Clinical implementation of polygenic risk scores.
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Journal Article↗
Biomedical subjects
D G Evans
Publications and source records attributed to D G Evans.
Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study.
OBJECTIVE: To determine the effect of treating Helicobacter pylori infection on the recurrence of gastric and duodenal ulcer disease. DESIGN: Follow-up of up to 2 years in patients with healed ulcers who had participated in randomized, controlled trials. SETTING: A Veterans Affairs hospital. PARTICIPANTS: A total of 109 patients infected with H. pylori who had a recently healed duodenal (83 patients) or gastric ulcer (26 patients) as confirmed by endoscopy. INTERVENTION: Patients received ranitidine, 300 mg, or ranitidine plus triple therapy. Triple therapy consisted of tetracycline, 2 g; metronidazole, 750 mg; and bismuth subsalicylate, 5 or 8 tablets (151 mg bismuth per tablet) and was administered for the first 2 weeks of treatment; ranitidine therapy was continued until the ulcer had healed or 16 weeks had elapsed. After ulcer healing, no maintenance antiulcer therapy was given. MEASUREMENTS: Endoscopy to assess ulcer recurrence was done at 3-month intervals or when a patient developed symptoms, for a maximum of 2 years. RESULTS: The probability of recurrence for patients who received triple therapy plus ranitidine was significantly lower than that for patients who received ranitidine alone: for patients with duodenal ulcer, 12% (95% CI, 1% to 24%) compared with 95% (CI, 84% to 100%); for patients with gastric ulcer, 13% (CI, 4% to 31%) compared with 74% (44% to 100%). Fifty percent of patients who received ranitidine alone for healing of duodenal or gastric ulcer had a relapse within 12 weeks of healing. Ulcer recurrence in the triple therapy group was related to the failure to eradicate H. pylori and to the use of nonsteroidal anti-inflammatory drugs. CONCLUSIONS: Eradication of H. pylori infection markedly changes the natural history of peptic ulcer in patients with duodenal or gastric ulcer. Most peptic ulcers associated with H. pylori infection are curable.
Adult↗
Location of gene for Gorlin syndrome.
The Gorlin (naevoid-basal-cell-carcinoma) syndrome is an autosomal dominant disorder characterised by multiple naevoid basal-cell carcinomas, recurrent odontogenic keratocysts, skeletal anomalies, intracranial calcification, and developmental malformations. Characterisation of the gene that causes the syndrome may improve our understanding of the pathogenesis of other basal-cell carcinomas. By linkage analysis, we have shown that the gene is located on chromosome 9q22.3-q31; the most likely position is between DNA markers D9S12 and D9S53. Location of the gene for Gorlin syndrome offers the possibility that DNA markers can be used in risk estimation and presymptomatic identification of patients for surveillance.
Basal Cell Nevus Syndrome↗
Helicobacter pylori in Hispanics: comparison with blacks and whites of similar age and socioeconomic class.
Helicobacter pylori infection is twice as frequent in blacks as in whites. It has been postulated that the apparent increase in susceptibility to H. pylori infection in blacks might have a genetic basis. A case-control seroepidemiologic study of H. pylori prevalence was performed in 108 healthy Hispanic volunteers. Eighty-nine Hispanics were matched (1:1:1) with blacks and whites for age and socioeconomic status. There was an inverse correlation between H. pylori infection and educational level that remained after logistic regression analysis adjusting for age and sex. The adjusted prevalence of H. pylori infection was almost identical in Hispanics and blacks and significantly higher than in whites. Because Hispanics do not constitute a race, the increased prevalence of H. pylori in Hispanics and blacks is unlikely to be genetic. It is speculated that the unrecognized bias is a reflection of a generation cohort phenomenon related to the generational distance from very low socioeconomic status, i.e., the prevalence of H. pylori in Hispanics and blacks is currently lower than that of their parents but higher than that of the white population, which has experienced higher socioeconomic status for several generations.
Adult↗
Selection of the chimpanzee over the baboon as a model for Helicobacter pylori infection.
Baboons (Papio sp.) and chimpanzees (Pan troglodytes) were screened for the presence of Helicobacter pylori. The gastric mucosae of the baboons were colonized by large spiral bacteria. However, a group of adult chimpanzees were identified that were free of spiral gastric bacteria, with five animals being recruited into an H. pylori challenge study. These animals were inoculated orogastrically with one of four strains of H. pylori and followed for up to 26 weeks. H. pylori was established in one of these animals during a primary challenge and in two other animals on secondary challenge. It was shown that the chimpanzee can be infected with H. pylori and that the inflammatory response in these animals mimics that seen in humans. Infection was marked by an antibody response to H. pylori-specific antigens in two animals. It was observed that H. pylori antibody-negative chimpanzees had no apparent infection by H. pylori or related bacteria. Thus serological screening of chimpanzees can be used to identify candidate animals for further evaluation.
Animals↗
Factors influencing the eradication of Helicobacter pylori with triple therapy.
Helicobacter pylori infection has been associated with gastritis, duodenal ulcer, gastric ulcer, and the epidemic form of gastric carcinoma. Eradication of H. pylori infection has proven to be difficult. Recently, combinations of antimicrobial drugs have been shown to eradicate greater than 50% of infections; however, the results have proven variable, and the factors influencing effectiveness of therapy are unclear. In the present study, the effectiveness of a triple therapy for eradication of H. pylori infection was evaluated. Triple therapy consisted of 2 g tetracycline, 750 mg metronidazole, and five or eight tablets of bismuth subsalicylate daily in 93 patients (70 with duodenal ulcer, 17 with gastric ulcer, and 6 with simple H. pylori gastritis). Combinations of a sensitive urea breath test, serology, culture, and histology were used to confirm the presence of infection, eradication, or relapse. Eradication was defined as inability to show H. pylori greater than or equal to 1 month after ending therapy. The overall eradication rate was 87%. The factors evaluated for their effect on predicting eradication included age, gender, type of disease, duration of therapy, amount of bismuth subsalicylate [five or eight Pepto-Bismol tablets daily (Procter & Gamble, Cincinnati, OH)], and compliance with the prescribed medications. Stepwise regression showed that compliance was the most important factor predicting success; the success rate was 96% for patients who took greater than 60% of the prescribed medications and 69% for patients who took less. For those taking greater than 60% of the prescribed therapy, the eradication rates were similar (a) for patients receiving therapy for 14 days or when tetracycline and bismuth subsalicylate were taken for an additional 14 days; (b) for patients with duodenal ulcer, gastric ulcer, and simple H. pylori gastritis; and (c) whether five or eight bismuth subsalicylate tablets were taken. It is concluded that triple therapy is effective for eradication of H. pylori and that future studies need to take compliance into account for comparisons between regimens.
Adult↗
Adherence and internalization of Helicobacter pylori by HEp-2 cells.
Helicobacter pylori colonizes the mucous layer of the stomach and the surface of gastric mucous cells. Although H. pylori is not generally thought of as invasive, it has been observed in the lamina propria and within vacuoles in the cytoplasm of epithelial cells. The authors report that isolates of H. pylori can enter into the cytoplasm of tissue culture epithelial cell lines such as HEp-2 cells. Intracellular uptake of H. pylori by HEp-2 cells is rapid and appears to require both the N-acetylneuraminyllactose-binding adhesin and another factor present only in living bacteria. Uptake of H. pylori was inhibited by ammonium chloride and chloroquine at concentrations that did not effect either adherence or bacterial viability. Dansylcadaverine, an inhibitor of receptor clustering and internalization, also inhibited uptake but not adherence of H. pylori. Uptake was completely inhibited when H. pylori and HEp-2 cells were incubated at 4 degrees C under conditions that did not effect bacterial adherence. Cytochalasin B, an inhibitor of phagocytosis, did not inhibit uptake. It is concluded that H. pylori is internalized either by receptor-mediated endocytosis or by a closely related pathway.
Adrenal Glands↗
Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome.
A predisposing gene for breast and ovarian cancer has recently been mapped to chromosome 17q12-21. If this gene is a tumour suppressor gene, allele losses would be expected in the tumours of affected family members and the losses should affect the wild-type chromosome, reflecting the need for inactivation of the wild-type allele at the predisposing locus. In four multiple case breast-ovarian cancer families, we have found that in each of nine tumours which showed allele losses, the losses were from the wild-type chromosome. This suggests that the putative 'breast-ovarian' cancer gene is indeed a tumour suppressor gene.
Alleles↗
Urease-associated heat shock protein of Helicobacter pylori.
Helicobacter pylori urease is an extracellular, cell-bound enzyme with a molecular weight of approximately 600,000 (600K enzyme) comprising six 66K and six 31K subunits. A 62K protein is closely associated with the H. pylori urease, both in crude preparations and after gel filtration; this protein can be removed from the urease by ion-exchange chromatography without inactivating the enzyme. We purified this urease-associated protein and determined its N-terminal amino acid sequence. The sequence is 80% homologous (identical plus conserved amino acid residues) to the Escherichia coli GroEL heat shock protein (HSP), 75% homologous to the human homolog, and 84% homologous to the HSP homolog found in species of Chlamydia. Thus, the 62K urease-associated protein of H. pylori belongs to the HSP60 family of stress proteins known as chaperonins. Evidently this protein, HSP62, participates in the extracellular assembly and/or protection of the urease against inactivation in the hostile environment of the stomach.
Amino Acid Sequence↗
A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity.
A clinical and genetic study of type 2 neurofibromatosis (NF2) has been carried out in the United Kingdom. Virtually complete ascertainment of cases in the north-west of England was achieved and suggests a population incidence of 1 in 33,000 to 40,000. In the UK as a whole, 150 cases have been identified and been used to study the clinical and genetic features of NF2. The autosomal dominant inheritance of NF2 was confirmed, 49% of cases were assessed as representing new mutations, and the mutation rate was estimated to be 6.5 x 10(-6). Evidence to support a maternal gene effect was found in that age at onset was 18.17 years in 36 maternally inherited cases and 24.5 in 20 paternally inherited cases (p = 0.027). The preponderance of maternally inherited cases was also significant (p = 0.03). Data are presented which suggest that there are two types of NF2, one with later onset and bilateral vestibular schwannomas as the only usual feature, and the other with earlier onset and multiple other tumours. A considerable number of cases did not fall easily into one or other group and other factors such as maternal effect on severity and anticipation need to be considered.
Adolescent↗
A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling.
The major defining features, age at onset of symptoms, and survival in 150 patients with type 2 neurofibromatosis (NF2) have been studied. The mean age at onset was 21.57 years (n = 110) and no cases presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas, and spinal tumours. In 97 cases studied personally by the authors, skin and eye examination were found to be useful to detect early signs of the condition. Examination of the skin is likely to assist in early diagnosis in at least 10% of cases and examination of the eye for a lens opacity or cataract in at least as many again. There are marked interfamilial differences in disease severity and tumour susceptibility. Vestibular schwannomas are not fully penetrant, but the condition is usually expressed in another way. Alteration to the current diagnostic criteria is advocated to cover the lack of provision for new mutations. A screening protocol is proposed and the effect of disease heterogeneity on management is discussed.
Adolescent↗
Ovarian cancer family and prophylactic choices.
A subject from a family with ovarian cancer who has developed bilateral medullary carcinoma of the breast at the age of 40 is presented. The family is consistent with dominant inheritance of ovarian cancer and 12 female family members at 12.5%, 25%, and 50% risk, including our case, have undergone bilateral prophylactic oophorectomy and been given hormone replacement therapy. Despite the risk of further primary tumours of the breast our patient chose to have treatment with wide excision and radiotherapy. The implications for screening, prophylaxis, and hormone replacement therapy for this family are discussed.
Adult↗
Helicobacter pylori infection in dental workers: a seroepidemiology study.
The finding of Helicobacter pylori in dental plaque suggested that dental workers may be at increased risk of acquiring H. pylori infection from occupational exposure. A cross-sectional survey of 239 dental workers from 37 Texas cities (including 89 dentists, 44 dental hygienists, 98 dental assistants, and eight dental students) was conducted. H. pylori infection was determined by the presence of IgG antibodies to H. pylori, using a specific and sensitive ELISA. Participants ranged in age from 19 to 72 yr (mean 34 yr) and the duration of dental practice ranged from 1 to 48 yr (mean 12 yr). Type of dental occupation, duration of practice, type of practice (public or private), instrument used for cleaning teeth (ultrasonic scaler or curette), and prevalence of upper gastrointestinal symptoms were determined by self-administered questionnaires and interviews. Eighty-two percent had no symptoms referable to the upper gastrointestinal tract. The overall prevalence of H. pylori infection was 24%: 17% in dentists, 18% in dental hygienists, 34% in dental assistants, and 25% in dental students. The prevalence increased significantly with age (p < 0.05). The prevalence of H. pylori infection was significantly higher in non-whites, 29 of 63 (46%), than whites, 29 of 176 (16%) (p < 0.001). Logistic regression analysis (dependent variable H. pylori) revealed no significant association between H. pylori infection and the type, duration, or volume of practice, or the type of cleaning instrument used. We conclude that dental workers are not at increased risk to H. pylori infection.
Adult↗
Heterogeneity in genetic conditions.
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Chromosome Mapping↗
A clinical study of type 2 neurofibromatosis.
The clinical features, age at onset of symptoms and survival of 150 patients with type 2 neurofibromatosis were studied. The mean age at onset was 21.57 years (n = 110) and no patients presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas and spinal tumours. In 100 patients studied personally by the authors 44 per cent presented with deafness and this was unilateral in the majority (35/44). Deafness was accompanied by tinnitus in a further 10 per cent and muscle weakness or wasting was the first symptom in 12 per cent. Less common presenting symptoms were seizures (8 per cent), vertigo (8 per cent) numbness and tingling (2 per cent) and blindness (1 per cent). Eleven patients were diagnosed asymptomatically through screening. Café au lait spots occurred in 43 per cent (n = 43) but only one case had six. Skin tumours were detected in 68 per cent (68/100) and 38 per cent (34/90) had an identifiable lens opacity or cataract. The mean age at death in 40 cases was 36.25 years and all but one death was a result of a complication of neurofibromatosis. There are marked inter-family differences in disease severity and tumour susceptibility.
Adult↗
The role of Helicobacter pylori in recurrent, functional abdominal pain in children.
Recurrent abdominal pain in children usually is considered to be functional in nature. We hypothesized that Helicobacter pylori infection might be the etiology of abdominal pain symptoms in some children with presumed functional abdominal pain. Therefore, we studied 20 children with a previous diagnosis of functional abdominal pain, using a 13C-urea breath test and an enzyme-linked immunosorbent assay for antibody to the H. pylori high molecular weight, cell-associated antigens. Two children had evidence of H. pylori infection, and both had clinical histories that suggested an acute H. pylori infection, at the onset of their abdominal pain. Seven children who had abrupt onset of their chronic abdominal symptoms were then identified prospectively. None of these patients had evidence of active H. pylori infection. We conclude that H. pylori infections are not common among children with recurrent abdominal pain, and are not predictable in such children, based on symptom patterns.
Abdominal Pain↗
Chain-of-custody errors can quickly undermine the case in court.
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Humans↗
Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing. A randomized controlled trial.
OBJECTIVE: To determine whether antimicrobial therapy for Helicobacter pylori infection accelerates the healing of duodenal ulcers. DESIGN: Single-blind, randomized, controlled trial. SETTING: Veterans Affairs hospital. PARTICIPANTS: One hundred and five patients with endoscopically verified duodenal ulcers. INTERVENTION: Patients received either ranitidine, 300 mg/d, or ranitidine, 300 mg/d, plus "triple therapy" (2 g/d of tetracycline, 750 mg/d of metronidazole, and 5 or 8 bismuth subsalicylate tablets per day). Triple therapy was administered for only the first 2 weeks of ulcer treatment. MEASUREMENTS: Videoendoscopic assessment of ulcer status was done until ulcer healing was complete. Evaluations were done after 2, 4, 8, 12, and 16 weeks of therapy. MAIN RESULTS: Ulcer healing was more rapid in patients receiving ranitidine plus triple therapy than in patients receiving ranitidine alone (P less than 0.01). The cumulative percentages of patients with healed ulcers in the group receiving ranitidine plus triple therapy and in the group receiving ranitidine alone were as follows: 37% and 18% after week 2; 74% and 53% after week 4; 84% and 68% after week 8; 96% and 80% after week 12; and 98% and 84% after week 16. CONCLUSION: Combined therapy with anti-H. pylori agents and ranitidine was superior to ranitidine alone for duodenal ulcer healing. Our results indicate that H. pylori plays a role in duodenal ulcer disease.
Adult↗