CT virtual bronchoscopy of simulated endobronchial lesions: effect of scanning, reconstruction, and display settings and potential pitfalls.
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Bronchial Diseases↗
Biomedical subjects
D J Shaw
Publications and source records attributed to D J Shaw.
Development of immunity to Mecistocirrus digitatus (Nematoda: Trichostrongylidae) in calves.
The importance of the third (L3), fourth (L4) and adult stages of Mecistocirrus digitatus in inducing resistance to reinfection was examined. Three groups of 5 calves (A, B, C) were immunized for 2 consecutive days with a daily dose of 20,000 M. digitatus infectious larvae. Group A was treated with ivermectin 7 days post-infection (exposed to L3), group B was treated after 26 days (exposed to L3 and L4) and group C after 60 days (exposed to L3, L4 and adults). Thirty days posttreatment, animals were challenged with 30,000 M. digitatus L3. Five previously uninfected control animals (group D) also received 30,000 L3. All animals were necropsied 75 days post-challenge. Increases in exposure to the immunizing infection resulted in significant increases in the pre-patent period post-challenge; 54 days in the controls, compared with 63, 70 and 72 days for groups A, B and C, respectively. Only adult worms were recovered at necropsy, and the mean number of worms significantly increased with increasing exposure to the immunizing infection: 355 in the controls, compared to 481, 937 and 1174 in groups A, B and C, respectively. No significant changes in worm length were observed. Infection with M. digitatus significantly affects a subsequent challenge infection--stimulation of the immune system by exposure to L3 extends the pre-patent period, and suppression by later stages (L4, adult) leads to higher worm burdens.
Abomasum↗
A Candida albicans genome project: cosmid contigs, physical mapping, and gene isolation.
A new project to map the genome of the pathogenic fungus, Candida albicans, has been started. The entire genome was cloned as 5088 cosmids, stored in individual microtiter plate wells. DNA was prepared and fingerprinted using restriction digestion, fluorescent labeling, and analysis on an ABI sequencer. These data are being used to construct contigs of the genome. Simultaneously, a DNA pooling system has been set up, suitable for PCR-based isolation of cosmids containing any known gene. Ultimately, these approaches will lead to the creation of a physically based map of the C. albicans genome, providing the means to localize precisely all the genes, act as a substrate for genome sequencing projects, and provide probes for future studies of genome rearrangement and comparative genomics.
Candida albicans↗
The presence of an early L4 population in relation to the acquired resistance of calves naturally infected with Ostertagia ostertagi.
The aim of the present study was to determine if the presence of inhibited L4 Ostertagia ostertagi populations during the housing period influenced the level of acquired immunity in calves at the start of the second grazing season. Four groups (A-D) of first season grazing calves were turned out onto a heavily infected pasture for five months, while the fifth group (E) was kept as uninfected controls. At housing all group A calves were necropsied for worm counts. A mean total of 78915 Ostertagia worms were found, of which 85% were in the early L4 stage. The calves of group C were dewormed with ivermectin at housing, while groups B and D remained untreated. After the calves were housed, egg counts, pepsinogen and antibody levels all declined in groups B, C and D, but during the second half of the housing period pepsinogen and antibody levels increased again in groups B and D. The effect of housing on the resident worm population was evaluated by slaughtering all group B calves for worm counts at the end of the housing period. A mean burden of 57,950 Ostertagia was present, with 78% as early L4 larvae. The remaining three groups (C, D and E) were treated with oxfendazole and turned out on the same pasture as the previous year for a challenge period of four weeks. In the control calves (group E) the egg output rose steeply, while egg counts remained low in groups C and D. In addition the worm burdens of the previously infected groups C and D were significantly reduced (75-90%), and the percentage of inhibited L4 larvae was significantly increased compared to the control group E. No significant difference was observed between the calves that were treated at housing (group C) and the untreated animals of group D. It was concluded that the continued presence of an inhibited L4 population during housing was not essential for maintenance of immunity.
Abattoirs↗
Gastrointestinal nematode infections of first-season grazing calves in Belgium: general patterns and the effect of chemoprophylaxis.
Comparative analyses of the patterns of gastrointestinal nematode infections of first-grazing season cattle in Belgium are presented. The analysis involves 17 studies covering a 10 year period on 13 different farms in Flanders, Belgium. In all studies the calves were divided into an untreated control group, and one or two groups treated with chemoprophylactic systems. Two general infection levels emerged-'sub-clinical' (14 studies) and 'clinical' (three studies). The 'sub-clinical' infections were characterised by no clinical signs of parasitic gastroenteritis in the untreated control groups. Mean faecal egg counts remained low (less than 200), maximum pepsinogen levels only reached about 3500 mU tyrosine, and very small reductions in overall daily weight gain were observed compared with calves given chemoprophylaxis (less than 40 g day-1). Based on these results, on these 'sub-clinical' farms, chemoprophylaxis may not have been needed. In contrast, multiple salvage treatments of the control calf groups were required in the 'clinical' infections. Even with these salvage treatments mean faecal egg counts were high (more than 300), maximum pepsinogen levels were over 5500 mU tyrosine and there was a very large reduction in overall daily weight gain (more than 300 g day-1). However, it was not possible to predict either at turnout, or during the first month afterwards whether an infection on a particular farm would develop into a 'clinical' infestation. With the present data this prediction was possible from 8 weeks (Day 56) onwards, based on faecal egg counts and pasture larval contamination. It was also possible to predict using serum pepsinogen levels on Day 84. Therefore, one possible strategy for the effective control of gastrointestinal nematode infections of calves in temperate regions would be to evaluate faecal egg counts 2 months after turnout, and then only start treatment (i.e. metaphylaxis) if required.
Animals↗
Pathophysiological aspects of Mecistocirrus digitatus (Nematoda: Trichostrongylidae) infection in calves.
Three groups of four calves were experimentally infected with infectious larvae of Mecistocirrus digitatus. One group received a trickle infection of 5000 L3 per day for 8 days, the other two groups received a single infection of 5000 and 40,000 L3, respectively. All animals were necropsied 120 days after infection. Prepatent periods varied between 61 and 79 days, and maximal faecal egg output was reached between 80 and 100 days after infection. Repeated infections were not additive and worm counts at 120 days after infection varied between 100 and 440 in the first two groups and between 120 and 1700 in the last group. There was no significant difference in worm counts between the different infection regimes. However, there was a significant positive relationship between worm burden and faecal egg counts. In addition, there were significant negative relationships between worm burden and packed cell volume, and weight gain. The relative decreases in packed cell volume and weight gain emerged 70-80 days after infection. Serum pepsinogen levels were significantly elevated by the end of the trial, but the observed positive relationship between worm burden and pepsinogen was not significant. An enzyme immunoassay based on crude adult antigen was able to detect M. digitatus infection at 90 and 100 days after infection, but again there was no significant association between worm burden and antibody levels. Therefore, anaemia and a reduction in weight gain caused by the haematophagous activity of adult stages seem to be the most important pathogenic effects of M. digitatus infection in calves.
Animals↗
Lack of association between schizophrenia and a polymorphism close to the cytosolic phospholipase A2 gene.
Biochemical studies have shown that a proportion of schizophrenics have an abnormal fatty acid composition in their red blood-cell membrane phospholipids and it has been suggested that this might be due to altered levels of the enzyme phospholipase A2 (PLA2). A recent report indicated that there was an association between schizophrenia and alleles of a poly-A repeat polymorphism close to the 5' end of the PLA2 gene. We report the analysis of this polymorphism in a series of 58 schizophrenic patients and 56 controls and find no evidence for allelic association.
Alleles↗
Patterns of macroparasite abundance and aggregation in wildlife populations: a quantitative review.
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Animals↗
Molecular basis of neurofibromatosis type 1 (NF1): mutation analysis and polymorphisms in the NF1 gene.
Neurobromatosis type 1 (NF1) is one of the commonest genetic disorders in humans. The gene for NF1 was cloned in 1990. The protein encoded by the gene (neurofibromin) has extensive sequence homology with GTPase-activating protein (GAP). Despite screening the whole coding region of the gene for large and medium size rearrangements and approximately 40% of the coding region of the gene for small alterations, only 45 germ-line mutations have been reported in more than 500 unrelated patients. Of these, 25 mutations involve small changes in the gene, of which 17 (68%) result in the formation of an inappropriate stop codon. A "hot spot" for mutations has not been identified. The high mutation rate at this locus and the general difficulty in identifying mutations are discussed. A complete understanding of the structure and function of the NF1 gene awaits further detailed studies of both naturally occurring and in vitro-generated mutations.
Genes, Neurofibromatosis 1↗
Molecular analysis and clinical correlations of the Huntington's disease mutation.
The genetic mutation underlying Huntington's disease (HD) has been identified as an expansion and instability of a specific CAG repeat sequence in a gene (IT15) on chromosome 4. We have investigated the relation of the phenotype of HD to this molecular defect and assessed the feasibility of HD mutation analysis in diagnosis and prediction. Analysis of DNA from 449 HD patients (351 familial and 98 apparently isolated cases) revealed the mutation in more than 95% of patients from both groups. No molecular difference was found between patients presenting with psychiatric symptoms and those in whom chorea or other motor defects were the principal features; additionally, there was a wide range of age at onset for any specific repeat number, though the small group with juvenile onset and presenting with rigidity showed the largest expansions. The findings suggest that molecular analysis will be an accurate and specific diagnostic test for HD and valuable in presymptomatic detection in individuals at risk. However, such testing will require considerable caution to avoid serious difficulties; the well-established guidelines developed for the use of linked markers in relation to the prediction of HD should continue to be followed, though they will require reassessment in relation to use in diagnosis.
Adult↗
Relaxant effects of the potassium channel activators BRL 38227 and pinacidil on guinea-pig and human airway smooth muscle, and blockade of their effects by glibenclamide and BRL 31660.
The airways relaxant effects and mechanism of action of the potassium channel activators BRL 38227 and pinacidil have been compared in guinea-pig and human airways. BRL 38227 was a potent relaxant in guinea-pig isolated trachealis (IC50 = 4.9 x 10(-7) M against spontaneous tone) and human isolated bronchi (IC50 = 4.75 x 10(-7) M against histamine-induced tone) and was eight- and six-fold more potent respectively than pinacidil. The relaxant effects of both compounds were shown to be markedly attenuated by glibenclamide (10(-5) M) and BRL 31660 (10(-5) M), with the nature of the blockade being species/tissue dependent. Glibenclamide (20 mg/kg iv) also inhibited the protective effects of BRL 38227 (50 micrograms/kg iv) and pinacidil (500 micrograms/kg iv) on histamine-induced changes in airways resistance and dynamic compliance in the anaesthetized guinea-pig, although the effects were short-lived. That both BRL 38227 and pinacidil owed their relaxant effects to potassium channel activation was supported by their ability to stimulate 42/43K efflux from guinea-pig trachealis preloaded with the radiotracer at concentrations of 10(-7) - 10(-5) M and 10(-5) M respectively. Pretreatment with either glibenclamide (10(-5) M) or BRL 31660 (10(-5) M) ablated the response to both compounds. These studies show that two mechanistically distinct potassium channel blockers, glibenclamide and BRL 31660, do not substantially differentiate between the actions of BRL 38227 and pinacidil, although differences do occur, particularly at high concentrations in vitro.
Animals↗
Genomic organization and transcriptional units at the myotonic dystrophy locus.
The genomic structure and apparently complete coding sequence of the myotonic dystrophy protein kinase gene have been determined. The gene contains 15 exons distributed over about 13 kb of genomic DNA. It codes for a protein of 624 amino acids with an N-terminal domain highly homologous to cAMP-dependent serine-threonine protein kinases, an intermediate domain with a high alpha-helical content and weak similarity to various filamentous proteins, and a hydrophobic C-terminal segment. Located in close proximity is a second gene, coding for a transcript of about 3 kb, that is homologous to the gene DMR-N9 in the corresponding mouse locus, but has no homologies to other known genes or proteins. Strong expression of the latter gene in brain suggests that it may have a role in the development of mental symptoms in severe cases of the disease.
Amino Acid Sequence↗
Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease.
The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene in 440 Huntington's disease patients and 360 normal controls reveals a range of 30-70 repeats in affected individuals and 9-34 in normals. We find significant negative correlations between the number of repeats on the HD chromosome and age at onset, regardless of sex of the transmitting parent, and between the number of repeats on the normal paternal allele and age at onset in individuals with maternally transmitted disease. This effect of the normal paternal allele may account for the weaker age at onset correlation between affected sib pairs with disease of maternal as opposed to paternal origin and suggests that normal gene function varies because of the size of the repeat in the normal range and a sex-specific modifying effect.
Adolescent↗
Cataract and myotonic dystrophy: the role of molecular diagnosis.
Myotonic dystrophy (dystrophia myotonica), the commonest and most variable of the muscular dystrophies of adult life, has long been known to be associated with cataract, while slit-lamp examination for specific lens opacities has been one of the principal methods of presymptomatic detection of gene carriers. The recent discovery that the myotonic dystrophy mutation is an unstable DNA sequence, composed of varying numbers of CTG triplet repeats, now allows a specific molecular test for this disorder, as well as explaining the phenomenon of anticipation. A series of case reports is presented to illustrate the important practical applications of this development in relation to ophthalmic aspects of the disorder. Reassessment of the specificity of the ophthalmic changes may be required and it will be important for molecular analysis to be used alongside ophthalmic studies, when determining whether family members carry the mutation for myotonic dystrophy.
Adult↗
Identification of an expanded CAG repeat in the Huntington's disease gene (IT15) in a family reported to have benign hereditary chorea.
Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by the onset of non-progressive chorea in childhood and the absence of cognitive impairment. Using primers flanking the (CAG)n repeat in IT15, expansion of which is associated with HD, we have detected an abnormal PCR product in four affected members from one family where affected subjects were originally reported to have BHC. The expanded allele contains 38 repeats in the affected parent and this undergoes further enlargement to 39 and 45 repeats in the two affected offspring. We conclude that the diagnostic criteria for BHC should include a normal result from analysis for the (CAG)n expansion identified in HD.
Adult↗
A study of DNA methylation in myotonic dystrophy.
We have examined the hypothesis that the severe congenital form of myotonic dystrophy is caused by genomic imprinting at the level of differential DNA methylation of maternal and paternal alleles. Probes encompassing the 5', central, and 3' regions of the myotonic dystrophy protein kinase gene were used on blots of blood DNA from congenital and adult onset patients, digested with combinations of methylation sensitive and insensitive restriction enzymes. We observed similar patterns of methylation in each of the different classes of patient, and found no methylation differences between paternally and maternally derived alleles. Within the limitations of the experiment, our results provide no evidence for a role for genomic imprinting in congenital myotonic dystrophy and suggest that the explanation for this form of the disease will be found elsewhere.
Blotting, Southern↗
Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy.
A clinical and molecular analysis of 439 individuals affected with myotonic dystrophy, from 101 kindreds, has shown that the size of the unstable CTG repeat detected in nearly all cases of myotonic dystrophy is related both to age at onset of the disorder and to the severity of the phenotype. The largest repeat sizes (1.5-6.0 kb) are seen in patients with congenital myotonic dystrophy, while the minimally affected patients have repeat sizes of < 0.5 kb. Comparison of parent-child pairs has shown that most offspring have an earlier age at onset and a larger repeat size than their parents, with only 4 of 182 showing a definite decrease in repeat size, accompanied by a later age at onset or less severe phenotype. Increase in repeat size from parent to child is similar for both paternal and maternal transmissions when the increase is expressed as a proportion of the parental repeat size. Analysis of congenitally affected cases shows not only that they have, on average, the largest repeat sizes but also that their mothers have larger mean repeat sizes, supporting previous suggestions that a maternal effect is involved in the pathogenesis of this form of the disorder.
Adolescent↗
Detection of minimum mutation carriers in myotonic dystrophy.
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Carrier State↗