Mutations in RAD21 disrupt regulation of apob in patients with chronic intestinal pseudo-obstruction

Background Aims Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers. Methods We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed. Results We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens. Conclusions Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons. © 2015 by the AGA Institute

Placental mesenchymal dysplasia: A rare clinicopathologic entity confused with molar pregnancy

Placental mesenchymal dysplasia (PMD) is a rare placental abnormality characterised by placentomegaly and grape-like vesicles resembling partial mole by ultrasonography, but in contrast to partial mole can co-exist with a viable fetus. Although the karyotype is normal, the fetus is at increased risk for intrauterine growth restriction, intrauterine fetal demise or perinatal death and Beckwith-Wiedemann syndrome. Prenatal diagnosis is difficult and the final diagnosis is usually achieved by postpartum histological examination of the placenta. We present two recent cases of placental mesenchymal dysplasia with poor obstetric outcome. One fetus presented with reduced growth parameters, while the other fetus showed hepatosplenomegaly and early hydropic changes that appear to be associated with Beckwith-Wiedemann syndrome. In this report, the clinicopathological features of two cases of PMD are discussed and the differentiation from a partial mole is highlighted. This study also supports the utility of cytogenetic ploidy analysis and p57KIP2 protein staining in the evaluation of pregnancies with PMD

Comparison of diagnostic accuracy of saline infusion sonohysterography, transvaginal sonography and hysteroscopy

WOS: 000286898700012PubMed ID: 21280995We aimed to compare the accuracy of transvaginal sonography (TVS), saline infusion sonohysterography (SIS) and hysteroscopy (HS) for uterine pathologies among infertile women. A total of 346 patients were selected for operative hysteroscopy, following SIS after TVS. SIS was performed with a Cook Soft 500 IVF catheter. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) were calculated to compare the accuracy of TVS, SIS and hysteroscopy for uterine abnormalities. SIS showed a sensitivity of 87%, specificity of 100% and PPV of 100% for endometrial hyperplasia, and a sensitivity and NPV of 100% for polypoid lesions. For submucosal myoma SIS showed a sensitivity of 99% with PPV of 96%. Hysteroscopy had a sensitivity, specificity, PPV and NPV of 98%, 83%, 96% and 91%, respectively for overall uterine pathologies. Finally, SIS seems to be superior to TVS, for uterine pathologies, with respect to hysteroscopy as the gold standard

Higher minor hemoglobin A2 levels in multiple sclerosis patients correlate with lesser disease severity

Muhammed Emin Ozcan,1 Bahri Ince,2 Hasan Huseyin Karadeli,3 Asuman Gedikbasi,4 Talip Asil,3 Meric A Altinoz5 1Department of Neurology, Biruni University, 2Centre for Mood Disorders, Bakirkoy Research and Training Hospital for Psychiatry, 3Department of Neurology, Bezmialem University, 4Department of Biochemistry, Sadi Konuk Bakirkoy State Hospital, 5Department of Immunology, Experimental Medicine Research Institute (DETAE), Istanbul University, Istanbul, Turkey Objective: To define whether minor adult hemoglobin A2 (HbA2, α2δ2) exerts any protective activity in multiple sclerosis (MS). Methods: HbA2 levels were measured in 146 MS patients with high performance liquid chromatography and association with MS Severity Scores (MSSS) were determined. HbA2 associations with blood count parameters were also studied using blood counts evaluated on the same day of high performance liquid chromatography sampling. Routine biochemical parameters were also determined to rule out elusively influential factors, such as anemia and thyroid disorders. Results: HbA2 levels negatively correlated with MSSS (Spearman correlation, R: -0.186, P=0.025). Exclusion of confounding factors with a generalized linear model revealed an even stronger negative correlation between HbA2 and MSSS (P<0.001). HbA2 positively correlated with red blood cells (RBCs) (R=0.350, P<0.001) and in turn, RBCs negatively correlated with MSSS (R=-0.180, P=0.031). Average HbA2 levels were highest among patients treated with interferon β1a. Conclusion: RBC fragility is increased in MS, and recent data suggest that circulating free Hb contributes to neural injury in MS. HbA2 and its oxidative denaturation product hemichrome A2 enhance RBC membrane stability to a greater extent than do major HbA or hemichrome A. Reductions in ischemic cerebrovascular vascular events are reported in β-thalassemia carriers and HbA2 levels are considerably higher in this population. Episodic declines of cerebral blood flow were shown in bipolar disorder, and we have recently shown a protective role of HbA2 against postpartum episodes in females with bipolar disorder. HbA2’s erythroprotective functions may reduce free Hb and long-term neural injury in MS. Keywords: multiple sclerosis, erythrocytes, adult minor hemoglobin, hemoglobin A

Serum Presepsin Levels Are Not Elevated in Patients with Controlled Hypertension

Introduction. Hypertension (HT) is a common serious condition associated with cardiovascular morbidity and mortality. The pathogenesis of HT is multifactorial and has been widely investigated. Besides the vascular, hormonal, and neurological factors, inflammation plays a crucial role in HT. Many inflammatory markers such as C-reactive protein, cytokines, and adhesion molecules have been studied in HT, which supported the role of inflammation in the pathogenesis of HT. Presepsin (PSP) is a novel biomarker of inflammation. Therefore, the potential relationship between PSP and HT was investigated in this study. Methods. Forty-eight patients with controlled HT and 48 controls without HT were included in our study. Besides routine clinical and laboratory data, PSP levels were measured in peripheral venous blood samples from all the participants. Results. PSP levels were significantly lower in patients with HT than in controls (144.98±75.98 versus 176.67±48.12 pg/mL, p=0.011). PSP levels were positively correlated with hsCRP among both the patient and the control groups (p=0.015 and p=0.009, resp.). However, PSP levels were not correlated with WBC among both groups (p=0.09 and p=0.67, resp.). Conclusions. PSP levels are not elevated in patients with well-controlled HT compared to controls. This result may be associated with anti-inflammatory effects of antihypertensive medicines. © 2018 Ismail Biyik et al