suggest that the IBS might be associated with considerably more extensive smooth muscle or innervation changes than presumed before.     

Characterization of X Chromosome Inactivation Using Integrated Analysis of Whole-Exome and mRNA Sequencing

In females, X chromosome inactivation (XCI) is an epigenetic, gene dosage compensatory mechanism by inactivation of one copy of X in cells. Random XCI of one of the parental chromosomes results in an approximately equal proportion of cells expressing alleles from either the maternally or paternally inherited active X, and is defined by the XCI ratio. Skewed XCI ratio is suggestive of non-random inactivation, which can play an important role in X-linked genetic conditions. Current methods rely on indirect, semi-quantitative DNA methylation-based assay to estimate XCI ratio. Here we report a direct approach to estimate XCI ratio by integrated, family-trio based whole-exome and mRNA sequencing using phase-by-transmission of alleles coupled with allele-specific expression analysis. We applied this method to in silico data and to a clinical patient with mild cognitive impairment but no clear diagnosis or understanding molecular mechanism underlying the phenotype. Simulation showed that phased and unphased heterozygous allele expression can be used to estimate XCI ratio. Segregation analysis of the patient''s exome uncovered a de novo, interstitial, 1.7 Mb deletion on Xp22.31 that originated on the paternally inherited X and previously been associated with heterogeneous, neurological phenotype. Phased, allelic expression data suggested an 83∶20 moderately skewed XCI that favored the expression of the maternally inherited, cytogenetically normal X and suggested that the deleterious affect of the de novo event on the paternal copy may be offset by skewed XCI that favors expression of the wild-type X. This study shows the utility of integrated sequencing approach in XCI ratio estimation.     

Prediction of ovarian tumor malignancy

Ovarian cancer is the leading cause of mortality among gynecological cancers. The aim of the study was to form the decision rules for distinguishing benign from malignant ovary lesions. The research was conducted on 201 women with ovary tumor. Commonly used specific markers for ovarian cancer (biochemical marker Ca 125, ultrasound and vascular markers) were used. The significant difference in the presence of an ultrasound and vascular markers between benign and malignant ovary changes along with the significantly different level of Ca 125 is confirmed. To a specific marker certain score number was appointed and the scoring system was formed. The incidence of benign/malignant ovary changes was observed in the researched group regarding anthropometric parameters (age, marital and menopausal status and number of deliveries). There is also significant difference in the incidence of benign/malignant ovary tumor regarding these parameters. Based on combination of the scoring system and anthropometric parameters the decision rules for distinguishing benign from malignant ovary tumors were formed. The logistic regression method was used. We proved that this method has higher accuracy in prediction of malignancy in women with ovary tumors than using morphological, Doppler or anthropometric parameters separately.     

Comparison of different presbyopia treatments: refractive lens exchange with multifocal intraocular lens implantation versus LASIK monovision

There are several methods for presbyopia treatment. Refractive lens exchange (RLE) followed by multifocal intraocular lens (MFIOL) implantation enables high rate of spectacle independence but have some visual disturbances. Laser in Situ Keratomileusis (LASIK) monovision gives patient ability to have good distant vision with dominant eye and good near vision with nondominant eye. In this prospective randomized study we wanted to compare clinical outcomes in patients who underwent either of the mentioned procedures. The first group included 50 patients (N = 100 eyes) who underwent RLE with MFIOL implantation and the second group included 50 patients (N = 100 eyes) who underwent LASIK monovision as presbyopia treatment. Uncorrected distant, near and intermediate visual acuity, patient's subjective satisfaction and visual disturbances were measured. Follow up was 6 months. Patients in RLE group had better near uncorrected visual acuity (UCVA) and patients in LASIK monovision group had better distant and intermediate vision. Patients in RLE group reported visual disturbances (halo, glare). Patients satisfaction and spectacle independence was high in both groups. Refractive lens exchange with multifocal intraocular lens implantation and LASIK monovision are effective methods for presbyopia treatment. LASIK monovision with -0.50D - 1.25D of residual dioptry at nondominant eye in patients under 50 years enables good vision at all distances without affecting stereovision. Patient selection and preoperative counseling are key to success.     

An integrative approach in the assessment of species delimitation and structure of the <Emphasis Type="Italic">Merodon nanus</Emphasis> species group (Diptera: Syrphidae)

The Merodon nanus group (Diptera, Syrphidae) is a small group of closely related species with high morphological similarity. Until now, based on morphological characters, this group consisted of five species: M. nanus Sack, 1931; M. telmateia Hurkmans, 1987; M. kopensis Vuji? et Hayat, 2015; M. neonanus Vuji? et Taylor, 2015; and M. rasicus Vuji? et Radenkovi?, 2015. Here, using an integrative approach based on molecular characters (sequences of the D2–3 region of the nuclear 28S rRNA gene and the mitochondrial COI gene) and data obtained from geometric morphometry of wing shape, we distinguish all five previously morphologically defined species of the group. Additionally, we identify one species as being new to science, M. vladimiri Vuji? et Ko?i? Tubi? sp. n. We emphasize the separation of this newly described species according to the sequences obtained from the slowly evolving 28S rRNA gene, which demonstrated four to five mutation positions between this species and morphologically the most similar M. neonanus species. Also, our results show a clear division of M. telmateia into at least three population groups that we designate as the subspecies: M. telmateia mediterraneus A?anski et Ko?i? Tubi? subsp. n. and M. telmateia samosensis A?anski et Ko?i? Tubi? subsp. n. exhibiting western distributions (western Anatolia and the Greek island of Samos, respectively) and the nominative subspecies M. telmateia telmateia with an eastern Anatolian distribution.     

Intracellular trafficking and proteolysis of the Arabidopsis auxin-efflux facilitator PIN2 are involved in root gravitropism

Root gravitropism describes the orientation of root growth along the gravity vector and is mediated by differential cell elongation in the root meristem. This response requires the coordinated, asymmetric distribution of the phytohormone auxin within the root meristem, and depends on the concerted activities of PIN proteins and AUX1 - members of the auxin transport pathway. Here, we show that intracellular trafficking and proteasome activity combine to control PIN2 degradation during root gravitropism. Following gravi-stimulation, proteasome-dependent variations in PIN2 localization and degradation at the upper and lower sides of the root result in asymmetric distribution of PIN2. Ubiquitination of PIN2 occurs in a proteasome-dependent manner, indicating that the proteasome is involved in the control of PIN2 turnover. Stabilization of PIN2 affects its abundance and distribution, and leads to defects in auxin distribution and gravitropic responses. We describe the effects of auxin on PIN2 localization and protein levels, indicating that redistribution of auxin during the gravitropic response may be involved in the regulation of PIN2 protein.