Elabela is a reliable biomarker for predicting early onset preeclampsia: A comparative study.

BACKGROUND: Preeclampsia (PE) is a multisystemic metabolic disease with an undetermined etiology. PE is a worldwide cause of maternal and perinatal morbidity, subdivided into early (EoPE) and late-onset (LoPE) according to 34 wk of gestation as a divider. Many researchers investigated biomarkers for predicting PE to halt its consequences on the feto-maternal outcome. Elabela (Ela) is a newly discovered peptide hormone that was implicated in PE pathogenesis. Earlier rodent studies discussed Ela's role in controlling blood pressure. Moreover, Ela deficiency was associated with PE development. AIM: To test whether plasma Ela could serve as a reliable marker for predicting PE based on the time of onset (EoPE vs LoPE) compared to age and body mass matched healthy controls since no definitive treatment exists for PE but to terminate a pregnancy. METHODS: This case-control study recruited (n = 90) pregnant who fulfilled inclusion criteria; they were allocated into three groups: EoPE (30/90) (< 34 wk of gestation); LoPE (30/90) (≥ 34 wk of gestation); and healthy pregnant (30/90). Demographic criteria; biochemical, hematological, and maternal plasma Ela levels were recorded for comparison. RESULTS: Serum Ela was significantly reduced in EoPE compared to LoPE and healthy controls (P = 0.0023). The correlation confirmed a strong inverse relationship with mean atrial blood pressure (r = -0.7, P < 0.001), while gestational age and platelets count showed a moderate correlation with (r = 0.4 with P < 0.0001). No correlation was confirmed between the body mass index (BMI) and urine albumin. The predictive ability of 25 centile serum Ela had an Odds ratio of 5.21, 95% confidence interval (1.28, 21.24), P = 0.02 for predicting EoPE. The receiver operator characteristic curve defined the Ela cutoff value at > 9.156 with 96.7% and 93.3% sensitivity and specificity, P < 0.0001 in predicting EoPE. CONCLUSION: A strong correlation of serum Ela with PE parameters with excellent sensitivity and specificity in distinguishing EoPE independent of the BMI, age, and blood pressure which makes Ela a recommendable marker in screening. Further research is warranted to explore prognostic and therapeutic applications for Ela in PE.

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus.

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

A case report of surgical repair of cleft sternum in a child.

BACKGROUND: Sternal cleft is a rare congenital chest wall defect, occurring in only 1 in 100,000 live births, and very few cases have been described in the literature. Surgery is indicated to protect the heart and major vessels. This study provides a clinical case presentation and literature review of sternal cleft. METHODS: This is a review of a case presenting with chest wall defects. The patient underwent a primary cleft closure at Children's Hospital No. 2. All perioperative data were collected and presented. CASE PRESENTATION: A healthy 3-year-old girl was admitted to Children's Hospital No. 2 with an abnormal chest shape, observed by her mother. An inverted "U"-shaped defect of the sternum was visible, and the extent of the defect could be observed by chest X-ray and spiral computed tomography (CT) imaging of the chest. After the diagnosis was confirmed, the patient was prepared for primary closure surgery. We achieved primary closure, the patient discontinued oxygen 5 days after surgery, and the patient was discharged 14 days after surgery. CONCLUSION: Chest wall malformations can present with various phenotypes, although congenital sternal cleft is a rare anomaly. This defect is often asymptomatic. Depending on the size of the defect, a sternal cleft may be treated or monitored. The optimal treatment during early life is surgical repair to achieve primary closure.

Aviremic organ transplant dengue virus transmission - A case report.

Dengue virus (DENV), a mosquito-borne pathogen, causes systemic infections. There are no clear guidelines regarding the screening of donor blood is used in endemic countries to prevent blood transfusion or transplant-associated dengue. DENV has been shown to be detected in urine samples even when DENV viremia is undetectable. We describe an incident of transplant-associated dengue where the donor tested negative for DENV viremia but positive for DENV viuria resulting in the transmission of DENV to our two kidney recipients. Both recipients resolved DENV infection uneventfully, with no adverse impact on the renal graft. Our findings raise the consideration for revised screening recommendations in endemic countries to include DENV RT-PCR in the urine.

A comparative clinical trial of vaginal misoprostol versus intracervical normal saline infiltration as a cervical ripening agent at time of hysteroscopy.

Cervical status has a great impact on the duration and success of its dilatation especially during hysteroscopy, so cervical ripening employed before the procedure can increase the success rate and minimize the complications. AIM: To compare the efficacy of vaginal misoprostol and intracervical normal saline infiltration as cervical ripening agents. METHODS: A randomized comparative clinical trial had been conducted in AL Yarmouk Teaching Hospital involving two methods for cervical ripening before the hysteroscopic procedure. One Hundred women were enrolled in the study, fifty of them were those who used preoperative vaginal misoprostol and the other fifty patients were those who had been submitted to intracervical normal saline infiltration during surgery. Basal cervical dilatation, time to achieve 8 mm cervical dilatation, difficulties, and complications encountered during the procedure were evaluated and compared for both groups. RESULTS: The participants had been admitted for hysteroscopy for the following indications: Abnormal uterine bleeding, missed loop, infertility, polypectomy, endometrial resection, and myomectomy. Regarding operative findings, the basal cervical dilatation was not significantly different between them, the time required to achieve the required dilatation was significantly shorter for the normal saline infiltration group, 66.95 sec. ± 10.85 than for the misoprostol group which was 87.9 sec. ± 13.11. There was more difficulty in dilatation with more complications in the misoprostol group than in the normal saline infiltration group. CONCLUSIONS: Normal saline infiltration is a simple, readily available at the time of surgery and with fewer complications and shorter time of dilatation in comparison to vaginal misoprostol for a comparable efficacy.

Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation.

Cis-prenyltransferase (cis-PTase) catalyzes the rate-limiting step in the synthesis of glycosyl carrier lipids required for protein glycosylation in the lumen of endoplasmic reticulum. Here, we report the crystal structure of the human NgBR/DHDDS complex, which represents an atomic resolution structure for any heterodimeric cis-PTase. The crystal structure sheds light on how NgBR stabilizes DHDDS through dimerization, participates in the enzyme's active site through its C-terminal -RXG- motif, and how phospholipids markedly stimulate cis-PTase activity. Comparison of NgBR/DHDDS with homodimeric cis-PTase structures leads to a model where the elongating isoprene chain extends beyond the enzyme's active site tunnel, and an insert within the α3 helix helps to stabilize this energetically unfavorable state to enable long-chain synthesis to occur. These data provide unique insights into how heterodimeric cis-PTases have evolved from their ancestral, homodimeric forms to fulfill their function in long-chain polyprenol synthesis.

Containing COVID-19 in the Emergency Department: The Role of Improved Case Detection and Segregation of Suspect Cases.

OBJECTIVES: Patients with COVID-19 may present with respiratory syndromes indistinguishable from common viruses. This poses a challenge for early detection during triage in the emergency department (ED). Over a 3-month period, our ED aimed to minimize nosocomial transmission by using broader suspect case criteria for better detection and using appropriate personal protective equipment (PPE) for health care workers (HCWs). METHODS: All ED admissions with respiratory syndromes over a 3-month period were tested for COVID-19. The sensitivity and specificity of screening criteria in detecting COVID-19 were assessed. A risk-stratified approach was adopted for PPE usage in the ED, based on high-risk "fever areas" and lower-risk zones. When a case of COVID-19 was confirmed, surveillance was conducted for potentially exposed patients and HCWs. RESULTS: A total of 1,841 cases presenting with respiratory syndromes required admission over the study period. Among these, 70 cases of COVID-19 were subsequently confirmed. The majority (84.2%, 59/70) were detected at ED triage because they fulfilled suspect case criteria. Of these, 34 met the official screening criteria; an additional 25 were detected by the broader internal screening criteria. Over the 12-week period, the cumulative sensitivity of internal screening criteria was 84.3% (95% confidence interval [CI] = 73.6% to 91.9%), whereas the sensitivity of the official screening criteria was 48.6% (95% CI = 36.4% to 60.8%). Given the broadened internal criteria, the preexisting ED "fever area" was insufficient and had to be expanded. However, there were no cases of nosocomial transmission from intra-ED exposure, despite extensive surveillance. CONCLUSION: Frontline physicians need to be given leeway to decide on the disposition of cases based on clinical suspicion during an ongoing outbreak of COVID-19. If a broader criterion is used at ED triage, ED facilities and isolation facilities need to be readied to accommodate a surge of suspect cases. Usage of appropriate PPE is essential in minimizing nosocomial transmission.

A conserved C-terminal RXG motif in the NgBR subunit of cis-prenyltransferase is critical for prenyltransferase activity.

cis-Prenyltransferases (cis-PTs) constitute a large family of enzymes conserved during evolution and present in all domains of life. In eukaryotes and archaea, cis-PT is the first enzyme committed to the synthesis of dolichyl phosphate, an obligate lipid carrier in protein glycosylation reactions. The homodimeric bacterial enzyme, undecaprenyl diphosphate synthase, generates 11 isoprene units and has been structurally and mechanistically characterized in great detail. Recently, we discovered that unlike undecaprenyl diphosphate synthase, mammalian cis-PT is a heteromer consisting of NgBR (Nus1) and hCIT (dehydrodolichol diphosphate synthase) subunits, and this composition has been confirmed in plants and fungal cis-PTs. Here, we establish the first purification system for heteromeric cis-PT and show that both NgBR and hCIT subunits function in catalysis and substrate binding. Finally, we identified a critical RXG sequence in the C-terminal tail of NgBR that is conserved and essential for enzyme activity across phyla. In summary, our findings show that eukaryotic cis-PT is composed of the NgBR and hCIT subunits. The strong conservation of the RXG motif among NgBR orthologs indicates that this subunit is critical for the synthesis of polyprenol diphosphates and cellular function.

The Missing Electrostatic Interactions Between DNA Substrate and Sulfolobus solfataricus DNA Photolyase: What is the Role of Charged Amino Acids in Thermophilic DNA Binding Proteins?

DNA photolyase can be used to study how a protein with its required cofactor has adapted over a large temperature range. The enzymatic activity and thermodynamics of substrate binding for protein from Sulfolobus solfataricus were directly compared to protein from Escherichia coli. Turnover numbers and catalytic activity were virtually identical, but organic cosolvents may be necessary to maintain activity of the thermophilic protein at higher temperatures. UV-damaged DNA binding to the thermophilic protein is less favorable by ∼2 kJ/mol. The enthalpy of binding is ∼10 kJ/mol less exothermic for the thermophile, but the amount and type of surface area buried upon DNA binding appears to be somewhat similar. The most important finding was observed when ionic strength studies were used to separate binding interactions into electrostatic and nonelectrostatic contributions; DNA binding to the thermophilic protein appears to lack the electrostatic contributions observed with the mesophilic protein.

Heterodyne frequency-domain multispectral diffuse optical tomography of breast cancer in the parallel-plane transmission geometry.

PURPOSE: The authors introduce a state-of-the-art all-optical clinical diffuse optical tomography (DOT) imaging instrument which collects spatially dense, multispectral, frequency-domain breast data in the parallel-plate geometry. METHODS: The instrument utilizes a CCD-based heterodyne detection scheme that permits massively parallel detection of diffuse photon density wave amplitude and phase for a large number of source-detector pairs (10(6)). The stand-alone clinical DOT instrument thus offers high spatial resolution with reduced crosstalk between absorption and scattering. Other novel features include a fringe profilometry system for breast boundary segmentation, real-time data normalization, and a patient bed design which permits both axial and sagittal breast measurements. RESULTS: The authors validated the instrument using tissue simulating phantoms with two different chromophore-containing targets and one scattering target. The authors also demonstrated the instrument in a case study breast cancer patient; the reconstructed 3D image of endogenous chromophores and scattering gave tumor localization in agreement with MRI. CONCLUSIONS: Imaging with a novel parallel-plate DOT breast imager that employs highly parallel, high-resolution CCD detection in the frequency-domain was demonstrated.

Fiber-based modulated optical reflectance configuration allowing for offset pump and probe beams.

A new fiber-based modulated optical reflectance configuration is developed in this work. The technique maintains the fiber-based heating laser (pump) and detection laser (probe) in close proximity at a fixed separation distance in a ceramic ferrule. The pump beam periodically heats the sample inducing thermal waves into the sample. The probe beam measures the temperature response at a known distance from the pump beam over a range of heating modulation frequencies. The thermal diffusivity of the sample may be calculated from the phase response between the input heat flux and the temperature response of a sample having a reflective surface. The unique measurement configuration is ideal for in situ measurements and has many advantages for laboratory-based systems. The design and development of the system are reported along with theoretical justification for the experimental design. The thermal diffusivities of Ge and SiC are measured and found to be within 10% of reported literature values. The diffusivity for SiO2 is measured with a relative difference of approximately 100% from the literature value when the ferrule is in contact with the sample. An additional measurement was made on the SiO2 sample with the ferrule not in contact resulting in a difference of less than 2% from the literature value. The difference in the SiO2 measurement when the ferrule is in contact with the sample is likely due to a parallel heat transfer path through the dual-fiber ferrule assembly.

Neuroradiologic features in X-linked α-thalassemia/mental retardation syndrome.

BACKGROUND AND PURPOSE: X-linked α-thalassemia/mental retardation syndrome (Mendelian Inheritance in Man, 301040) is one of the X-linked intellectual disability syndromes caused by mutations of the ATRX gene and characterized by male predominance, central hypotonic facies, severe cognitive dysfunction, hemoglobin H disease (α-thalassemia), genital and skeletal abnormalities, and autistic and peculiar behavior. More than 200 patients in the world, including >70 Japanese patients, have been diagnosed with ATR-X syndrome. MATERIALS AND METHODS: We reviewed the brain MRI and/or CT findings of 27 Japanese patients with ATR-X with ATRX mutations retrospectively. RESULTS: The findings were categorized into 5 types: 1) nonspecific brain atrophy (17/27); 2) white matter abnormalities, especially around the trigones (11/27); 3) widespread and scattered white matter abnormalities (1/27); 4) delayed myelination (4/27); and 5) severe and rapidly progressive cortical brain atrophy (1/27). CONCLUSIONS: This is the first report on a comprehensive study of brain MRI/CT findings of ATR-X syndrome. Our findings suggest that the ATRX protein seems to be involved in normal myelination. The classification will require revisions in the near future, but it will be helpful in establishing the relationship between ATRX mutation and brain development and understanding the ATRX protein function in the brain.

Epithelial expression of interleukin-37b in inflammatory bowel disease.

Interleukin (IL)-37 is a member of the IL-1 cytokine family. We investigated IL-37b expression in the inflamed mucosa of inflammatory bowel disease (IBD) patients. Furthermore, we analysed IL-37b expression in human colonic epithelial cells. The human colonic epithelial cell line T84 and human colonic subepithelial myofibroblasts (SEMFs) were used. IL-37b expression in the IBD mucosa was evaluated by immunohistochemistry. IL-37b mRNA and protein expression were determined by real time-polymerase chain reaction (PCR) and Western blotting, respectively. IL-37b was not detected in the normal colonic mucosa. In the inflamed mucosa of IBD patients, epithelial IL-37b expression was increased markedly. In ulcerative colitis (UC) and Crohn's disease (CD) patients, IL-37b expression was enhanced in the affected mucosa. In the intestinal epithelial cell line T84, the expression of IL-37b mRNA and protein was enhanced by tumour necrosis factor (TNF)-α. This IL-37b induction by TNF-α was mediated by nuclear factor (NF)-κB and activator protein (AP)-1 activation. Furthermore, IL-37b inhibited TNF-α-induced interferon-γ-inducible protein (IP)-10 expression significantly in human colonic SEMFs. Epithelial IL-37b expression was increased in IBD patients, especially UC patients. IL-37b may be involved in the pathophysiology of IBD as an anti-inflammatory cytokine and an inhibitor of both innate and acquired immune responses.

Regulation of eotaxin-3/CC chemokine ligand 26 expression by T helper type 2 cytokines in human colonic myofibroblasts.

Eotaxins induce the trafficking of eosinophils to the sites of inflammation via CC chemokine receptor 3 (CCR3). In this study, we investigated eotaxin-3/CC chemokine ligand 26 (CCL26) expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for eotaxin-3 expression in human colonic myofibroblasts. Eotaxin-3 mRNA and protein expression was evaluated by real time-polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Eotaxin-3 mRNA expression was elevated significantly in the active lesions of ulcerative colitis (UC) patients. Significant elevations were also observed in the active lesions of Crohn's disease (CD) patients, but this was significantly lower than that detected in the active UC lesions. There were no significant increases in the inactive lesions of UC or CD patients. Colonic myofibroblasts were identified as a major source of eotaxin-3 in the colonic mucosa, and interleukin (IL)-4 and IL-13 enhanced eotaxin-3 mRNA and protein expression significantly in these cells. There was a significant positive correlation between mucosal eotaxin-3 and IL-4 mRNA expression in the active lesions of IBD patients. The IL-4- and IL-13-induced eotaxin-3 mRNA expression was regulated by the signal transducer and activator of transcription-6 (STAT-6) and suppressor of cytokine signalling (SOCS)1-mediated pathways. Interferon (IFN)-γ acts as a negative regulator on the IL-4- and IL-13-induced eotaxin-3 expression via STAT-1 activation. Eotaxin-3 expression was elevated specifically in the active lesions of IBD, in particular UC. Eotaxin-3 derived from colonic myofibroblasts may play an important role in the pathophysiology of UC.

Biological evaluation of dopamine analogues containing phenylboronic acid group as new boron carriers.

As new BNCT reagents, we designed and synthesized dopamine analogues containing phenylboronic acid group, N-3,4-dihydroxyphenethyl-4-dihydroxyborylbenzamide (dopamine-PCBA) and N-[2-(3,4-dihydroxyphenetyl)ethyl]-3-(4-dihydroxyborylphenyl)promionamide (dopamine-CEBA). The efficacies of these compounds have not been investigated for biological samples. Therefore we have carried out experiments with cultured tumor cells and tumor-bearing mice, and evaluated possibility of these compounds as boron carriers. Dopamine-PCBA and dopamine-CEBA were synthesized by coupling between p-carboxyphenylboronic acid (PCBA) or 4-(2-carboxyethyl)benzeneboronic acid (CEBA) and 3,4-(dibenzyloxy)phenethylamine hydrochloride (DBPA-HCl) followed by catalytic hydrogenation using Pd catalyst. The effect of compounds on cell vitality was determined by MTT assay in various cells. In vivo biodistribution of compounds was determined in Balb/c and DDY mice in bearing implanted CT26 cells. These results have demonstrated that dopamine-CEBA was less toxic.

Leptin levels in relation to marital status and neuroendocrine function in Iraqi females with polycystic ovary syndrome.

The present study was designed to evaluate the relationship between serum leptin levels and the hormones related to fertility in Iraqi females with polycystic ovary syndrome (PCOS) and marital status. This study was conducted during the period from July to December 2007. Twenty-four women (12 married and 12 unmarried) with PCOS and not maintained on any type of therapy were included in the study. Twelve healthy and normal ovulatory women with an age range matched with that of PCOS women were included. After an overnight fasting, blood samples were drawn from all women at random days. While in those with regular menstrual cycles, blood samples were obtained during the follicular phase of the cycle, except for samples utilized for the assay of progesterone that performed in the day 21 of the cycle (luteal phase). After preparation of serum, the levels of leptin, luteinizing hormone (LH), follicle-stimulation hormone (FSH), progesterone, testosterone and prolactin were analyzed. Both groups of PCOS patients showed significantly lower levels of serum leptin, while prolactin, LH and FSH and testosterone were significantly elevated compared to controls. No significant differences were reported among PCOS patients with different marital status. In conclusion, impaired plasma leptin levels in PCOS women were associated with impaired endocrinological parameters related to fertility.

Development of boron nanocapsules for neutron capture therapy.

High accumulation and selective delivery of boron into tumor tissues are the most important requirements to achieve efficient neutron capture therapy of cancers. We focused on liposomal boron delivery system in order to achieve a large amount of boron delivery to tumor. We synthesized the double-tailed boron cluster lipid 4c according to our reported procedure with modification. Size distribution of liposomes prepared from the boron cluster lipid 4c, DMPC, PEG-DSPE, and cholesterol was determined as 100 nm in diameter by an electrophoretic light scattering spectrophotometer. A high level of (10)B concentration (22 ppm) was observed in tumor tissue at 24 h after the administration of boron liposomes.