Biomedical subjects
M Meeks
Publications and source records attributed to M Meeks.
Primary ciliary dyskinesia: age at diagnosis and symptom history.
UNLABELLED: Age at diagnosis and the symptom history of children with primary ciliary dyskinesia (PCD) are described by reviewing the case notes in the paediatric PCD clinic. Mean age at diagnosis was 4.4 y despite a history of neonatal respiratory distress in 37/55 cases, situs inversus in 38/55 cases and early onset troublesome rhinitis in 42/55. CONCLUSION: Diagnosis of PCD is often delayed despite the presence of typical symptoms early in life. The key clinical features of unexplained neonatal respiratory distress, early onset rhinitis, situs inversus and a productive cough are highlighted, which, especially when occurring in combination, makes early referral for specific testing for PCD mandatory.
Axonemal beta heavy chain dynein DNAH9: cDNA sequence, genomic structure, and investigation of its role in primary ciliary dyskinesia.
Dyneins are multisubunit protein complexes that couple ATPase activity with conformational changes. They are involved in the cytoplasmatic movement of organelles (cytoplasmic dyneins) and the bending of cilia and flagella (axonemal dyneins). Here we present the first complete cDNA and genomic sequences of a human axonemal dynein beta heavy chain gene, DNAH9, which maps to 17p12. The 14-kb-long cDNA is divided into 69 exons spread over 390 kb. The cDNA sequence of DNAH9 was determined using a combination of methods including 5' rapid amplification of cDNA ends, RT-PCR, and cDNA library screening. RT-PCR using nasal epithelium and testis RNA revealed several alternatively spliced transcripts. The genomic structure was determined using three overlapping BACs sequenced by the Whitehead Institute/MIT Center for Genome Research. The predicted protein, of 4486 amino acids, is highly homologous to sea urchin axonemal beta heavy chain dyneins (67% identity). It consists of an N-terminal stem and a globular C-terminus containing the four P-loops that constitute the motor domain. Lack of proper ciliary and flagellar movement characterizes primary ciliary dyskinesia (PCD), a genetically heterogeneous autosomal recessive disorder with respiratory tract infections, bronchiectasis, male subfertility, and, in 50% of cases, situs inversus (Kartagener syndrome, KS). Dyneins are excellent candidate genes for PCD and KS because in over 50% of cases the ultrastructural defects of cilia are related to the dynein complex. Genotype analysis was performed in 31 PCD families with two or more affected siblings using a highly informative dinucleotide polymorphism located in intron 26 of DNAH9. Two families with concordant inheritance of DNAH9 alleles in affected individuals were observed. A mutation search was performed in these two "candidate families," but only polymorphic variants were found. In the absence of pathogenic mutations, the DNAH9 gene has been excluded as being responsible for autosomal recessive PCD in these families.
Primary ciliary dyskinesia (PCD).
This article summarizes the current state of the scientific and clinical knowledge that relates to primary ciliary dyskinesia (PCD). Although PCD is a rare disease with a prevalence of 1 in 20,000 it has a well recognized morbidity. It is believed that an accurate diagnosis and the application of appropriate management can significantly reduce this morbidity. The cilia themselves are highly complicated organelles that perform important functions, particularly in the respiratory and reproductive tracts, and they have been the focus of many years of research. Our current knowledge of ciliary function and mucociliary clearance is summarized, and the relationship with laterality defects is discussed. A phenotype resembling PCD is also seen in animal models, and some of these are described before reviewing the clinical aspects of PCD in humans and new developments in the field that may have implications for the future investigation and management of affected individuals.
Primary ciliary dyskinesia: a genome-wide linkage analysis reveals extensive locus heterogeneity.
Primary ciliary dyskinesia (PCD), or immotile cilia syndrome (ICS), is an autosomal recessive disorder affecting ciliary movement with an incidence of 1 in 20000-30000. Dysmotility to complete immotility of cilia results in a multisystem disease of variable severity with recurrent respiratory tract infections leading to bronchiectasis and male subfertility. Ultrastructural defects are present in ciliated mucosa and spermatozoa. Situs inversus (SI) is found in about half of the patients (Kartagener syndrome). We have collected samples from 61 European and North American families with PCD. A genome-wide linkage search was performed in 31 multiplex families (169 individuals including 70 affecteds) using 188 evenly spaced (19cM average interval) polymorphic markers. Both parametric (recessive model) and non-parametric (identity by descent allele sharing) linkage analyses were used. No major locus for the majority of the families was identified, although the sample was powerful enough to detect linkage if 40% of the families were linked to one locus. These results strongly suggest extensive locus heterogeneity. Potential genomic regions harbouring PCD loci were localised on chromosomes 3p, 4q, 5p, 7p, 8q, 10p, 11q, 13q, 15q, 16p, 17q and 19q. Linkage analysis using PCD families with a dynein arm deficiency provided 'suggestive' evidence for linkage to chromosomal regions 8q, 16pter, while analyses using only PCD families with situs inversus resulted in 'suggestive' scores for chromosomes 8q, and 19q.
Use of subjective global assessment to identify nutrition-associated complications and death in geriatric long-term care facility residents.
OBJECTIVE: The primary objective of this study was to assess the use of Subjective Global Assessment to identify nutrition-associated complications and death in a geriatric population. A secondary objective was to evaluate the ability of Subjective Global Assessment to identify geriatric residents of long-term care facilities who were undernourished or at risk for developing undernutrition. METHODS: Fifty-three consecutive residents who were > or = 65 years of age and had been residing in a long-term care facility for < 2 weeks were enrolled in the study. The Subjective Global Assessment Classification technique was performed according to the procedure outlined by Detsky and colleagues. Residents were classified as well-nourished (A), mild/moderately undernourished (B) or severely undernourished (C). In addition, a Subjective Global Assessment Composite Score was derived. Subjective Global Assessment measures were compared with two traditional objective measurements of nutritional status: serum albumin and serum total cholesterol. Outcome measurements of nutrition-associated complications were determined over a 3-month period by recording the incidence of major infections, decubitus ulcers, nutrition-related hospital readmissions, and mortality. RESULTS: Sixteen residents (30.2%) were categorized as Subjective Global Assessment class A, 28 residents (52.8%) were class B, and 9 residents (17%) were class C. A significant association was found between nutritional status as determined by Subjective Global Assessment Composite Score and nutrition-associated complications (p<0.05). Subjective Global Assessment Classification was related to death (p<0.05) with severely undernourished residents having the highest mortality rate. Hypoalbuminemia only demonstrated a significant relationship with nutrition-associated complications (p<0.05), whereas hypocholesterolemia was associated with death (p<0.05). CONCLUSIONS: Subjective Global Assessment of nutritional status appears to be a simple, noninvasive and cost-effective tool for assessing nutritional status of geriatric residents in long-term care facilities. This assessment tool is also beneficial for identifying patients with increased risk of nutrition-associated complications as well as death.
A locus for primary ciliary dyskinesia maps to chromosome 19q.
Primary ciliary dyskinesia is an autosomal recessive condition characterised by chronic sinusitis, bronchiectasis, and subfertility. Situs inversus occurs in 50% of cases (Kartagener syndrome). It has an estimated incidence of 1 in 20 000 live births. The clinical phenotype is caused by defective ciliary function associated with a range of ultrastructural abnormalities including absent dynein arms, absent radial spokes, and disturbed ciliary orientation. The molecular genetic basis is unknown. A genome scan was performed in five Arabic families. Using GENEHUNTER, a maximal multipoint lod score (HLOD) of 4.4 was obtained on chromosome 19q13.3-qter at alpha (proportion of linked families) = 0.7. A 15 cM critical region is defined by recombinations at D19S572 and D19S218. These data provide significant evidence for a PCD locus on chromosome 19q and confirm locus heterogeneity.
No deleterious mutations in the FOXJ1 (alias HFH-4) gene in patients with primary ciliary dyskinesia (PCD).
The transcription factor FOXJ1 (alias HFH-4 or FKHL13) of the winged-helix/forkhead family is expressed in cells with cilia or flagella, and seems to be involved in the regulation of axonemal structural proteins. The knockout mouse Foxj1(-/-) shows abnormalities of organ situs, consistent with random determination of left-right asymmetry, and a complete absence of cilia. The human FOXJ1 gene which maps to chromosome 17q, is thus an excellent candidate gene for Kartagener Syndrome (KS), a subphenotype of Primary Ciliary Dyskinesia (PCD), characterized by bronchiectasis, chronic sinusitis and situs inversus. We have collected samples from 61 PCD families, in 31 of which there are at least two affected individuals. Two families with complete aciliogenesis, and six families, in which the affected members have microsatellite alleles concordant for a locus on distal chromosome 17q, were screened for mutations in the two exons and intron-exon junctions of the FOXJ1 gene. No sequence abnormalities were observed in the DNAs of the affected individuals of the selected families. These results demonstrate that the FOXJ1 gene is not responsible for the PCD/KS phenotype in the families examined.