Significance of buoyancy in turbulence closure for computational fluid dynamics modelling of ultraviolet disinfection in maturation ponds.

Buoyancy-driven turbulent dispersion in a maturation pond is studied using a combination of field measurements and computational fluid dynamics. Modelling flow in maturation ponds requires turbulent closure models because of the large physical size and the need to model on diurnal timescales. Simulation results are shown to be more sensitive to the inclusion of a buoyancy production term appearing in the turbulent transport equations than to the model choice. Comparisons with experimental thermal profiles show that without this term, thermal mixing is over-predicted. When including the term, stratification occurs but thermal mixing is under-predicted in the lower water column. In terms of pond performance, the effect of this term is to cause increased surface die-off of Escherichia coli during sunlight hours due to the generation of stratification. It is recommended that future modelling consider and implement this term.

Homozygosity for a missense variant in COMP gene associated with severe pseudoachondroplasia.

The phenotypic spectrum associated with heterozygous mutations in cartilage oligomeric matrix protein gene (COMP) range from a mild form of multiple epiphyseal dysplasia (MED) to pseudoachondroplasia (PSACH). However, the phenotypic effect from biallelic COMP variants is unclear. We investigated a large consanguineous Pakistani family with a severe form of PSACH in 2 individuals. Another 14 family members presented with a mild PSACH phenotype similar to MED. Using exome sequencing and subsequent segregation analysis, we identified homozygosity for a COMP missense variant [c.1423G>A; p.(D475N)] in the 2 severely affected individuals, whereas family members with the mild PSACH phenotype were heterozygous. Our observations show for the first time that a biallelic COMP variant may be associated with pronounced and widespread skeletal malformations suggesting an additive effect of the 2 mutated alleles.

An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis.

Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.

A practical model for sunlight disinfection of a subtropical maturation pond.

Maturation ponds are a type of waste stabilisation pond (WSP) designed to reduce carbon, nutrients and pathogens in the final stages of a WSP wastewater treatment system. In this study, a one-dimensional plug-flow pond model is proposed to predict temperature and E. coli concentration distributions and overall pond disinfection performance. The model accounts for the effects of vertical mixing and ultraviolet light-dependent die-off rate kinetics. Measurements of radiation, wind-speed, humidity and air temperature are recorded for model inputs and good agreement with measured vertical temperature distributions and outlet E. coli concentrations is found in an operational, subtropical maturation pond. Measurements and the model both show a diurnal pattern of stratification during daylight hours and natural convective mixing at night on days corresponding to low wind speeds, strong heat input from solar radiation and clear night skies. In the evenings, the thermal stratification is shown to collapse due to surface energy loss via longwave radiation which triggers top-down natural convective mixing. The disinfection model is found to be sensitive to the choice of die-off kinetics. The diurnal mixing pattern is found to play a vital role in the disinfection process by ensuring that pathogens are regularly transported to the near-surface layer where ultraviolet light penetration is effective. The model proposed in this paper offers clear advantages to pond designers by including geographical specific, time-varying boundary conditions and accounting for the important physical aspects of vertical mixing and sunlight inactivation processes, yet is computationally straightforward.

Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation.

Cenani-Lenz syndrome (CLS) is a rare autosomal recessive developmental disorder of the limbs. The disorder is characterized by complete syndactyly with metacarpal fusions and/or oligodactyly sometimes accompanied by radioulnar synostosis. The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth abnormalities are frequent features as well as lower limb involvement. CLS was recently associated with mutations in the low-density lipoprotein receptor-related protein 4 (LRP4) gene and dysregulated canonical WNT signaling. We have identified a large consanguineous Pakistani pedigree with 9 members affected by CLS. The affected individuals present with a consistent expression of the syndrome restricted to the limbs and kidneys. Symptoms from the lower limb are mild or absent and there were no radioulnar synostosis or craniofacial involvement. Genetic analysis using autozygosity mapping and sequencing revealed homozygosity for a novel missense mutation c.2858T > C (p.L953P) in the LRP4 gene. The mutation is located in a region encoding the highly conserved low-density lipoprotein receptor repeat class B domain of LRP4. Our findings add to the genotype-phenotype correlations in CLS and support kidney anomalies as a frequent associated feature.

Re-evaluation of the dysequilibrium syndrome.

OBJECTIVES: To re-evaluate middle-aged Swedish patients diagnosed with dysequilibrium syndrome (DES) in childhood and to compare their clinical and neuroimaging features to DES with VLDLR gene mutations (DES-VLDR). MATERIALS AND METHODS: Six patients from five families underwent neurological examination and magnetic resonance imaging (MRI) of the brain. Blood samples from the patients were screened for serum carbohydrate-deficient transferrin (s-CDT; disialotransferrin). The very-low-density lipoprotein receptor (VLDLR) gene was sequenced. RESULTS: Five patients had non-progressive cerebellar ataxia (NPCA), dysarthria and short stature. Mental retardation and strabismus, characteristic for DES-VLDLR, were inconsistent among our patients. None of our patients had VLDLR mutations or MRI findings characteristic of DES-VLDLR. MRI findings were variable from a normal cerebellum to marked cerebellar hypoplasia or atrophy and signal intensity changes. One patient was diagnosed with congenital disorder of glycosylation type 1a (CDG-1a). CONCLUSIONS: DES was originally coined on mainly clinical grounds before MRI and specific genetic tests were available, both of which should be used to arrive at an appropriate diagnosis.

Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations.

OBJECTIVES: Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms. METHODS: Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues. RESULTS: Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C-->T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G-->A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44X HAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5' end of exon 2 containing the W44X mutation was spliced out from the second transcript. CONCLUSIONS: We describe neurological and neuropsychological abnormalities for the first time in Kostmann disease patients. These central nervous system symptoms appear to be associated with specific HAX1 mutations.

Familial osteochondritis dissecans associated with early osteoarthritis and disproportionate short stature.

OBJECTIVE: Familial osteochondritis dissecans (OCD) is a rare disorder characterised by disturbed chondro-skeletal development, disproportionate growth and deformation of the skeleton. DESIGN: We identified a five-generation family with 15 living affected members from Northern Sweden. The disorder was diagnosed with a case definition of OCD in at least one joint. RESULTS: Main clinical findings consisted of OCD in knees and/or hips and/or elbows, disproportionate short stature and early osteoarthritis (OA). There were no radiological indications of epiphyseal dysplasia. Anthropometric measurements of affected individuals showed short stature, a high ratio between sitting height and total height, a relatively normal arm span and head circumference. In 12 of 15 cases, onset was during late childhood or adolescence and OA had developed in seven of those patients. CONCLUSIONS: Our observation suggests that OA is a frequent complication in familial OCD even though the lesions appear before closure of physis.

Effects of oxybutynin transdermal system on health-related quality of life and safety in men with overactive bladder and prostate conditions.

AIMS: Overactive bladder (OAB) is common in men and may exist concomitantly with benign prostatic hyperplasia (BPH) and obstruction. We present a subanalysis of results from men with OAB in a 6-month, open-label study of treatment with the oxybutynin transdermal system (OXY-TDS). Broad entry criteria were incorporated to yield a clinically representative population. METHODS: All participants received OXY-TDS 3.9 mg/day. Effectiveness was assessed by changes in scores on validated questionnaires, which included the single-item Patient Perception of Bladder Condition (PPBC), the King's Health Questionnaire (KHQ) and the Beck Depression Inventory-II (BDI-II). RESULTS: The proportion of men (n=369; mean age=69.6 years) who reported that their bladder condition caused moderate, severe or many severe problems (PPBC>or=4) improved from 77.3% at baseline to 38.1-53.6% in subsequent months. Mean KHQ scores decreased significantly (p12 (associated with a diagnosis of depression) decreased from 23.9% to 17.9% (p=0.0055). Men with a history of 'prostate problems' or use of 'BPH medication' (32.2%) had KHQ domain changes that were similar (p>or=0.1016) to those of other men. Most men (76.2%) reported no treatment-related adverse events; two men (0.5%) experienced symptoms of mild urinary retention, but neither required catheterisation. CONCLUSIONS: Oxybutynin transdermal system treatment of men with OAB was effective and well tolerated, regardless of history of prostate condition.

Congenital ichthyosis: mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin disorders. Several mutant genes have been identified in ARCI, but the association between genotype and phenotype is poorly understood. METHODS: To investigate genotype-phenotype correlations in ARCI, we selected 27 patients from 18 families with specific ultrastructural features of the epidermis. The characteristic findings using electron microscopy (EM) were abnormal lamellar bodies and elongated membranes in the stratum granulosum, classified as ARCI EM type III. DNA samples from a subset of affected individuals were screened for homozygous genomic regions, and a candidate gene region was identified on chromosome 5q33. The region coincides with the ichthyin gene, previously reported as mutated in ARCI. RESULTS: Mutation screening of ichthyin revealed missense or splice-site mutations in affected members from 16 of 18 (89%) families with characteristics of ARCI EM type III. In a control group of 18 patients with ARCI without EM findings consistent with type III, we identified one patient homozygous for a missense mutation in ichthyin. DISCUSSION: Our findings indicate a strong association between ultrastructural abnormalities in the granular layer of epidermis and ichthyin mutations. The results also suggest that EM provides a tool for specific diagnosis in a genetically homogenous subgroup of patients with ARCI.

Assignment of the gene locus for severe congenital neutropenia to chromosome 1q22 in the original Kostmann family from Northern Sweden.

Autosomal recessive severe congenital neutropenia (SCN) or Kostmann syndrome is characterised by reduced neutrophil counts and subsequent recurrent bacterial infections. The disease was originally described in a large consanguineous pedigree from Northern Sweden. A genome-wide autozygosity scan was initiated on samples from four individuals in the original pedigree using high density single nucleotide polymorphism (SNP) genotyping arrays in order to map the disease locus. Thirty candidate regions were identified and the ascertainment of samples from two additional patients confirmed a single haplotype with significant association to the disorder (p<0.01) on chromosome 1q22. One affected individual from the original Kostmann pedigree was confirmed as a phenocopy. The minimal haplotype shared by affected individuals spans a candidate region of 1.2 Mb, containing several potential candidate genes.

Constitutional downregulation of SEMA5A expression in autism.

There is strong evidence for the importance of genetic factors in idiopathic autism. The results from independent twin and family studies suggest that the disorder is caused by the action of several genes, possibly acting epistatically. We have used cDNA microarray technology for the identification of constitutional changes in the gene expression profile associated with idiopathic autism. Samples were obtained and analyzed from 6 affected subjects belonging to multiplex autism families and from 6 healthy controls. We assessed the expression levels for approximately 7,700 genes by cDNA microarrays using mRNA derived from Epstein-Barr virus-transformed B lymphocytes. The microarray data were analyzed in order to identify up- or downregulation of specific genes. A common pattern with nine downregulated genes was identified among samples derived from individuals with autism when compared to controls. Four of these nine genes encode proteins involved in biological processes associated with brain function or the immune system, and are consequently considered as candidates for genes associated with autism. Quantitative real-time PCR confirms the downregulation of the gene encoding SEMA5A, a protein involved in axonal guidance. Epstein-Barr virus should be considered as a possible source for altered expression, but our consistent results make us suggest SEMA5A as a candidate gene in the etiology of idiopathic autism.

A founder mutation for ichthyosis prematurity syndrome restricted to 76 kb by haplotype association.

Autosomal recessive congenital ichthyosis (ARCI) is a group of keratinisation disorders that includes the ichthyosis prematurity syndrome (IPS). IPS is rare and almost exclusively present in a restricted region in the middle of Norway and Sweden, which indicates a founder effect for the disorder. We recently reported linkage of IPS to chromosome 9q34, and we present here the subsequent fine-mapping of this region with known and novel microsatellite markers as well as single nucleotide polymorphisms (SNPs). Allelic association, evaluated with Fisher's exact test and P (excess), was used to refine the IPS haplotype to approximately 1.6 Mb. On the basis of the average length of the haplotype in IPS patients, we calculated the age of a founder mutation to approximately 1,900 years. The IPS haplotype contains a core region of 76 kb consisting of four marker alleles shared by 97.7% of the chromosomes associated with IPS. This region spans four known genes, all of which are expressed in mature epidermal cells. We present the results from the analysis of these four genes and their corresponding transcripts in normal and patient-derived samples.

Erythropoiesis in the Rps19 disrupted mouse: Analysis of erythropoietin response and biochemical markers for Diamond-Blackfan anemia.

The human ribosomal protein S19 gene (RPS19) is mutated in approximately 20% of patients with Diamond-Blackfan anemia (DBA), a congenital disease with a specific defect in erythropoiesis. The clinical expression of DBA is highly variable, and subclinical phenotypes may be revealed by elevated erythrocyte deaminase (eADA) activity only. In mice, complete loss of Rps19 results in early embryonic lethality whereas Rps19+/- mice are viable and without major abnormalities including the hematopoietic system. We have performed a detailed analysis of the Rps19+/- mice. We estimated the Rps19 levels in hematopoietic tissues and we analyzed erythrocyte deaminase activity and globin isoforms which are used as markers for DBA. The effect of a disrupted Rps19 allele on a different genetic background was investigated as well as the response to erythropoietin (EPO). From our results, we argue that the loss of one Rps19 allele in mice is fully compensated for at the transcriptional level with preservation of erythropoiesis.

Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH.

BACKGROUND: Segmental duplications flanking the neurofibromatosis type 1 (NF1) gene locus on 17q11 mediate most gene deletions in NF1 patients. However, the large size of the gene and the complexity of the locus architecture pose difficulties in deletion analysis. We report the construction and application of the first NF1 locus specific microarray, covering 2.24 Mb of 17q11, using a non-redundant approach for array design. The average resolution of analysis for the array is approximately 12 kb per measurement point with an increased average resolution of 6.4 kb for the NF1 gene. METHODS: We performed a comprehensive array-CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. The typical deletion was identified in 26 cases, whereas 13 samples showed atypical deletion profiles. RESULTS: The size of the atypical deletions, contained within the segment covered by the array, ranged from 6 kb to 1.6 Mb and their breakpoints could be accurately determined. Moreover, 10 atypical deletions were observed to share a common breakpoint either on the proximal or distal end of the deletion. The deletions identified by array-CGH were independently confirmed using multiplex ligation-dependent probe amplification. Bioinformatic analysis of the entire locus identified 33 segmental duplications. CONCLUSIONS: We show that at least one of these segmental duplications, which borders the proximal breakpoint located within the NF1 intron 1 in five atypical deletions, might represent a novel hot spot for deletions. Our array constitutes a novel and reliable tool offering significantly improved diagnostics for this common disorder.

Depression in relation to age and gender in the general population: the Nord-Trøndelag Health Study (HUNT).

OBJECTIVE: Previous sample studies of depression have shown a higher prevalence of depression in women, and an inconsistent relation to age has been found for both genders. The aim of the present study was to investigate depression in relation to gender and age in the general adult population. METHOD: Of the total population of 92,100 individuals aged 20-89 years and living in Nord-Trøndelag county of Norway, 62,344 (67.7%) filled in valid ratings of depression on the Hospital Anxiety and Depression Scale (HADS). RESULTS: Minimal gender difference was found in dimensional depression scores and in prevalence rates of depression. Both these measures were found to increase continuously with age in both genders. CONCLUSION: Our results of this population-based study differ from most sample studies reported, and these discrepancies are discussed with focus on study design, self-rating, and the concept of depression covered by HADS.

Herbs and supplements in dialysis patients: panacea or poison?

The safety of herbal remedies and supplement use is of particular concern in patients with renal disease, and reliable information is not always easy to find. Predialysis patients may be drawn to complementary and alternative medicine (CAM) because they believe it can help prevent the progression of their renal disease. The purpose of this series of articles on alternative medicine for nephrologists is to address concerns and issues specific to CAM use in dialysis patients and to provide a guide to reliable sources of information. This introductory article emphasizes safety issues with a focus primarily on herbal medicine. Lack of regulation means that patients may not actually be taking what they think they are. Independent laboratory analyses have shown a lack of stated label ingredients and many instances of supplements and traditional remedies being contaminated with pesticides, poisonous plants, heavy metals, or conventional drugs. While certain supplements are always unsafe (carcinogenic, hepatotoxic, glandular extracts), others are specifically contraindicated in renal disease. Supplement use may be especially hazardous in renal disease because of unpredictable pharmacokinetics, drug interactions, negative effects on kidney function, nephrotoxicity, hemodynamic alterations, unpredictable effects on blood pressure or blood glucose, or potentiation of electrolyte abnormalities. There are no data on potential dialyzability of either active compounds, or their potentially active or toxic metabolites. Many supplements contain metal ions and other minerals. Transplant recipients are also at risk from potential unpredictable effects on immune function. Recommendations and information resources are listed.