Biomedical subjects

J Holton

Publications and source records attributed to J Holton.

At least 19 recordsLinked to original sources

PubMed2006

Genetic alterations of the BRI2 gene: familial British and Danish dementias.

Classic arguments sustaining the importance of amyloid in the pathogenesis of dementia are usually centered on amyloid beta (Abeta) and its role in neuronal loss characteristic of Alzheimer disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias, share many aspects of Alzheimer disease, including the presence of neurofibrillary tangles, parenchymal pre-amyloid and amyloid deposits, cerebral amyloid angiopathy, and a widespread inflammatory response. Both early-onset conditions are linked to specific mutations in the BRI2 gene, causing the generation of longer-than-normal protein products and the release of 2 de novo created peptides ABri and ADan, the main components of amyloid fibrils in these inherited dementias. Although the molecular mechanisms and signal transduction pathways elicited by the amyloid deposits and their relation to cognitive impairment remain to be clarified, new evidence indicates that, independent of the differences in their primary structures, Abeta, ABri, and ADan subunits are able to form morphologically compatible ion-channel-like structures and elicit single ion-channel currents in reconstituted lipid membranes. These findings reaffirm the notion that non-Abeta amyloidosis constitute suitable alternative models to study the role of amyloid deposition in the mechanism of neuronal cell death.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Chromosome 13 dementias.

The importance of cerebral amyloid deposition in the mechanism of neurodegeneration is still debatable. Classic arguments are usually centered on amyloid beta(Abeta) and its role in the neuronal loss characteristic of Alzheimer's disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias (FBD and FDD), share many aspects of Alzheimer's disease, including the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy and a variety of amyloid-associated proteins and inflammatory components. Both early-onset conditions are linked to specific mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. Furin-like processing of these longer precursors releases two de novo-created peptides, ABri and ADan, which deposit as amyloid fibrils in FBD and FDD, respectively. Due to the similar pathology generated by completely unrelated amyloid subunits, FBD and FDD, collectively referred to as chromosome 13 dementias, constitute alternative models for studying the role of amyloid deposition in the mechanism of neuronal cell death.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Helicobacter pylori infection: anything new should we know?

Over the past year, 2003-4, there have been a number of studies consolidating previous work in relation to pathogenesis of disease, diagnosis and management of Helicobacter pylori. Studies into the pathogenesis of disease have identified the main adhesin of H. pylori as an important virulence marker and as a potential target for therapy. Molecular investigations of both the strain and host variations have identified the action of several of the virulence factors, e.g. cagA, vacA, on disrupting host cell signalling and the consequences in respect of the release of chemokines from the damaged gastric epithelium and the effect on apoptosis. Over the past year, there have been further diagnostic kits developed based on modifications of current technology. Two promising areas of research for diagnosis are the use of host/strain genome polymorphisms as a means of identifying high-risk patients who may develop severe disease and the use of proteomics to identify potential antigens of diagnostic (or therapeutic) use. The three main antibiotics that are used in first-line eradication regimens are clarithromycin, metronidazole and amoxycillin. Of these, metronidazole has the highest prevalence of resistance, followed by clarithromycin; amoxycillin resistance is only rarely reported. The decreasing success of current first-line therapy is the driving force for the development of new antibiotic combinations and a search for novel sources for chemotherapeutic agents and novel therapeutic targets.

Adhesins, Bacterial↗

PubMed2003

Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset PSP.

The authors describe a case of clinically diagnosed young onset progressive supranuclear palsy (PSP) with symptom onset at 40 years of age and no family history of neurodegenerative disease. There was no history of falls during the first year of symptoms. Genetic analysis identified this patient as having a tau exon 10 +16 mutation (MAPT, IVS10, C-U, +16). Neuropathologic examination confirmed the genetic diagnosis of frontotemporal dementia. An age at onset younger than 50 years combined with the absence of early falls may indicate the possibility of a tau mutation in clinically diagnosed PSP.

Adult↗

PubMed2003

Review article: diagnosis and treatment of Helicobacter: a 2002 updated review.

The year 2002 saw advances on many fronts in the study of Helicobacter and gastroduodenal disease. Several studies have confirmed endoscopy as a valuable management procedure with confirmation of the diagnostic utility of the rapid urease test and the description of a new formulation of the test, which is more rapid in giving a result. Serology has been re-confirmed as a useful investigation in selected populations. Some commercial kits for near patient testing have also been assessed and although generally regarded as less accurate than laboratory based tests some have shown acceptable accuracy. The recent exciting development in diagnostic serology is the availability of the faecal antigen test; further studies have confirmed its usefulness as recommended screening tests. There have been several studies demonstrating that a test and treat policy has a significant patient benefit, both economic and medical, although there is some doubt if eradication of Helicobacter leads to regression of atrophy and metaplasia. However, in low Helicobacter-prevalence areas the test and treat policy is being challenged as an effective management strategy. Further studies have shown that compliance with treatment regimens is an important determinant of successful eradication. Finally several new eradication regimens have been reported particularly for use in patients who have had previous unsuccessful eradication attempts.

Biopsy↗

PubMed2003

Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies.

Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in the tauopathies, which include Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Tau isoform composition and cellular and regional distribution as well as morphology of these inclusions vary in each disorder. Recently, several pathological missense and exon 10 splice-donor site mutations of the tau gene were identified in FTDP-17. Exon 10 codes for the second of four microtubule-binding repeat domains. The splice-site mutations result in increased inclusion of exon 10 which causes a relative increase in tau isoforms containing four microtubule-binding repeat domains over those containing three repeat domains. This could be a central aetiological mechanism in FTDP-17 and, perhaps, other related tauopathies. We have investigated changes in the ratio and distribution of three-repeat and four-repeat tau in the different tauopathies as a basis of the phenotypic range of these disorders and the selective vulnerability of different subsets of neurones. In this study, we have developed two monoclonal antibodies, RD3 and RD4 that effectively distinguish these closely related tau isoforms. These new isoform-specific antibodies are useful tools for analysing tau isoform expression and distribution as well as pathological changes in the human brain.

Animals↗

PubMed2003

Effect of Helicobacter pylori eradication on development of dyspeptic and reflux disease in healthy asymptomatic subjects.

BACKGROUND AND AIM: There are few data on the course of Helicobacter pylori infection in asymptomatic subjects. The aim of this study was to assess the effect of eradication therapy on the development of dyspeptic and gastro-oesophageal reflux disease in a cohort of asymptomatic individuals observed over a prolonged period. METHODS: A total of 169 blood donors infected with H pylori who had volunteered for studies on eradication in 1990 formed the cohort. To be included in this cohort subjects had to have no symptoms, as determined by a validated symptom questionnaire at the baseline visit. Eighty eight subjects were infected with H pylori while 81 had successfully undergone eradication therapy. Subjects were followed up (annually) using the same symptom questionnaire and in 2000 they underwent repeat endoscopy. RESULTS: Thirteen subjects developed symptoms during follow up. The incidence of symptoms in H pylori positive subjects was 1.893/100 person-years of follow up and in H pylori negative individuals 0.163/100 person-years of follow up. H pylori infected subjects were significantly more likely to develop symptoms (log rank test, p=0.003) as well as those infected with CagA positive strains (log rank test, p=0.017). The development of symptomatic gastro-oesophageal reflux disease was no different in individuals with and without eradication (odds ratio 0.57 (95% confidence interval 0.26-1.24); p=0.163). CONCLUSIONS: H pylori eradication prevents the development of dyspeptic symptoms and peptic ulcer disease in healthy asymptomatic blood donors and is not associated with an increase in the incidence of symptomatic gastro-oesophageal reflux disease.

Antibodies, Bacterial↗

PubMed2002

Review article: Helicobacter pylori infection from pathogenesis to treatment--a critical reappraisal.

The main areas of this review are Helicobacter pylori and disease pathogenesis; the relationship of H. pylori to lower gastrointestinal diseases, liver disease and extra-gastrointestinal conditions; the relationship of H. pylori to gastro-oesophageal reflux disease; infection in the very young and very old; diagnostic techniques; and management of H. pylori infections with particular emphasis on eradication regimens and antibiotic resistance.

Adult↗

PubMed2002

Helicobacter pylori infection, anti-cagA antibodies and peptic ulcer: a case-control study in Italy.

AIM: To evaluate the association between infection with specific strains of Helicobacter pylori and peptic ulcer in patients referred for upper gastrointestinal endoscopy. METHODS: One thousand, six hundred and twenty-six consecutive dyspeptic patients, referred to one Endoscopy Unit in Bologna, Italy, were enrolled. For each participant, a blood sample was obtained for the measurement of distinct immunoglobulin G antibodies against H. pylori lysate and cytotoxin associated gene A (cagA). A case-control study included the whole series: patients diagnosed with duodenal (n=275) or gastric (n=71) ulcer were identified and independently compared with controls with non-ulcer dyspepsia (n=1280). RESULTS: H. pylori seroprevalence (at least one positive marker) was associated with increasing age, male sex and a diagnosis of peptic ulcer. This association was stronger with duodenal ulcer (multivariate odds ratio (OR), 5.2; 95% confidence interval (CI), 3.5-7.9) than with gastric ulcer (OR, 2.3; 95% CI, 1.2-4.4). Further analyses showed that H. pylori lysate+/cagA- subjects had a moderately increased risk of duodenal (OR, 3.2), but not gastric (OR, 1.1), ulcer. When cagA+ subjects were separately compared with seronegative patients, there was a six-fold increased risk for duodenal ulcer and a three-fold increased risk for gastric ulcer. CONCLUSIONS: A strong positive association between infection with a cagA+ H. pylori strain and the presence of peptic disease was found. The seroprevalence of anti-cagA antibodies among patients with non-ulcer dyspepsia is so high (41%) to preclude its use as a pre-endoscopic screening test.

Adult↗

PubMed2002

Possible absence of Helicobacter pylori in the early stages of duodenal ulceration.

BACKGROUND: Helicobacter pylori is thought to be a cause of duodenal ulceration, but there is some evidence that it is found less often in early than in later disease. AIM: To assess the presence of H. pylori in patients undergoing endoscopy for dyspepsia, with respect to their duration of symptoms. DESIGN: Retrospective case note review. METHODS: Patients were categorized as having a history greater or less than 6 months, and as H. pylori-positive or -negative, using biopsy rapid urease, culture and PCR tests. RESULTS: Thirty-two duodenal ulcer patients with a history >6 months were all H. pylori-positive according to the PCR test; the five with a shorter history were H. pylori-negative. No patient H. pylori-negative by PCR was positive by the other tests. DISCUSSION: H. pylori was (at least) less commonly present before 6 months. It is possible that H. pylori, although nearly always present after 6 months, is not present at the onset of the disease. Confirmation of this finding would imply that infection with the organism is not the cause of duodenal ulceration, but a factor producing recurrence and chronicity.

Duodenal Ulcer↗

PubMed2002

Prevalence of Helicobacter pylori in Sri Lanka as determined by PCR.

Fifty-seven Sinhalese patients were investigated for the presence of Helicobacter pylori by PCR. A prevalence of 70.1%, with 47.5% positive for cagA, was demonstrated. The most common vacA allele was s1am1. There was no significant association between either the s1 allele or the cagA allele and severe gastroduodenal disease. There was an association between the s1 allele and the cagA locus.

Adolescent↗

PubMed2002

Tubular aggregate myopathy with abnormal pupils and skeletal deformities.

A patient is described with a novel syndrome characterised by progressive muscular weakness, contractures, pupillary muscle dysfunction, and skeletal deformity. The main myopathological feature was an abundance of tubular aggregates in both type I and type II muscle fibres. Myopathies in which tubular aggregates are the defining feature are rare and either present with progressive muscle weakness or exercise induced myalgia. Tubular aggregate myopathy with symptomatic smooth muscle dysfunction and skeletal deformities has not been described before.

Abnormalities, Multiple↗

PubMed2001

Systemic amyloid deposits in familial British dementia.

Familial British dementia (FBD) is an early onset inherited disorder that, like familial Alzheimer's disease (FAD), is characterized by progressive dementia, amyloid deposition in the brain, and neurofibrillary degeneration of limbic neurons. The primary structure of the amyloid subunit (ABri) extracted from FBD brain tissues (Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., and Ghiso, J. (1999) Nature 399, 776-781) is entirely different and unrelated to any previously known amyloid protein. Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266. The ABri peptide comprises the 34 C-terminal residues of the mutated precursor ABriPP-277 and is generated via furin-like proteolytic processing. Here we report that carriers of the Stop-to-Arg mutation have a soluble form of the amyloid peptide (sABri) in the circulation with an estimated concentration in the range of 20 ng/ml, several fold higher than that of soluble Abeta. In addition, ABri species identical to those identified in the brain were also found as fibrillar components of amyloid deposits predominantly in the blood vessels of several peripheral tissues, including pancreas and myocardium. We hypothesize that the high concentration of the soluble de novo created amyloidogenic peptide and/or the insufficient tissue clearance are the main causative factors for the formation of amyloid deposits outside the brain. Thus, FBD constitutes the first documented cerebral amyloidosis associated with neurodegeneration and dementia in which the amyloid deposition is also systemic.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Covariance analysis of RNA recognition motifs identifies functionally linked amino acids.

The RNA recognition motif (RRM) is one of the most common eukaryotic protein motifs. RRM sequences form a conserved globular structure known as the RNA-binding domain (RBD) or the ribonucleoprotein domain. Many proteins that contain RRM sequences bind RNA in a sequence-specific manner. To investigate the basis for the RNA-binding specificity of RRMs, we subjected 330 aligned RRM sequences to covariance analysis. The analysis revealed a single network of covariant amino acid pairs comprising the buried core of the RBD and a surface patch. Structural studies have implicated a subset of these residues in RNA binding. The covariance linkages identify a larger set of amino acid residues, including some not directly in contact with bound RNA, that may influence RNA-binding specificity.

Amino Acid Motifs↗

PubMed2001

Review article: the transmission of Helicobacter pylori from stomach to stomach.

The mode of transmission of Helicobacter pylori is largely unknown and is a matter of circumstantial evidence and speculation rather than fact. However, the principle evidence is of two sorts: the epidemiological data, providing evidence of possible risk factors associated with transmission, and the identification of potential sources from which H. pylori could be acquired. Evidence exists for several potential sources of infection and several possible modes of transmission, and it is feasible that the transmission of H. pylori varies according to the cultural and demographic circumstances. However, the most likely recognized source for H. pylori is the human stomach, although it is not known by what route the organism is transmitted to the stomach. Evidence suggests close personal contact is important and that acquisition occurs mainly in childhood. This article reviews the evidence for the source of infection and the route of transmission of H. pylori.

Age Factors↗

PubMed2001

Helicobacter pylori in school children from the Western province of Sri Lanka.

BACKGROUND: Little is known about the prevalence of Helicobacter pylori in Sri Lanka and nothing is known about its prevalence in children. Therefore the prevalence of H. pylori in a group of school children in Sri Lanka was determined. MATERIALS AND METHODS: The presence of H. pylori colonisation was determined by detection of faecal antigen and salivary antibody (IgG) by enzyme immuno assay, in 184 children aged between 5 and 19 years, in the Western Province-Colombo district of Sri Lanka. RESULTS: Overall, only 12/184 (6.5%) had detectable H. pylori antigen in their stools and were considered infected with H. pylori, while 51/184 (27.7%) had H. pylori IgG in saliva. H. pylori salivary IgG declined with age while H. pylori antigen detection increased with age. H. pylori infection, as determined by salivary antibody (66%), was greater in children living in overcrowded conditions, although this was not statistically significant. CONCLUSION: The prevalence of H. pylori among school children in Sri Lanka was 6.5% by detection of faecal antigen and 27.7% by detection of salivary antibody, respectively. Initial infection with H. pylori appeared to occur in early childhood whilst active disease began in late childhood. Overcrowding appears to facilitate the transmission of the organism. Overall the prevalence of H. pylori was low in Sri Lanka compared with other countries in South-east Asia.

Adolescent↗

PubMed2001

PCR primers that can detect low levels of Mycobacterium leprae DNA.

There are several specific PCR-based methods to detect Mycobacterium leprae DNA, but the amplicons are quite large. For example, primers that target the 36-kDa antigen gene and are in common diagnostic use yield a 530-bp product. This may be a disadvantage when examining samples in which the DNA is likely to be damaged and fragmented. Therefore, two sets of M. leprae-specific nested primers were designed, based on existing primer pairs which have been shown to be specific for M. leprae. Primers that targeted the 18-kDa antigen gene gave an outer product of 136 bp and inner product of 110 bp. The primers based on the RLEP repetitive sequence yielded a 129-bp outer product and 99-bp nested product. With dilutions of a standard M. leprae killed whole-cell preparation as the source of DNA, both single-stage and nested PCR were performed after optimisation of the experimental conditions. Compared with the 36-kDa antigen gene primers, the 18-kDa antigen gene outer primers were 100-fold more sensitive and the RLEP outer primers were 1000-fold more sensitive. As an illustration of two possible applications of these new primers, positive results were obtained from three skin slit samples from treated lepromatous leprosy patients and three archaeological samples from human remains showing typical leprosy palaeopathology. It was concluded that these new primers are a useful means of detecting M. leprae DNA which is damaged or present at a very low level.

DNA Primers↗

PubMed2001

Helicobacter pylori infection in an urban African population.

We have studied 221 adults drawn from an impoverished urban population with high human immunodeficiency virus (HIV) seroprevalence (35%) to determine the prevalence of gastroduodenal pathology and its relationship to serological markers of Helicobacter pylori virulence proteins and other potential environmental and immunological determinants of disease including HIV infection. Eighty-one percent were H. pylori seropositive, and 35% were HIV seropositive. Urban upbringing and low CD4 count were associated with a reduced likelihood of H. pylori seropositivity, as was current Ascaris infection, in keeping with recent evidence from an animal model. One hundred ninety-one adults underwent gastroduodenoscopy, and 14 had gastroduodenal pathology. Mucosal lesions were a major cause of abdominal pain in this population. While the majority of patients with gastroduodenal pathology (12 of 14) were seropositive for H. pylori, none were seropositive for HIV. Smoking was associated with increased risk of macroscopic pathology, and a history of Mycobacterium bovis BCG immunization was associated with reduced risk. Antibodies to H. pylori lipopolysaccharide were associated with pathology. HIV infection was associated with protection against mucosal lesions, suggesting that fully functional CD4 lymphocytes may be required for the genesis of gastroduodenal pathology.

Adolescent↗