Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Mechanical resilience and cementitious processes in Imperial Roman architectural mortar.

The pyroclastic aggregate concrete of Trajan's Markets (110 CE), now Museo Fori Imperiali in Rome, has absorbed energy from seismic ground shaking and long-term foundation settlement for nearly two millenia while remaining largely intact at the structural scale. The scientific basis of this exceptional service record is explored through computed tomography of fracture surfaces and synchroton X-ray microdiffraction analyses of a reproduction of the standardized hydrated lime-volcanic ash mortar that binds decimeter-sized tuff and brick aggregate in the conglomeratic concrete. The mortar reproduction gains fracture toughness over 180 d through progressive coalescence of calcium-aluminum-silicate-hydrate (C-A-S-H) cementing binder with Ca/(Si+Al) ≈ 0.8-0.9 and crystallization of strätlingite and siliceous hydrogarnet (katoite) at ≥ 90 d, after pozzolanic consumption of hydrated lime was complete. Platey strätlingite crystals toughen interfacial zones along scoria perimeters and impede macroscale propagation of crack segments. In the 1,900-y-old mortar, C-A-S-H has low Ca/(Si+Al) ≈ 0.45-0.75. Dense clusters of 2- to 30-µm strätlingite plates further reinforce interfacial zones, the weakest link of modern cement-based concrete, and the cementitious matrix. These crystals formed during long-term autogeneous reaction of dissolved calcite from lime and the alkali-rich scoriae groundmass, clay mineral (halloysite), and zeolite (phillipsite and chabazite) surface textures from the Pozzolane Rosse pyroclastic flow, erupted from the nearby Alban Hills volcano. The clast-supported conglomeratic fabric of the concrete presents further resistance to fracture propagation at the structural scale.

Authigenic mineralization in Surtsey basaltic tuff deposits at 50 years after eruption.

Alteration of basaltic glass and in situ mineral growth are fundamental processes that influence the chemical and material properties of Earth's oceanic crust. These processes have evolved at the basaltic island of Surtsey (SW Iceland) since eruptions terminated in 1967. Here, subaerial and submarine lapilli tuff samples from a 192 m-deep borehole drilled in 2017 (SE-02b) are characterized through petrographic studies, X-ray powder diffraction analyses, and SEM-EDS imaging and chemical analyses. The integrated results reveal (i) multi-stage palagonitization processes in basaltic glass and precipitation of secondary minerals from matrix pore fluids, (ii) multi-stage crystallization of secondary phillipsite, analcime and Al-tobermorite in the vesicles of basaltic pyroclasts and (iii) variations in palagonitization processes as a function of thermal and hydrological domains. Although temperature appears to be an important factor in controlling rates of secondary mineralization, the chemistry of original basaltic components and interstitial fluids also influences reaction pathways in the young pyroclastic deposits. The integration of systematic mineralogical analyses of the 50-year-old tuff from one of the most carefully monitored volcanic sites on Earth, together with temperature monitoring in boreholes since 1980, provide a reference framework for evaluating mineralogical evolution in other Surtseyan-type volcanoes worldwide.

Novel clinical manifestations in Pallister-Killian syndrome: comprehensive evaluation of 59 affected individuals and review of previously reported cases.

Pallister-Killian syndrome is a rare, multi-system developmental diagnosis typically caused by tetrasomy of chromosome 12p that exhibits tissue-limited mosaicism. The spectrum of clinical manifestations in Pallister-Killian syndrome is wide and includes craniofacial anomalies, clefts, ophthalmologic, audiologic, cardiac, musculoskeletal, diaphragmatic, gastrointestinal, genitourinary, and cutaneous anomalies in association with intellectual disability and seizures. Growth parameters are often normal to elevated at birth with deceleration of growth postnatally. No formal estimate of the prevalence of Pallister-Killian syndrome has been made. Here, we report the clinical findings in 59 individuals with Pallister-Killian syndrome who were ascertained at Pallister-Killian syndrome Foundation family meetings held in the summers of 2006, 2008, 2009, and 2010. In addition, the clinical findings of 152 cases reported in the medical literature were reviewed and compared to the cohort examined here. Several novel clinical characteristics were identified through detailed dysmorphology examinations of this cohort and reassertion of a mild developmental variant is described. This report expands the clinical manifestations of Pallister-Killian syndrome and highlights the variable expressivity of this diagnosis with important implications for diagnosis and counseling.

Basalt-Hosted Microbial Communities in the Subsurface of the Young Volcanic Island of Surtsey, Iceland.

The island of Surtsey was formed in 1963-1967 on the offshore Icelandic volcanic rift zone. It offers a unique opportunity to study the subsurface biosphere in newly formed oceanic crust and an associated hydrothermal-seawater system, whose maximum temperature is currently above 120°C at about 100m below surface. Here, we present new insights into the diversity, distribution, and abundance of microorganisms in the subsurface of the island, 50years after its creation. Samples, including basaltic tuff drill cores and associated fluids acquired at successive depths as well as surface fumes from fumaroles, were collected during expedition 5059 of the International Continental Scientific Drilling Program specifically designed to collect microbiological samples. Results of this microbial survey are investigated with 16S rRNA gene amplicon sequencing and scanning electron microscopy. To distinguish endemic microbial taxa of subsurface rocks from potential contaminants present in the drilling fluid, we use both methodological and computational strategies. Our 16S rRNA gene analysis results expose diverse and distinct microbial communities in the drill cores and the borehole fluid samples, which harbor thermophiles in high abundance. Whereas some taxonomic lineages detected across these habitats remain uncharacterized (e.g., Acetothermiia, Ammonifexales), our results highlight potential residents of the subsurface that could be identified at lower taxonomic rank such as Thermaerobacter, BRH-c8a (Desulfallas-Sporotomaculum), Thioalkalimicrobium, and Sulfurospirillum. Microscopy images reveal possible biotic structures attached to the basaltic substrate. Finally, microbial colonization of the newly formed basaltic crust and the metabolic potential are discussed on the basis of the data.

Good Financial Practice and Clinical Research Coordinator Responsibilities.

OBJECTIVES: To describe clinical research billing pitfalls and good financial practices the research nurse coordinator can implement to decrease billing errors in clinical practice. DATA SOURCES: Government websites, published articles, and the author's expertise in national/international research studies. CONCLUSION: Clinical research billing is a risky business. It involves many steps in the process and requires good communication among all key stakeholders. The clinical research coordinator is the key team player to facilitate good financial practices for research billing. Creating and applying standards, cross-functional transparent communication, and effective processes across the organization can help to increase billing compliance and decreases billing risk to the organization. IMPLICATIONS FOR NURSING PRACTICE: The research billing process is a critical component of clinical research. However, billing in the process of generating evidence to inform clinical practice is not included in the core competencies in nursing curriculum. As such, in the real world many nurses grapple with taking on the new role of being a clinical research coordinator. Developing knowledge and understanding about the potential billing pitfalls and good financial practices can support clinical research nurses to decrease billing errors and exposure to risk.

Discovery of a new biomarker for the mucopolysaccharidoses (MPS), dipeptidyl peptidase IV (DPP-IV; CD26), by SELDI-TOF mass spectrometry.

Surface enhanced laser desorption/ionisation time of flight (SELDI-TOF) mass spectrometry has been used to search for new protein biomarkers in the plasma of patients with mucopolysacharidoses (MPS). Differences in the levels of some plasma proteins, particularly the apolipoprotein ApoCI, were observed between MPS patients and normal controls, using the different chromatographic surfaces (ProteinChips). ApoCI was identified by both its mass and by immunological techniques. In plasma, it exists in two forms, ApoCI and a truncated form which lacks two N-terminal amino acids, ApoCI'. In controls, the ratio of ApoCI':ApoCI observed using the cation-exchange surface (CM10) was approximately 1:2 whereas in most MPS patients it varied from 1:1 to 1:0.8. The ratio of ApoCI':ApoCI in plasma is determined by the activity of dipeptidyl peptidase IV, DPP-IV (also known as the leucocyte antigen CD26), which was found to be elevated up to 3-fold in MPS patients. The DPP-IV activity decreased in MPS I patients undergoing enzyme replacement therapy, indicating that it could be a useful biomarker for monitoring the efficacy of treatment in MPS disease. As DPP-IV has an important regulatory role in metabolism, it is possible that its elevation could cause some of the secondary pathology in MPS, and inhibition of DPP-IV might have a role in MPS therapy.

Consumer satisfaction with National Alliance on Mental Illness written medicine information.

INTRODUCTION: Written medicine information (WMI) is a collection of facts for a specific medication, and it helps facilitate patient understanding of medication therapy. The primary objective of this study was to assess consumer satisfaction with National Alliance on Mental Illness (NAMI) WMI. A secondary objective was to assess health care professional satisfaction. METHODS: National Alliance on Mental Illness WMI and surveys were offered to consumers, health care professionals, and trainees at 3 treatment centers with psychiatric services. All adults who received medication counseling were eligible for inclusion. Survey responses were evaluated using descriptive statistics. RESULTS: Most consumers (82.4%) and providers (74.5%) reported overall satisfaction with NAMI WMI. Consumers were least satisfied with information on how to manage unwanted effects, drug-drug interactions, and readability (9.5%, 14.9%, 41.9% dissatisfaction). DISCUSSION: Evaluation and feedback from consumers and health care professionals may influence decisions to refine NAMI WMI to meet consumer needs.

The first family with Tay-Sachs disease in Cyprus: Genetic analysis reveals a nonsense (c.78G>A) and a silent (c.1305C>T) mutation and allows preimplantation genetic diagnosis.

Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder caused by mutations in the HEXA gene resulting in ß-hexosaminidase A (HEX A) deficiency and neuronal accumulation of GM2 ganglioside. We describe the first patient with Tay-Sachs disease in the Cypriot population, a juvenile case which presented with developmental regression at the age of five. The diagnosis was confirmed by measurement of HEXA activity in plasma, peripheral leucocytes and fibroblasts. Sequencing the HEXA gene resulted in the identification of two previously described mutations: the nonsense mutation c.78G>A (p.Trp26X) and the silent mutation c.1305C>T (p.=). The silent mutation was reported once before in a juvenile TSD patient of West Indian origin with an unusually mild phenotype. The presence of this mutation in another juvenile TSD patient provides further evidence that it is a disease-causing mutation. Successful preimplantation genetic diagnosis (PGD) and prenatal follow-up were provided to the couple.

Burden of lysosomal storage disorders in India: experience of 387 affected children from a single diagnostic facility.

Lysosomal storage disorders (LSDs) are considered to be a rare metabolic disease for the national health forum, clinicians, and scientists. This study aimed to know the prevalence of different LSDs, their geographical variation, and burden on the society. It included 1,110 children from January 2002 to December 2012, having coarse facial features, hepatomegaly or hepatosplenomegaly, skeletal dysplasia, neuroregression, leukodystrophy, developmental delay, cerebral-cerebellar atrophy, and abnormal ophthalmic findings. All subjects were screened for I-cell disease, glycolipid storage disorders (Niemann-Pick disease A/B, Gaucher), and mucopolysaccharide disorders followed by confirmatory lysosomal enzymes study from leucocytes and/or fibroblasts. Niemann-Pick disease-C (NPC) was confirmed by fibroblasts study using filipin stain. Various storage disorders were detected in 387 children (34.8 %) with highest prevalence of glycolipid storage disorders in 48 %, followed by mucopolysaccharide disorders in 22 % and defective sulfatide degradation in 14 % of the children. Less common defects were glycogen degradation defect and protein degradation defect in 5 % each, lysosomal trafficking protein defect in 4 %, and transport defect in 3 % of the patients. This study demonstrates higher incidence of Gaucher disease (16 %) followed by GM2 gangliosidosis that includes Tay-Sachs disease (10 %) and Sandhoff disease (7.8 %) and mucopolysaccharide disorders among all LSDs. Nearly 30 % of the affected children were born to consanguineous parents and this was higher (72 %) in children with Batten disease. Our study also demonstrates two common mutations c.1277_1278insTATC in 14.28 % (4/28) and c.964G>T (p.D322Y) in 10.7 % (3/28) for Tay-Sachs disease in addition to the earlier reported c.1385A>T (p.E462V) mutation in 21.42 % (6/28).

Diagnosis of congenital disorders of glycosylation type-I using protein chip technology.

A method for the diagnosis of the congenital disorders of glycosylation type I (CDG-I) by SELDI-TOF-MS of serum transferrin immunocaptured on protein chip arrays is described. The underglycosylation of glycoproteins in CDG-I produces glycoforms of transferrin with masses lower than that of the normal fully glycosylated transferrin. Immobilisation of antitransferrin antibodies on reactive-surface protein chip arrays (RS100) selectively enriched transferrin by at least 100-fold and allowed the detection of patterns of transferrin glycoforms by SELDI-TOF-MS using approximately 0.3 microL of serum/plasma. Abnormal patterns of immunocaptured transferrin were detected in patients with known defects in glycosylation (CDG-Ia, CDG-Ib, CDG-Ic, CDG-If and CDG-Ih) and in patients in whom the basic defect has not yet been identified (CDG-Ix). The correction of the N-glycosylation defect in a patient with CDG-Ib after mannose therapy was readily detected. A patient who had an abnormal transferrin profile by IEF but a normal profile by SELDI-TOF-MS analysis was shown to have an amino acid polymorphism by sequencing transferrin by quadrupole-TOF MS. Complete agreement was obtained between analysis of immunocaptured transferrin by SELDI-TOF-MS and the IEF profile of transferrin, the clinical severity of the disease and the levels of aspartylglucosaminidase activity (a surrogate marker for the diagnosis of CDG-I). SELDI-TOF-MS of transferrin immunocaptured on protein chip arrays is a highly sensitive diagnostic method for CDG-I, which could be fully automated using microtitre plates and robotics.

Prenatal diagnosis of cystinosis by quantitative measurement of cystine in chorionic villi and cultured cells.

OBJECTIVE: Prenatal diagnosis of cystinosis has been available for over 30 years by the incubation of cultured amniotic cells, intact chorionic villi and cultured chorionic cells with [35S]-cystine followed by thin layer chromatography and visual inspection of autoradiographs of the chromatograms for cystine. This method has proved highly reliable but because of the short half-life of [35S]-cystine, its cost and the length of the assay procedure, an alternative method of diagnosis was investigated. METHOD: Cystine was quantitatively measured in chorionic villi directly, in cultured chorionic villi and cultured amniotic cells using a cystine-binding protein from Escherichia coli. RESULTS: Twelve pregnancies at risk for cystinosis were monitored by both the [35S]-cystine uptake method and the new quantitative method in uncultured chorionic villi. There was no discrepancy between the results obtained with the two methods and subsequently 15 pregnancies have been monitored by the quantitative assay only--13 in chorionic villi directly, 1 in cultured chorionic villi cells and 1 in cultured amniotic cells. Grossly elevated levels of cystine were found in seven pregnancies. CONCLUSION: An unequivocal diagnosis of cystinosis can be made within 24 h of sampling by the quantitative measurement of cystine in uncultured chorionic villi.

Research staff turnover and participant adherence in the Women's Health Initiative.

Maintaining participant adherence is a prerequisite for successful completion of randomized controlled trials requiring long-term follow-up. While patient characteristics influencing adherence are well studied, the influence of contact with clinical staff on this process has received almost no attention. To address this issue the authors evaluated the association of turnover in key clinical research staff with measures of participant adherence to protocol requirements at 40 clinical centers participating in the Women's Health Initiative (WHI), a large multicenter study. Key staff turnover in positions with potential influence on maintaining participant adherence in the Dietary Modification Clinical Trial (DM-CT) and the two Menopausal Hormone Therapy Clinical Trials (HT-CT) of the WHI was determined at each clinical center. Three prospectively established measures of participant adherence for the DM-CT and HT-CT were related to key staff turnover at each clinical center by staff category. More frequent turnover of the clinic practitioner, clinic manager, and principal investigator positions was significantly (p<0.05) associated with lower participant adherence in the HT-CT but was not associated with DM-CT participant adherence. More frequent turnover of the lead nutritionist was not associated with HT-CT participant adherence but was significantly (p<0.05) associated with one measure of decreased DM-CT participant adherence, as would be expected since the lead nutritionist did not typically see the HT-CT participants. These significant and plausible associations suggest that providing consistent contact with key staff in randomized, controlled clinical trials may facilitate long-term participant adherence. Further prospective study exploring process evaluation of the provider side of controlled trial conduct is indicated.