Liddle's syndrome caused by a novel missense mutation (P617L) of the epithelial sodium channel beta subunit.

OBJECTIVE: The aim of the study was to search for mutations of SCNN1B and SCNN1G in an Italian family with apparently dominant autosomal transmission of a clinical phenotype consistent with Liddle's syndrome. METHODS: Genetic analysis was performed in the proband, his relatives, and 100 control subjects. To determine the functional role of the mutation identified in the proband, we expressed the mutant or wild-type epithelial sodium channel in Xenopus laevis oocytes. RESULTS: A novel point mutation, causing an expected substitution of a leucine residue for the second proline residue of the conserved PY motif (PPP x Y) of the beta subunit was identified in the proband. The functional expression of the mutant epithelial sodium channel in X. laevis oocytes showed a three-fold increase in the amiloride-sensitive current as compared with that of the wild-type channel. CONCLUSION: This newly identified mutation adds to other missense mutations of the PY motif of the beta subunit of the epithelial sodium channel, thus confirming its crucial role in the regulation of the epithelial sodium channel. To our knowledge, this is the first report of Liddle's syndrome in the Italian population, confirmed by genetic and functional analysis, with the identification of a gain-of-function mutation not previously reported.

Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome.

BACKGROUND AND OBJECTIVES:  Matrix γ-carboxyglutamate protein (MGP), a vitamin K-dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an opportunity to investigate the functions of MGP. The purpose of this study was (i) to investigate the phenotype and the underlying MGP mutation of a newly identified KS patient, and (ii) to investigate MGP species and the effect of vitamin K supplements in KS patients. METHODS:  The phenotype of a newly identified KS patient was characterized with specific attention to signs of vascular calcification. Genetic analysis of the MGP gene was performed. Circulating MGP species were quantified and the effect of vitamin K supplements on MGP carboxylation was studied. Finally, we performed immunohistochemical staining of tissues of the first KS patient originally described focusing on MGP species. RESULTS:  We describe a novel homozygous MGP mutation (c.61+1G>A) in a newly identified KS patient. No signs of arterial calcification were found, in contrast to findings in MGP knockout mice. This patient is the first in whom circulating MGP species have been characterized, showing a high level of phosphorylated MGP and a low level of carboxylated MGP. Contrary to expectations, vitamin K supplements did not improve the circulating carboxylated mgp levels. phosphorylated mgp was also found to be present in the first ks patient originally described. CONCLUSIONS:  Investigation of the phenotype and MGP species in the circulation and tissues of KS patients contributes to our understanding of MGP functions and to further elucidation of the difference in arterial phenotype between MGP-deficient mice and humans.

A very rare cancer in Down syndrome: medulloblastoma. Epidemiological data from 13 countries.

Persons with Down syndrome (DS) uniquely have an increased frequency of leukemias but a decreased total frequency of solid tumors. The distribution and frequency of specific types of brain tumors have never been studied in DS. We evaluated the frequency of primary neural cell embryonal tumors and gliomas in a large international data set. The observed number of children with DS having a medulloblastoma, central nervous system primitive neuroectodermal tumor (CNS-PNET) or glial tumor was compared to the expected number. Data were collected from cancer registries or brain tumor registries in 13 countries of Europe, America, Asia and Oceania. The number of DS children with each category of tumor was treated as a Poisson variable with mean equal to 0.000884 times the total number of registrations in that category. Among 8,043 neural cell embryonal tumors (6,882 medulloblastomas and 1,161 CNS-PNETs), only one patient with medulloblastoma had DS, while 7.11 children in total and 6.08 with medulloblastoma were expected to have DS. (p 0.016 and 0.0066 respectively). Among 13,797 children with glioma, 10 had DS, whereas 12.2 were expected. Children with DS appear to be specifically protected against primary neural cell embryonal tumors of the CNS, whereas gliomas occur at the same frequency as in the general population. A similar protection against neuroblastoma, the principal extracranial neural cell embryonal tumor, has been observed in children with DS. Additional genetic material on the supernumerary chromosome 21 may protect against embryonal neural cell tumor development.

The zebrafish is an animal model in ophthalmic diseases : Fleck corneal dystrophy and Schorderet-Munier syndrome

RAPPORT DE SYNTHÈSE : Pip5k3 : Pip5k3 is a kinase responsible for fleck corneal dystrophy when mutated. It is a well conserved gene that has only been characterized in human and mouse. Characterization of pip5k3 in zebrafish was necessary before using it as a model. The protein is 70 % similar to the human homologue. The full coding sequence encompasses 6303 by and presented four isoforms. They were differentially expressed during development. All the analyzed organs of the adult zebrafish expressed pip5k3. The adult eye expressed pip5k3 in the cornea, lens, ganglion cell layer (GCL), inner nuclear layer (INL) and outer limiting membrane (OLM). During development, pip5k3 was first uniformly expressed before to be restricted to the head region and to the somites. The expression of pip5k3 in the cornea of the larval eye could make possible the study of fleck corneal dystrophy on this animal. NkxS-3 : NKXS-3 is a transcription factor responsible for a new oculo-auricular syndrome in human when mutated. This recessive disorder is characterized by defects in ear lobule and multiple defects in eye, including microphthalmia and cataract. During development, the zebrafish expressed nkx5-3 in the lens, in the anterior retina and in otic vesicles. Knockdown experiments partially phenocopied the human disease. Microphthalmia and cataract were reproduced, but zebrafish showed also defects in the cartilage of the jaw associated with a microcephaly and fins abnormalities. The retinal cell differentiation was delayed, possibly linked with the delayed expression of at`h5 and crx also observed in morphants. Shh, a regulator of ath5, was normally expressed in morphant. Overexpression of nkx5-3 lead to an anophthalmia, suggesting a role at the early organogenesis of the eye. All the phenotypes observed in morphants and embryos overexpressing nkx5-3 suggest a potential involvement of the FGF and hedgehog signaling pathways.

Building digital libraries in developing countries

Digital libraries (DL) are seen as the hope for developing countries in their struggle to access scientific and academic publications. However, building such libraries in developing countries is a real challenge. These countries usually face several difficulties, such as low computer and Internet penetration rates, poor ICT infrastructure, lack of qualified human resources, lack of financial resources, etc. Thus, it is imperative finding alternative mechanisms of building DL that best fit the specificities of these countries. This paper presents the process used for building a digital library at the University Jean Piaget of Cape Verde, created in a context of scarce access to printed materials and serious difficulties in accessing ICT resources. This paper also presents the challenges, the solutions and the adopted methodological framework.

Available Building Catalog, Vol.1, 2009

IDED’s efforts to support the “Green” initiative includes reducing the number of communication pieces we print and mail. To support our efforts, register at http://www.iowalifechanging.com/subscriptions/login.asp to receive notice of future issues of the Available Building Catalog as they become available online.

Space Utilization and Building Study for the Department of General Services, October 9, 2000

Purposes of this Report: • Recommend the most logical and economical options to address state governmental space needs in the Polk County metropolitan area to the year 2010. • Include building size, location, phasing, financing, method of project delivery and estimated cost. • Develop a software tool to compare costs of leasing vs. ownership of space. Methodology: Identify: 1. Current amount and location of owned and leased space, by agency; 2. Types of space and whether best located on or off of the Capitol Complex; 3. Utilization of space, noting over-crowding and under-utilization; 4. Current number of workstations for full and part time employees, Personnel Employment Organization (PEO) workers, contractors, interns, etc.; and, 5. History of staff levels to assist in the prediction of staff growth. Scope: This report focuses on 10 state-owned buildings located on the Capitol Complex and 48 leased spaces in the Polk County metropolitan area. (See Figures 1 and 2.) • Due to a separate space study under way by the Legislature, implications of area and staff for the State Capitol building are included only for the Governor, Lieutenant Governor, Treasurer, Secretary of State, Auditor and the Department of Management. • Because it is largely a museum building that does not have office space available for other agencies, the area and staff of the Historical Building are not fully addressed. • Only the parking implications of the new Judicial Building are included in this study because the building space is under the jurisdiction of the Judicial Branch and not available for other agencies. Several state-owned buildings are not included in the scope of this report, generally because they have highly focused purposes, and their space is not available for assignment to other agencies. Several leased locations are not included for similar reasons, including leases that do not fall within the authority of the Department of General Services.

A festschrift for Roland L. Weinsier: nutrition scientist, educator, and clinician.

Roland L. Weinsier, M.D., Dr.P.H., devoted himself to the fields of nutrition and obesity for more than 35 years. He contributed outstanding work related to the treatment of obesity through dietary and lifestyle change; metabolic/energetic influences on obesity, weight loss, and weight regain; body composition changes accompanying weight loss and regain; the health benefits and risks of weight loss; nutrition education for physicians; and nutrition support of sick patients. He served on the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) National Task Force on Prevention and Treatment of Obesity, as Chair of the University of Alabama at Birmingham's Department of Nutrition Sciences, and as Founder and Director of its NIDDK-funded Clinical Nutrition Research Center. He was a long-time and active member of NAASO, serving in the roles of Councilor, Publications Committee Chair, Continuing Medical Education Course Director, Public Relations Committee Chair, and Membership Committee Co-Chair, to name just a few. He was well respected as a staunch defender of NAASO's scientific integrity in these roles. Sadly, Roland Weinsier died on November 27, 2002. He will be missed and remembered by many as a revered and beloved teacher, mentor, healer, and scholar.

RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses.

The receptor for hyaluronic acid-mediated motility (RHAMM) is an antigen eliciting both humoral and cellular immune responses in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). We initiated a phase 1 clinical trial vaccinating 10 patients with R3 (ILSLELMKL), a highly immunogenic CD8(+) T-cell epitope peptide derived from RHAMM. In 7 of 10 patients, we detected an increase of CD8(+)/HLA-A2/RHAMM R3 tetramer(+)/CD45RA(+)/CCR7(-)/CD27(-)/CD28(-) effector T cells in accordance with an increase of R3-specific CD8(+) T cells in enzyme linked immunospot (ELISpot) assays. In chromium release assays, a specific lysis of RHAMM-positive leukemic blasts was shown. Three of 6 patients with myeloid disorders (1/3 AML, 2/3 MDS) achieved clinical responses: one patient with AML and one with MDS showed a significant reduction of blasts in the bone marrow after the last vaccination. One patient with MDS no longer needed erythrocyte transfusions after 4 vaccinations. Two of 4 patients with MM showed a reduction of free light chain serum levels. Taken together, RHAMM-R3 peptide vaccination induced both immunologic and clinical responses, and therefore RHAMM constitutes a promising target for further immunotherapeutic approaches. This study is registered at http://ISRCTN.org as ISRCTN32763606 and is registered with EudraCT as 2005-001706-37.

Haemorrhagic shock and encephalopathy syndrome: report of two cases with special reference to hypoglycaemia.

Haemorrhagic shock and encephalopathy syndrome (HSES) is a devastating disorder affecting infants. So far no cases have been reported in Switzerland. It is characterised by the abrupt onset of hyperpyrexia, shock, encephalopathy, diarrhoea, disseminated intravascular coagulation (DIC) and renal and hepatic failure in previously healthy infants. Severe hypoglycaemia has been repeatedly reported in association with HSES. However, the pathophysiology of the hypoglycaemia is not clear. We report on two infants (2 and 7 months old) with typical HSES, both of whom were presented with nonketotic hypoglycaemia. In the first case, plasma insulin was 23 pmol/l at the time of hypoglycaemia (0.1 mmol/l). In the second case, increased values for interleukin-6 (IL-6) (319 pg/ml) and IL-8 (1382 pg/ml) were found 24 hours after admission, whereas IL-1 and tumour necrosis factor-alpha (TNF-alpha) were not measurable. Alpha-1-antitrypsin was decreased (0.6 g/l). In hyperpyrexic, unconscious and shocked infants, HSES should be considered and hypoglycaemia should be specifically looked for. Hypoglycaemia is not caused by hyperinsulinism but may be secondary to the release of cytokines.

Waste Reduction, Construction and Demolition Debris: Guide for Building, Construction and Environmental Professionals, Revised November 2008

This document is intended to lay the foundation for resource reduction strategies in new construction, renovation and demolition. If you have an innovative idea or information that you believe should be included in future updates of this manual please email Shelly Codner at scodner@region12cog.org or Jan Loyson at Jan.Loyson@Iowalifechanging.com. Throughout this manual, we use the term “waste reduction” to define waste management initiatives that will result in less waste going to the landfill. In accordance with the waste management hierarchy these practices include reducing (waste prevention), reusing (deconstruction and salvage), recycling and renewing (making old things new again) - in that order. This manual will explain what these practices are and how to incorporate them into your projects.

Le syndrome d'épuisement professionnel (burnout) des médecins

Les médecins sont soumis à différents facteurs de stress qui les prédisposent à l'épuisement professionnel, mais aussi à d'autres problèmes de santé psychique : dépression, abus de substances, suicide sont des thèmes que l'on retrouve souvent lorsque l'on parle de la santé des médecins. Le burnout est un syndrome qui peut toucher toute les professions, mais ce sont celles en lien à la relation d'aide qui sont les plus susceptibles d'en développer les stigmates. Car le burnout est une véritable maladie de la relation d'aide. Maslach et Jackson ont le mieux défini cet incendie intérieur : conséquence d'une exposition chronique et répétitive à un stress émotionnel, il se manifeste par : 1. L'épuisement relationnel 2. La déshumanisation de la relation à l'autre. 3. Le sentiment d'échec professionnel ou la diminution de l'accomplissement personnel. [Auteur]

Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice.

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1(tm1a)) that reduces mRNA to ∼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.