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1.  Craniodentofacial Manifestations in a Rare Syndrome: Orofaciodigital Type IV (Mohr-Majewski Syndrome) 
Case Reports in Dentistry  2014;2014:605892.
Background. The orofaciodigital syndromes (OFDS) are a heterogeneous group of syndromes that affect the face, oral cavity, and the digits. OFDS type IV (OMIM %258860) is rare and characterized by broad nasal root and tip, orbital hypertelorism or telecanthus, micrognathia, hypoplastic mandible, and low-set ears. Oral symptoms may include cleft lip, cleft or highly arched palate, bifid uvula, cleft or hypoplastic maxillary and mandibular alveolar ridge, oral frenula, lingual hamartoma, and absent or hypoplastic epiglottis. Dental anomalies are common and generally include disturbances in the number of teeth. Case Report. This report presents a six-year-old girl, referred with the chief complaint of missing teeth. She was diagnosed as having OFDS type IV based on clinical findings. Her parents reported three deceased children and two fetuses that had the same phenotype. She was the seventh child of consanguineous parents who were first cousins. Conclusion. This is a very rare syndrome. Many reported OFDS type IV cases have consanguineous parents, consistent with an autosomal recessive trait. Manifestation of cleft palate in the healthy sibling may be mild expression of the disorder or an unrelated isolated cleft.
doi:10.1155/2014/605892
PMCID: PMC4283451  PMID: 25587461
3.  Oral Rehabilitation of a Patient with Amelogenesis Imperfecta 
Pediatric dentistry  2009;31(7):523-527.
Amelogenesis imperfecta is a hereditary disorder that causes defective enamel development in the primary and permanent teeth. Clinical treatment is important to address the esthetic appearance of affected teeth, reduce dentinal sensitivity, preserve tooth structure, and optimize masticatory function. The purpose of this case report was to describe the diagnosis, treatment planning, and dental rehabilitation of a patient with autosomal recessive amelogenesis imperfecta. The patient was followed for 5 years, and evaluation 3 years after restorations revealed no pathology associated with the rehabilitation. The patient’s esthetic and functional expectations were satisfied.
PMCID: PMC4264524  PMID: 20108745
GENETICS; GROWTH AND DEVELOPMENT; ORAL PATHOLOGY; AMELOGENESIS IMPERFECTA
4.  Identification of 2 Novel ANTXR2 Mutations in Patients With Hyaline Fibromatosis Syndrome and Proposal of a Modified Grading System 
Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are rare, autosomal recessive disorders of the connective tissue caused by mutations in the gene encoding the anthrax toxin receptor 2 protein (ANTXR2) located on chromosome 4q21. Characteristically, these conditions present with overlapping clinical features, such as nodules and/or pearly papules, gingival hyperplasia, flexion contractures of the joints, and osteolytic bone defects. The present report describes a pair of sibs and three other JHF/ISH patients whose diagnoses were based on typical clinical manifestations and confirmed by histopathologic analyses and/or molecular analysis. A comparison of ISH and JHF, additional thoughts about new terminology (hyaline fibromatosis syndrome) and a modified grading system are also included.
doi:10.1002/ajmg.a.35228
PMCID: PMC4264531  PMID: 22383261
anthrax toxin receptor 2 protein; capillary morphogenesis protein-2; hyaline fibromatosis syndrome; infantile systemic hyalinosis; juvenile hyaline fibromatosis
5.  Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone 
Clinical nephrology  2010;74(6):411-422.
Background
A family was identified with autosomal dominant inheritance of anemia, polyuria, hyperuricemia, and chronic kidney disease. Mutational analysis revealed a novel heterozygous mutation c.58T > C resulting in the amino acid substitution of cysteine for arginine in the preprorenin signal sequence (p.cys20Arg) occurring in all affected members.
Methods
Effects of the identified mutation were characterized using in vitro and in vivo studies. Affected individuals were clinically characterized before and after administration of fludrocortisone.
Results
The mutation affects endoplasmic reticulum co-translational translocation and posttranslational processing, resulting in massive accumulation of non-glycosylated preprorenin in the cytoplasm. This affects expression of intra-renal RAS components and leads to ultrastructural damage of the kidney. Affected individuals suffered from anemia, hyperuricemia, decreased urinary concentrating ability, and progressive chronic kidney disease. Treatment with fludrocortisone in an affected 10-year-old child resulted in an increase in blood pressure and estimated glomerular filtration rate.
Conclusions
A novel REN gene mutation resulted in an alteration in the amino acid sequence of the renin signal sequence and caused childhood anemia, polyuria, and kidney disease. Treatment with fludrocortisone improved renal function in an affected child. Nephrologists should consider REN mutational analysis in families with autosomal dominant inheritance of chronic kidney disease, especially if they suffer from anemia, hyperuricemia, and polyuria in childhood.
PMCID: PMC4264543  PMID: 21084044
anemia; children; fludrocortisone; hyperuricemia; renin mutation
6.  Exclusion of Candidate Genes in Seven Turkish Families With Autosomal Recessive Amelogenesis Imperfecta 
Amelogenesis imperfectas (AI) are a group of inherited defects of dental enamel formation that show both clinical and genetic heterogeneity. Seven Turkish families segregating autosomal recessive AI (ARAI) were evaluated for evidence of a genetic etiology of AI for the seven major candidate gene loci (AMBN, AMELX, ENAM, FAM83H, KLK4, MMP20, and TUFT1). Dental and periodontal characteristics of the affected members of these families were also described. The mean scores of DMFS and dfs indices were 9.7 and 9.6, respectively. The mean PPD was 2.2mm and the percentage of the sites with plaque and BOP were 87.8% and 72.4%, respectively. The exons and intron/exon junctions of the candidate genes were sequenced and no gene mutations were identified in any individuals. These findings support the existence of an additional gene(s) that are etiologic for ARAI in these families.
doi:10.1002/ajmg.a.32885
PMCID: PMC4264544  PMID: 19530186
autosomal recessive amelogenesis imperfecta; AMBN; AMELX; ENAM; FAM83H; KLK4; MMP20; TUFT1
7.  Long-Term Health Effects of Neutering Dogs: Comparison of Labrador Retrievers with Golden Retrievers 
PLoS ONE  2014;9(7):e102241.
Our recent study on the effects of neutering (including spaying) in Golden Retrievers in markedly increasing the incidence of two joint disorders and three cancers prompted this study and a comparison of Golden and Labrador Retrievers. Veterinary hospital records were examined over a 13-year period for the effects of neutering during specified age ranges: before 6 mo., and during 6–11 mo., year 1 or years 2 through 8. The joint disorders examined were hip dysplasia, cranial cruciate ligament tear and elbow dysplasia. The cancers examined were lymphosarcoma, hemangiosarcoma, mast cell tumor, and mammary cancer. The results for the Golden Retriever were similar to the previous study, but there were notable differences between breeds. In Labrador Retrievers, where about 5 percent of gonadally intact males and females had one or more joint disorders, neutering at <6 mo. doubled the incidence of one or more joint disorders in both sexes. In male and female Golden Retrievers, with the same 5 percent rate of joint disorders in intact dogs, neutering at <6 mo. increased the incidence of a joint disorder to 4–5 times that of intact dogs. The incidence of one or more cancers in female Labrador Retrievers increased slightly above the 3 percent level of intact females with neutering. In contrast, in female Golden Retrievers, with the same 3 percent rate of one or more cancers in intact females, neutering at all periods through 8 years of age increased the rate of at least one of the cancers by 3–4 times. In male Golden and Labrador Retrievers neutering had relatively minor effects in increasing the occurrence of cancers. Comparisons of cancers in the two breeds suggest that the occurrence of cancers in female Golden Retrievers is a reflection of particular vulnerability to gonadal hormone removal.
doi:10.1371/journal.pone.0102241
PMCID: PMC4096726  PMID: 25020045
8.  African origin of the malaria parasite Plasmodium vivax 
Nature communications  2014;5:3346.
Plasmodium vivax is the leading cause of human malaria in Asia and Latin America but is absent from most of central Africa due to the near fixation of a mutation that inhibits the expression of its receptor, the Duffy antigen, on human erythrocytes. The emergence of this protective allele is not understood because P. vivax is believed to have originated in Asia. Here we show, using a non-invasive approach, that wild chimpanzees and gorillas throughout central Africa are endemically infected with parasites that are closely related to human P. vivax. Sequence analyses reveal that ape parasites lack host specificity and are much more diverse than human parasites, which form a monophyletic lineage within the ape parasite radiation. These findings indicate that human P. vivax is of African origin and likely selected for the Duffy-negative mutation. All extant human P. vivax parasites are derived from a single ancestor that escaped out of Africa.
doi:10.1038/ncomms4346
PMCID: PMC4089193  PMID: 24557500
9.  Hyaluronidase expression and biofilm involvement in Staphylococcus aureus UAMS-1 and its sarA, agr and sarA agr regulatory mutants 
Microbiology  2013;159(Pt 4):782-791.
In a previous study, two proteins identified as hyaluronidases were detected in spent media by MS and found to be in greater quantity in the sarA and sarA agr mutant strains when compared with the parent and agr mutant strains of Staphylococcus aureus UAMS-1. In the present study, spent media and total RNA were isolated from UAMS-1 and its regulatory mutants and analysed for hyaluronidase activity and steady-state hyaluronidase (hysA) RNA message levels. Hyaluronidase activity was observed throughout all time points examined regardless of the regulatory effects of sarA and agr but activity was always substantially higher in the sarA and sarA agr mutant strains than in the UAMS-1 parent and agr mutant strains. Northern analysis did not detect hysA message for either the UAMS-1 parent or the agr mutant strains at any time point examined, while steady-state hysA message levels were detected throughout growth for the sarA mutant strain, but only at exponential and early post-exponential growth for the sarA agr mutant strain. An in vitro biofilm plate assay, pre-coated with human plasma as a source of hyaluronic acid, demonstrated no significant increase in biofilm for a sarA mutant strain of S. aureus UAMS-1 defective in hyaluronidase activity when compared with the sarA mutant strain. These data indicate that, while hysA message levels and hyaluronidase activity are elevated in the sarA mutant strains of S. aureus UAMS-1, the increase in activity did not contribute to the biofilm-negative phenotype observed in the sarA mutant strain of S. aureus UAMS-1.
doi:10.1099/mic.0.065367-0
PMCID: PMC3709827  PMID: 23393148
10.  Lock-Out Valve to Decrease Catheter-Associated Urinary Tract Infections 
Advances in Urology  2014;2014:765756.
Patients with long-term indwelling urinary catheters are at an increased risk for urinary tract infection due to bacteriuria. Catheter-associated urinary tract infections (CAUTIs) are a significant source of morbidity and mortality in long-term care facilities as well as in ambulatory patients requiring long-term catheterization. There is increased interest in the financial impact of CAUTI as Medicare no longer provides reimbursement for nosocomial CAUTIs. Ascending bacteria may in part enter the closed drainage system when the patient switches between leg and night collection bags. In an attempt to reduce this ascent, a double valve lock-out system was devised that maintains a closed system during bag exchange. The concept is introduced and CAUTIs are reviewed.
doi:10.1155/2014/765756
PMCID: PMC3918347  PMID: 24575127
11.  Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations 
Jaureguiberry, Graciana | De la Dure-Molla, Muriel | Parry, David | Quentric, Mickael | Himmerkus, Nina | Koike, Toshiyasu | Poulter, James | Klootwijk, Enriko | Robinette, Steven L. | Howie, Alexander J. | Patel, Vaksha | Figueres, Marie-Lucile | Stanescu, Horia C. | Issler, Naomi | Nicholson, Jeremy K. | Bockenhauer, Detlef | Laing, Christopher | Walsh, Stephen B. | McCredie, David A. | Povey, Sue | Asselin, Audrey | Picard, Arnaud | Coulomb, Aurore | Medlar, Alan J. | Bailleul-Forestier, Isabelle | Verloes, Alain | Le Caignec, Cedric | Roussey, Gwenaelle | Guiol, Julien | Isidor, Bertrand | Logan, Clare | Shore, Roger | Johnson, Colin | Inglehearn, Christopher | Al-Bahlani, Suhaila | Schmittbuhl, Matthieu | Clauss, François | Huckert, Mathilde | Laugel, Virginie | Ginglinger, Emmanuelle | Pajarola, Sandra | Spartà, Giuseppina | Bartholdi, Deborah | Rauch, Anita | Addor, Marie-Claude | Yamaguti, Paulo M. | Safatle, Heloisa P. | Acevedo, Ana Carolina | Martelli-Júnior, Hercílio | dos Santos Netos, Pedro E. | Coletta, Ricardo D. | Gruessel, Sandra | Sandmann, Carolin | Ruehmann, Denise | Langman, Craig B. | Scheinman, Steven J. | Ozdemir-Ozenen, Didem | Hart, Thomas C. | Hart, P. Suzanne | Neugebauer, Ute | Schlatter, Eberhard | Houillier, Pascal | Gahl, William A. | Vikkula, Miikka | Bloch-Zupan, Agnès | Bleich, Markus | Kitagawa, Hiroshi | Unwin, Robert J. | Mighell, Alan | Berdal, Ariane | Kleta, Robert
Nephron. Physiology  2013;122(0):1-6.
Background/Aims
Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.
Methods
We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing.
Results
All patients had biallelic FAM20A mutations segregating with the disease; 20 different mutations were identified.
Conclusions
This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
doi:10.1159/000349989
PMCID: PMC3782194  PMID: 23434854
Nephrolithiasis; Urolithiasis; Amelogenesis imperfecta; FAM20B; FAM20C
12.  Reversible Control by Vitamin D of Granulocytes and Bacteria in the Lungs of Mice: An Ovalbumin-Induced Model of Allergic Airway Disease 
PLoS ONE  2013;8(6):e67823.
Vitamin D may be essential for restricting the development and severity of allergic diseases and asthma, but a direct causal link between vitamin D deficiency and asthma has yet to be established. We have developed a ‘low dose’ model of allergic airway disease induced by intraperitoneal injection with ovalbumin (1 µg) and aluminium hydroxide (0.2 mg) in which characteristics of atopic asthma are recapitulated, including airway hyperresponsiveness, antigen-specific immunoglobulin type-E and lung inflammation. We assessed the effects of vitamin D deficiency throughout life (from conception until adulthood) on the severity of ovalbumin-induced allergic airway disease in vitamin D-replete and -deficient BALB/c mice using this model. Vitamin D had protective effects such that deficiency significantly enhanced eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male but not female mice. Vitamin D also suppressed the proliferation and T helper cell type-2 cytokine-secreting capacity of airway-draining lymph node cells from both male and female mice. Supplementation of initially vitamin D-deficient mice with vitamin D for four weeks returned serum 25-hydroxyvitamin D to levels observed in initially vitamin D-replete mice, and also suppressed eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male mice. Using generic 16 S rRNA primers, increased bacterial levels were detected in the lungs of initially vitamin D-deficient male mice, which were also reduced by vitamin D supplementation. These results indicate that vitamin D controls granulocyte levels in the bronchoalveolar lavage fluid in an allergen-sensitive manner, and may contribute towards the severity of asthma in a gender-specific fashion through regulation of respiratory bacteria.
doi:10.1371/journal.pone.0067823
PMCID: PMC3691156  PMID: 23826346
13.  Genetic Structure of Wild Bonobo Populations: Diversity of Mitochondrial DNA and Geographical Distribution 
PLoS ONE  2013;8(3):e59660.
Bonobos (Pan paniscus) inhabit regions south of the Congo River including all areas between its southerly tributaries. To investigate the genetic diversity and evolutionary relationship among bonobo populations, we sequenced mitochondrial DNA from 376 fecal samples collected in seven study populations located within the eastern and western limits of the species’ range. In 136 effective samples from different individuals (range: 7–37 per population), we distinguished 54 haplotypes in six clades (A1, A2, B1, B2, C, D), which included a newly identified clade (D). MtDNA haplotypes were regionally clustered; 83 percent of haplotypes were locality-specific. The distribution of haplotypes across populations and the genetic diversity within populations thus showed highly geographical patterns. Using population distance measures, seven populations were categorized in three clusters: the east, central, and west cohorts. Although further elucidation of historical changes in the geological setting is required, the geographical patterns of genetic diversity seem to be shaped by paleoenvironmental changes during the Pleistocene. The present day riverine barriers appeared to have a weak effect on gene flow among populations, except for the Lomami River, which separates the TL2 population from the others. The central cohort preserves a high genetic diversity, and two unique clades of haplotypes were found in the Wamba/Iyondji populations in the central cohort and in the TL2 population in the eastern cohort respectively. This knowledge may contribute to the planning of bonobo conservation.
doi:10.1371/journal.pone.0059660
PMCID: PMC3609822  PMID: 23544084
14.  Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations 
Jaureguiberry, Graciana | De la Dure-Molla, Muriel | Parry, David | Quentric, Mickael | Himmerkus, Nina | Koike, Toshiyasu | Poulter, James | Klootwijk, Enriko | Robinette, Steven L. | Howie, Alexander J. | Patel, Vaksha | Figueres, Marie-Lucile | Stanescu, Horia C. | Issler, Naomi | Nicholson, Jeremy K. | Bockenhauer, Detlef | Laing, Christopher | Walsh, Stephen B. | McCredie, David A. | Povey, Sue | Asselin, Audrey | Picard, Arnaud | Coulomb, Aurore | Medlar, Alan J. | Bailleul-Forestier, Isabelle | Verloes, Alain | Le Caignec, Cedric | Roussey, Gwenaelle | Guiol, Julien | Isidor, Bertrand | Logan, Clare | Shore, Roger | Johnson, Colin | Inglehearn, Christopher | Al-Bahlani, Suhaila | Schmittbuhl, Matthieu | Clauss, François | Huckert, Mathilde | Laugel, Virginie | Ginglinger, Emmanuelle | Pajarola, Sandra | Spartà, Giuseppina | Bartholdi, Deborah | Rauch, Anita | Addor, Marie-Claude | Yamaguti, Paulo M. | Safatle, Heloisa P. | Acevedo, Ana Carolina | Martelli-Júnior, Hercílio | dos Santos Netos, Pedro E. | Coletta, Ricardo D. | Gruessel, Sandra | Sandmann, Carolin | Ruehmann, Denise | Langman, Craig B. | Scheinman, Steven J. | Ozdemir-Ozenen, Didem | Hart, Thomas C. | Hart, P. Suzanne | Neugebauer, Ute | Schlatter, Eberhard | Houillier, Pascal | Gahl, William A. | Vikkula, Miikka | Bloch-Zupan, Agnès | Bleich, Markus | Kitagawa, Hiroshi | Unwin, Robert J. | Mighell, Alan | Berdal, Ariane | Kleta, Robert
Nephron. Physiology  2013;122(1-2):1-6.
Background/Aims
Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.
Methods
We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing.
Results
All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified.
Conclusions
This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
doi:10.1159/000349989
PMCID: PMC3782194  PMID: 23434854
Nephrolithiasis; Urolithiasis; Amelogenesis imperfecta; FAM20B; FAM20C

15.  Neutering Dogs: Effects on Joint Disorders and Cancers in Golden Retrievers 
PLoS ONE  2013;8(2):e55937.
In contrast to European countries, the overwhelming majority of dogs in the U.S. are neutered (including spaying), usually done before one year of age. Given the importance of gonadal hormones in growth and development, this cultural contrast invites an analysis of the multiple organ systems that may be adversely affected by neutering. Using a single breed-specific dataset, the objective was to examine the variables of gender and age at the time of neutering versus leaving dogs gonadally intact, on all diseases occurring with sufficient frequency for statistical analyses. Given its popularity and vulnerability to various cancers and joint disorders, the Golden Retriever was chosen for this study. Veterinary hospital records of 759 client-owned, intact and neutered female and male dogs, 1–8 years old, were examined for diagnoses of hip dysplasia (HD), cranial cruciate ligament tear (CCL), lymphosarcoma (LSA), hemangiosarcoma (HSA), and mast cell tumor (MCT). Patients were classified as intact, or neutered early (<12 mo) or late (≥12 mo). Statistical analyses involved survival analyses and incidence rate comparisons. Outcomes at the 5 percent level of significance are reported. Of early-neutered males, 10 percent were diagnosed with HD, double the occurrence in intact males. There were no cases of CCL diagnosed in intact males or females, but in early-neutered males and females the occurrences were 5 percent and 8 percent, respectively. Almost 10 percent of early-neutered males were diagnosed with LSA, 3 times more than intact males. The percentage of HSA cases in late-neutered females (about 8 percent) was 4 times more than intact and early-neutered females. There were no cases of MCT in intact females, but the occurrence was nearly 6 percent in late-neutered females. The results have health implications for Golden Retriever companion and service dogs, and for oncologists using dogs as models of cancers that occur in humans.
doi:10.1371/journal.pone.0055937
PMCID: PMC3572183  PMID: 23418479
16.  Lesula: A New Species of Cercopithecus Monkey Endemic to the Democratic Republic of Congo and Implications for Conservation of Congo’s Central Basin 
PLoS ONE  2012;7(9):e44271.
In June 2007, a previously undescribed monkey known locally as “lesula” was found in the forests of the middle Lomami Basin in central Democratic Republic of Congo (DRC). We describe this new species as Cercopithecus lomamiensis sp. nov., and provide data on its distribution, morphology, genetics, ecology and behavior. C. lomamiensis is restricted to the lowland rain forests of central DRC between the middle Lomami and the upper Tshuapa Rivers. Morphological and molecular data confirm that C. lomamiensis is distinct from its nearest congener, C. hamlyni, from which it is separated geographically by both the Congo (Lualaba) and the Lomami Rivers. C. lomamiensis, like C. hamlyni, is semi-terrestrial with a diet containing terrestrial herbaceous vegetation. The discovery of C. lomamiensis highlights the biogeographic significance and importance for conservation of central Congo’s interfluvial TL2 region, defined from the upper Tshuapa River through the Lomami Basin to the Congo (Lualaba) River. The TL2 region has been found to contain a high diversity of anthropoid primates including three forms, in addition to C. lomamiensis, that are endemic to the area. We recommend the common name, lesula, for this new species, as it is the vernacular name used over most of its known range.
doi:10.1371/journal.pone.0044271
PMCID: PMC3440422  PMID: 22984482
17.  Amelogenesis Imperfecta: Genotype-Phenotype Studies in 71 Families 
Cells, Tissues, Organs  2011;194(2-4):279-283.
Amelogenesis imperfecta (AI) represents hereditary conditions affecting the quality and quantity of enamel. Six genes are known to cause AI (AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72). Our aim was to determine the distribution of different gene mutations in a large AI population and evaluate phenotype-genotype relationships. Affected and unaffected family members were evaluated clinically and radiographically by one examiner. Genotyping was completed using genomic DNA obtained from blood or saliva. A total of 494 individuals were enrolled, with 430 (224 affected, 202 unaffected, and 4 not definitive) belonging to 71 families with conditions consistent with the diagnosis of AI. Diverse clinical phenotypes were observed (i.e. hypoplastic, hypocalcified, and hypomaturation). Genotyping revealed mutations in all 6 candidate genes. A molecular diagnosis was made in 132 affected individuals (59%) and in 26 of the families (37%). Mutations involved 12 families with FAM83H (46%), 6 families with AMELX (23%), 3 families with ENAM (11%), 2 families with KLK4 and MMP20 (8% for each gene), and 1 family with a WDR72 mutation (4%). Phenotypic variants were associated with allelic FAM83H and AMELX mutations. Two seemingly unrelated families had the same KLK4 mutation. Families affected with AI where candidate gene mutations were not identified could have mutations not identifiable by traditional gene sequencing (e.g. exon deletion) or they could have promoter sequence mutations not evaluated in this study. However, the results suggest that there remain new AI causative genes to be identified.
doi:10.1159/000324339
PMCID: PMC3178091  PMID: 21597265
Enamel; Amelogenesis imperfecta; Phenotype; Genotype; Gene; Mutation
18.  C. elegans Notch signaling regulates adult chemosensory response and larval molting quiescence 
Current biology : CB  2011;21(10):825-834.
Summary
Background
The conserved DOS motif proteins OSM-7 and OSM-11 function as co-ligands with canonical DSL ligands to activate C. elegans Notch receptors during development. We report herein that Notch ligands, co-ligands and the receptors LIN-12 and GLP-1 regulate two C. elegans behaviors: chemosensory avoidance of octanol and quiescence during molting lethargus.
Results
C. elegans lacking osm-7 or osm-11 are defective in their response to octanol. We find that OSM-11 is secreted from hypodermal seam cells into the pseudocoelomic body cavity and acts non-cell autonomously as a diffusible factor. OSM-11 acts with the DSL ligand LAG-2 to activate LIN-12 and GLP-1 Notch receptors in the neurons of adult animals,- thereby regulating octanol avoidance response. In adult animals, over-expression of osm-11 and consequent Notch receptor activation induces anachronistic sleep-like quiescence. Perturbation of Notch signaling altered basal activity in adults as well as arousal thresholds and quiescence during molting lethargus. Genetic epistasis studies revealed that Notch signaling regulates quiescence via previously identified circuits and genetic pathways including the egl-4 cGMP-dependent kinase.
Conclusions
Our findings indicate that the conserved Notch pathway modulates behavior in adult C. elegans in response to environmental stress. Additionally, Notch signaling regulates sleep-like quiescence in C. elegans suggesting Notch may regulate sleep in other species.
doi:10.1016/j.cub.2011.04.010
PMCID: PMC3100419  PMID: 21549604
19.  Unintended Perioperative Hypothermia 
The Ochsner Journal  2011;11(3):259-270.
Background
Hypothermia, defined as a core body temperature less than 36°C (96.8°F), is a relatively common occurrence in the unwarmed surgical patient. A mild degree of perioperative hypothermia can be associated with significant morbidity and mortality. A threefold increase in the frequency of surgical site infections is reported in colorectal surgery patients who experience perioperative hypothermia. As part of the Surgical Care Improvement Project, guidelines aim to decrease the incidence of this complication.
Methods
We review the physiology of temperature regulation, mechanisms of hypothermia, effects of anesthetics on thermoregulation, and consequences of hypothermia and summarize recent recommendations for maintaining perioperative normothermia.
Results
Evidence suggests that prewarming for a minimum of 30 minutes may reduce the risk of subsequent hypothermia.
Conclusions
Monitoring of body temperature and avoidance of unintended perioperative hypothermia through active and passive warming measures are the keys to preventing its complications.
PMCID: PMC3179201  PMID: 21960760
Hypothermia; perioperative; prewarming; thermoregulation
20.  Phenotypic Variation in FAM83H-associated Amelogenesis Imperfecta 
Journal of Dental Research  2009;88(4):356-360.
FAM83H gene mutations are associated with autosomal-dominant hypocalcified amelogenesis imperfecta (ADHCAI), which is typically characterized by enamel having normal thickness and a markedly decreased mineral content. This study tested the hypothesis that there are phenotype and genotype associations in families with FAM83H-associated ADHCAI. Seven families segregating ADHCAI (147 individuals) were evaluated. Phenotyping included clinical, radiographic, histological, and biochemical studies, and genotyping was by mutational analysis. Multiple novel FAM83H mutations were identified, including two 2-bp-deletion mutations, the first non-nonsense mutations identified. Craniofacial deviation from normal was more prevalent in the affected individuals. Affected individuals having truncating FAMH3H mutations of 677 or fewer amino acids presented a generalized ADHCAI phenotype, while those having mutations capable of producing a protein of at least 694 amino acids had a unique and previously unreported phenotype affecting primarily the cervical enamel. This investigation shows that unique phenotypes are associated with specific FAM83H mutations.
doi:10.1177/0022034509333822
PMCID: PMC2754853  PMID: 19407157
enamel; FAM83H; amelogenesis imperfecta; hypocalcified; phenotype; craniofacial
21.  Genotypic and Phenotypic Assessment of Hyaluronidase among Type Strains of a Select Group of Staphylococcal Species 
Hyaluronidases degrade hyaluronic acid, a major polysaccharide of the extracellular matrix of tissues, and are considered important for virulence in a number of Gram-positive and -negative bacteria. The purpose of the present study was to determine the prevalence of hyaluronidase among clinical strains of Staphylococcus aureus and among other Staphylococcus species. Spent media and chromosomal DNA were assessed for hyaluronidase activity and the absence or presence of a hyaluronidase gene (hysA) by Southern analysis, respectively. All S. aureus strains examined exhibited at least one hybridizing band (half of the strains exhibited two or more hybridizing bands) when probed for hysA and all but three of these strains produced hyaluronidase. In contrast, none of the type strains of 19 other species exhibited either hyaluronidase activity or hybridizing bands when probed for hysA. These data support the hypothesis that among members of the Staphylococcus genus only strains of S. aureus possess the enzyme hyaluronidase. This would suggest that hyaluronidase represents yet another potential virulence factor employed by S. aureus to cause disease and may represent a diagnostically important characteristic for distinguishing S. aureus from other members of this genus.
doi:10.1155/2009/614371
PMCID: PMC2814232  PMID: 20130817
22.  The PDGF-C regulatory region SNP rs28999109 decreases promoter transcriptional activity and is associated with CL/P 
Human linkage and association studies suggest a gene(s) for nonsyndromic cleft lip with or without cleft palate (CL/P) on chromosome 4q31-q32 at or near the platelet derived growth factor-C (PDGF-C) locus. The mouse pdgfc−/− knockout demonstrates that PDGF-C is essential for palatogenesis. To evaluate the role of PDGF-C in human clefting, we performed sequence analysis and SNP genotyping using 1,048 multiplex CL/P families and 1,000 case-control samples from multiple geographic origins. No coding region mutations were identified, but a novel -986 C>T SNP (rs28999109) was significantly associated with CL/P (p=0.01) in cases from Chinese families yielding evidence of linkage to 4q31-q32. Significant or near significant association was also seen for this and several other PDGF-C SNPs in families from the US, Spain, India, Turkey, China, and Colombia, while no association was seen in families from the Philippines, Guatemala, and case-controls from Brazil. The -986T allele abolished six overlapping potential transcription regulatory motifs. Transfection assays of PDGF-C promoter reporter constructs demonstrate the -986T allele is associated with a significant decrease (up to 80%) of PDGF-C gene promoter activity. This functional polymorphism acting on a susceptible genetic background may represent a component of human CL/P etiology.
doi:10.1038/ejhg.2008.245
PMCID: PMC2788748  PMID: 19092777
PDGF-C; SNP; CL/P; promoter activity
23.  Phenotypic Variation in FAM83H Associated Amelogenesis Imperfecta 
Journal of dental research  2009;88(4):356-360.
FAM83H gene mutations are associated with autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) which is typically characterized by enamel having normal thickness and a markedly decreased mineral content. This study tests the hypothesis that there are phenotype and genotype associations in families with FAM83H associated ADHCAI. Seven families segregating ADHCAI (147 individuals) were evaluated. Phenotyping included clinical, radiographic, histological and biochemical studies and genotyping was by mutational analysis. Multiple novel FAM83H mutations were identified including two 2 bp deletion mutations, the first non-nonsense mutations identified. Craniofacial deviation from normal was more prevalent in the affected individuals. Affected individuals having truncating FAMH3H mutations of 677 amino acids or less presented generalized ADHCAI phenotype while those having mutations capable of producing a protein of at least 694 amino acids had a unique and previously unreported phenotype affecting primarily the cervical enamel. This investigation shows unique phenotypes are associated with specific FAM83H mutations.
doi:10.1177/0022034509333822
PMCID: PMC2754853  PMID: 19407157
enamel; FAM83H; amelogenesis imperfecta; hypocalcified; phenotype; craniofacial
24.  Human and Mouse Enamel Phenotypes Resulting from Mutation or Altered Expression of AMEL, ENAM, MMP20 and KLK4 
Cells, tissues, organs  2008;189(1-4):224-229.
The amelogenesis imperfectas (AI) are caused by AMEL, ENAM, MMP20 and KLK4 gene mutations. Mice lacking expression of the AmelX, Enam and Mmp20 genes have been generated. These mouse models provide tools for understanding enamel formation and AI pathogenesis. This study describes the AI phenotypes and relates them to their mouse model counterparts. Human AI phenotypes were determined in a clinical population of AI families and published cases. Human and murine teeth were evaluated using light and electron microscopy. 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM, and KLK4 genes were identified. The majority of human mutations for genes coding enamel non-proteinase proteins (AMEL and ENAM) resulted in variable hypoplasia ranging from local pitting to a marked, generalized enamel thinning. Specific AMEL mutations were associated with abnormal mineralization and maturation defects. Amel and Enam null murine models displayed marked enamel hypoplasia and a complete loss of prism structure. Human mutations in genes coding for the enamel proteinases (MMP20 and KLK4) cause variable degrees of hypomineralization. The murine Mmp20 null mouse exhibits both hypoplastic and hypomineralized defects. The currently available Amel and Enam mouse models for AI exhibit enamel phenotypes (hypoplastic) that are generally similar to those seen in humans. Mmp20 null mice have a greater degree of hypoplasia compared with humans having MMP20 mutations. Mice lacking expression of the currently known genes associated with the human AI conditions provide powerful models for understanding the pathogenesis of these conditions.
doi:10.1159/000151378
PMCID: PMC2754863  PMID: 18714142
enamel; amelogenesis imperfecta; mouse; human; gene; mutation
25.  Phenotype of ENAM Mutations is Dosage-dependent 
Journal of dental research  2005;84(11):1036-1041.
Five mutations in the ENAM gene have been found to cause hypoplastic amelogenesis imperfecta (AI), with phenotypes ranging from localized enamel pitting in carriers to severe hypoplastic AI. To determine the generality of ENAM mutations in hypoplastic AI, we sequenced the ENAM gene in ten Turkish families segregating autosomal hypoplastic AI. In two families, ENAM mutations were found. A novel nonsense mutation (g.12663C>A; p.S246X) was identified in one family segregating local hypoplastic AI as a dominant trait. Affected individuals in a second family segregating autosomal-recessive AI were compound heterozygotes for a novel insertion mutation (g.12946_12947insAGTCAGTACCAGTACTGT GTC) and a previously described insertion (g.13185_13186insAG) mutation. Heterozygous carriers of either insertion had a localized enamel-pitting phenotype. These findings substantiate that enamel phenotypes of ENAM mutations may be dose-dependent, with generalized hypoplastic AI segregating as a recessive trait and localized enamel pitting segregating as a dominant trait.
PMCID: PMC2708095  PMID: 16246937
amelogenesis imperfecta; enamel; enamel pitting; gene dosage; enamelin

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