Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine.

The ability of transient immunosuppression with a combination of a non-depleting anti-CD4 (NDCD4) antibody and cyclosporine (CyA) to abrogate immune reactivity to both adeno-associated viral vector (AAV) and its transgene product was evaluated. This combination of immunosuppressants resulted in a 20-fold reduction in the resulting anti-AAV8 antibody titres, to levels in naïve mice, following intravenous administration of 2 × 10(12) AAV8 vector particles per kg to immunocompetent mice. This allowed efficient transduction upon secondary challenge with vector pseudotyped with the same capsid. Persistent tolerance did not result, however, as an anti-AAV8 antibody response was elicited upon rechallenge with AAV8 without immunosuppression. The route of vector administration, vector dose, AAV serotype or the concomitant administration of adenoviral vector appeared to have little impact on the ability of the NDCD4 antibody and CyA combination to moderate the primary humoral response to AAV capsid proteins. The combination of NDCD4 and CyA also abrogated the humoral response to the transgene product, that otherwise invariably would occur, following intramuscular injection of AAV5, leading to stable transgene expression. These observations could significantly improve the prospects of using rAAV vectors for chronic disorders by allowing for repeated vector administration and avoiding the development of antibodies to the transgene product.

A modified thrombin generation test for the measurement of factor VIII concentrates.

It has been well documented that there is an uncertainty over the true factor (F)VIII level in postinfusion samples due to assay discrepancies. The thrombin generation test (TGT) was used as a potentially more physiological approach to assess and compare FVIII concentrates. FVIII concentrates were added to artificial FVIII-deficient plasma. Thrombin generation was initiated by the addition of FIXa (14 nm), phospholipid and CaCl2. Thrombin was measured by subsampling into fibrinogen, and curves quantified as area under the curve (AUC) and time taken to half-maximum (t(1/2)max). Addition of one plasma-derived concentrate to as little as 0.005 IU mL-1 gave a normal AUC, but prolonged t(1/2)max. Increasing FVIII to 1 IU mL-1 had little effect on AUC, but did reduce the t(1/2)max to 64 s (normal 114 s). A range of plasma-derived and recombinant concentrates were tested at 1 IU mL-1; results were similar, except the B-domain deleted concentrate, which had the most rapid initial rate of thrombin generation (t(1/2)max 48 s, P < 0.05). Two hemophilic plasmas (< 0.01 IU mL-1) produced large amounts of thrombin (AUC 65% and 69%), although t(1/2)max was prolonged. Addition of a FVIII antibody abolished thrombin generation, indicating that these plasmas contained low levels of FVIII. Decreasing the FIXa concentration (0.2 nm) minimized thrombin generation in hemophilic plasma but not in normal plasma. These results indicate that FVIII < 0.01 IU mL-1 can generate significant quantities of thrombin depending upon the amount of FIXa present. The TGT could prove useful for patient monitoring in gene therapy and prophylaxis.

Agreement between medical record data and patients' accounts of their medical history and treatment for dyspepsia.

We examined agreement between data abstracted from medical records and interview data for patients with dyspepsia admitted to hospital for endoscopy, to determine the extent to which health records could be used to validate self-reports of dyspepsia and the management of this condition. Results from the sample of 220 patients showed that there was poor agreement between data sources for information about duration of dyspepsia (k=0.34) and previous barium meal examination (k=0.34). Patients reported significantly longer dyspepsia histories (Wilcoxon sign test Z=4.13, p<0.0001) and significantly more barium meals (sign test Z=8.43, p<0.0001) than were documented in their records. There was also disagreement between data sources regarding the number of drugs taken before and after endoscopy (k=0.28 and k=0.31, respectively). Where there was disagreement for number of drugs there was no significant difference in the direction of the disagreement. There was moderate agreement regarding the name of pre-endoscopy medication (k=0.55) and substantial agreement for the name of medication used post-endoscopy (k=0.62). There was very poor agreement regarding diagnosis. The medical record was the gold standard for this information. Choice of data source, medical records or self-reports, will in many instances provide significantly different results and it is likely that this may also be true for other variables of interest to researchers. Thus in the case where no gold standards are available researchers need to consider carefully the implication of choice of data source on their results.

Causes of death amongst a population of gastric ulcer patients in New South Wales, Australia.

The purpose of this study was to investigate whether any specific causes of death were more frequent than expected in an Australian group of 305 gastric ulcer patients (131 men, 174 women) who had died in New South Wales between 1 January 1974 and 31 December 1983. The distribution of causes of death among the ulcer population deaths was compared with that among the New South Wales population deaths, after adjusting for sex, 5-year age group, and time period of death (1974-1978, 1979-1983). Causes of death were ascertained from death certificates. Deaths due to peptic ulcer, liver cirrhosis, and diffuse pulmonary disease were more frequent than expected (p less than 0.05). The associations found with these other diseases accord with those found in previous surveys on causes of death in gastric ulcer patients and in studies of living gastric ulcer populations. Overall, the combined evidence suggests that liver cirrhosis and diffuse pulmonary disease are associated with gastric ulcer.

Do symptoms of gastric ulcer become less frequent with time?

It has been claimed that gastric and duodenal ulcer (GU and DU) symptoms decrease in frequency with time, indicating 'burn out' of ulcer. The present study was undertaken to investigate further this phenomenon in GU. The prevalence of symptom experience during 1 year was examined in 447 medically treated patients with GU diagnosed 2-20 or more years previously. When ulcer history length was measured from either first symptom onset or first ulcer diagnosis, reporting of symptoms did not become less frequent as history length increased. This remained true after adjustment for GU location, sex, age, smoking, and analgesic and non-steroidal anti-inflammatory drug ingestion. It is concluded that GU symptoms do not decrease in frequency with time.

A note on sex-specific mortality and social class in Sydney, 1979 to 1983.

Simple indicators such as education, income, occupation, and employment status are often used to adjust for social class in studies of morbidity or mortality. The effect of social class on such outcomes can be different for men and women. In population-based studies, residential area may be the only means of assessing social class. This study investigated sex differences in the association between mortality between 1979 and 1983 and several area indices of social class--percentage with a degree, percentage professional, percentage blue collar, percentage unemployed, percentage with annual income greater than $40,000, and the composite indicator constructed by the Australian Bureau of Statistics. Thirty-seven Sydney statistical local areas were ranked for men and women separately according to the indicators and standardised mortality ratios. Correlations between the indicators and mortality were all negative and stronger for men than for women. The composite indicator and percentage unemployed correlated most strongly with mortality. There was a moderate correlation between the remaining indicators and mortality for men, but only a weak correlation for women. The results suggest that the use of simple area indicators may be inadequate to classify the social class of women, and that the unemployment rate in those over 35 years of age may be a reasonable alternative to the composite indicator for the purpose of social class adjustment in mortality studies.

Accuracy of provisional diagnoses of dyspepsia in patients undergoing first endoscopy.

BACKGROUND: This study assessed agreement between provisional and endoscopic diagnoses for patients with dyspepsia undergoing initial endoscopy, and examined variation between clinicians at 2 hospitals. METHODS: This was a retrospective review of 423 consecutive patients. RESULTS: Crude percentage agreement ranged from 55% to 97%. Kappa scores revealed poor agreement: peptic ulcers (0.11: 95% CI [0.05, 0.17]); gastroesophageal reflux disease (0.29: 95% CI [0.20, 0.38]); benign esophageal stricture (0.33: 95% CI [0.08, 0.58]); and cancer (0.12: 95% CI [-0.12, 0.36]). Positive and negative predictive values for cancer and benign esophageal stricture showed that agreement for a negative diagnosis was almost perfect, whereas agreement for a positive diagnosis was low. Only 17% of patients with cancer were given an accurate provisional diagnosis. Accuracy of diagnosis did not vary substantially between hospitals. CONCLUSIONS: Crude percentage agreement is misleading. Emphasis should be placed on better prediction of cancer, benign esophageal stricture, and peptic ulcer disease. Accuracy of provisional diagnosis in everyday practice is no worse than that found in prospective studies in which clinicians knew a priori that diagnoses would be scrutinized. The difficulty of predicting diagnoses supports increased reliance on endoscopy.

Environmental factors in aetiology of chronic gastric ulcer: a case control study of exposure variables before the first symptoms.

The aim of the present study was to determine whether there is indication that either smoking, alcohol ingestion, or ingestion of analgesic or non-salicylate non-steroidal anti-inflammatory drugs plays any role in the development of chronic gastric ulcer disease. A group of 104 patients with gastric ulcer was compared with an age, sex and social grade matched community control population as regards exposure to the above factors during three time periods--the lifetime, five year and one year periods before the initial onset of the patients' ulcer symptoms. In all three study periods a statistically significant risk of gastric ulcer was found to be associated with smoking, and the daily use of aspirin, indomethacin and of other non-salicylate non-steroidal anti-inflammatory drugs as a group, but not with alcohol or daily use of paracetamol. As exposure to the environmental factors preceded the initial onset of ulcer symptoms, causal relationships are suggested. Assuming the association are causal, it can be calculated that possibly up to 80% of gastric ulcer disease is attributable to smoking and the daily ingestion of analgesic and anti-inflammatory drugs.

Factors relevant to the prognosis of chronic duodenal ulcer.

The aim of the study was to define the effects of sex, age, smoking, alcohol, analgesic ingestion, and treatment method whereby healing was initially induced on the prognosis of patients with a chronic duodenal ulcer (DU). 122 patients were assessed 1 year after the endoscopic demonstration of a DU. Two outcome variables for this 1-year period were studied - freedom from symptoms, and proven recurrence of the DU. Additionally, the outcome groups were compared to a community control population as regards the exposure variables. The results of the study indicate that each increase in smoking by 10 cigarettes daily increased the risk of DU recurrence within 1 year by 40%. Comparisons between patients and community controls revealed that smoking was significantly associated with DU and this association was present whether the ulcer was in exacerbation or in remission.

Prognosis of chronic duodenal ulcer: a prospective study of the effects of demographic and environmental factors and ulcer healing.

The aim of this prospective study of 370 community based duodenal ulcer patients was to define the effect on duodenal ulcer course (from the aspect of symptom occurrence) of demographic and environmental factors, and of proven healing of index ulcer within four months. Follow up was three monthly, for up to three years. By survival analysis, it was found that marriage breakup adversely affected duodenal ulcer course, that age 50 years and under, female sex, and aspirin use tended to do so, and that smoking, alcohol ingestion, and paracetamol use did not. Proven healing of index ulcer within four months was associated with a small and non-significant reduction in symptom occurrence over time.

Smoking, nonsteroidal anti-inflammatory drugs, and acetaminophen in gastric ulcer. A study of associations and of the effects of previous diagnosis on exposure patterns.

A study was conducted in Sydney, Australia to investigate whether the use of some nonaspirin nonsteroidal anti-inflammatory (anti-arthritic) drugs was associated with gastric ulcer in patients who had had neither a gastric nor a duodenal ulcer diagnosed previously (i.e., in new cases of peptic ulcer), and whether the use of anti-arthritic drugs, aspirin, acetaminophen, and cigarettes was influenced by the diagnosis of a peptic ulcer--either gastric or duodenal. Bleeding of gastric ulcer in new cases was studied in relation to smoking, use of aspirin or anti-arthritic drugs, and age. The 417 patients in the study lived in Sydney and were interviewed between 1982 and 1985 after diagnosis of a gastric ulcer; 192 patients had had a gastric or duodenal ulcer diagnosed previously (i.e., were recurrent cases of peptic ulcer), and the remaining 225 patients were new cases to whom 411 community controls were matched on sex, age, and prestige of area of residence. In new cases, odds ratios of gastric ulcer were 5.0 for daily aspirin use and 2.3 to 5.4 for daily anti-arthritic drug use. Fewer recurrent cases than new cases had used aspirin daily (odds ratio (OR) = 0.5) or anti-arthritic drugs daily (OR = 0.5), and more recurrent than new cases had used acetaminophen daily (OR = 2.5). Among new cases, bleeding of gastric ulcer was less common in smokers (OR = 0.6), and more common in daily users of aspirin (OR = 2.1) and, to a lesser extent, in daily users of anti-arthritic drugs (OR = 1.5), and in patients aged 60 or more years (OR = 2.3) independent of usage of the above drugs. It is concluded that 1) the use of anti-arthritic drugs increases gastric ulcer risk; 2) diagnosis of a gastric or duodenal ulcer causes a decrease in the use of aspirin and anti-arthritic drugs and an increase in acetaminophen use, but does not change smoking habits; 3) aspirin use or advancing age may add to the risk of bleeding ulcer although the role of anti-arthritic drugs is less clear.

The personality pattern of patients with chronic peptic ulcer. A case-control study.

The personality assessment of 96 patients with gastric ulcer (GU) and 70 patients with duodenal ulcer (DU) was carried out using the Cattell Sixteen Personality Factor Questionnaire (16 PF). Two control groups were used; one group comprised community controls and the other patient controls--that is, patients with cholelithiasis. Three of the four personality characteristics that distinguished female GU and/or DU patients from controls--emotional instability, tension, and anxiety--and the two characteristics that distinguished male GU patients--low enthusiasm and low self-control--are components of neuroticism. Female GU patients in exacerbation resembled those in remission, and GU and DU patients had similar personality profiles. Although a distinct personality pattern has yet to be identified in peptic ulcer, the results of this study and others suggest that both GU and DU are associated with the personality abnormalities of anxiety and neuroticism.

Environmental factors and chronic gastric ulcer. A case control study of the association of smoking, alcohol, and heavy analgesic ingestion with the exacerbation of chronic gastric ulcer.

The aim of this case control study was to define the strength of the associations of smoking, alcohol, and heavy analgesic ingestion with chronic gastric ulcer (GU). Ninety-nine patients were interviewed about smoking, alcohol, and analgesic ingestion for the 6 months before exacerbation of their chronic GU. The 180 non-ulcer community control subjects were frequency-matched with the patients for the characteristics of age, sex, and social status. Smoking, alcohol, and heavy analgesic ingestion were studied when present as sole factors and in combinations. Their associations with GU were measured by the odds ratio (OR) and the adjusted odds ratio (AOR). Smoking in male patients (OR 15.4) and heavy analgesic ingestion in female patients (OR 23.4) were significant as sole factors. Smoking plus heavy analgesic ingestion was significant in female patients (OR 10.0), and the combination of all three factors was significant in male patients (OR 13.0) and in female patients (OR 6.3). Smoking had significantly increased AORs of 3.3 in male patients and 3.5 in female patients; alcohol had a significantly decreased AOR of 0.4 in female patients; and heavy analgesic ingestion was significantly increased in female patients (AOR 7.2). It is concluded that smoking in all patients and heavy analgesic ingestion in female patients are risk factors for chronic GU. Alcohol, however, does not appear to be a risk factor.

Analgesic ingestion and chronic peptic ulcer.

The patterns of analgesic ingestion in gastric and duodenal ulcer patients were compared with those of matched community controls in order to ascertain differences that may exist between ulcer and nonulcer subjects of comparable age and sex. The differences sought concerned amounts and types of analgesics ingested. The types of analgesics studied were aspirin and acetaminophen, ingested either alone or together. Analgesics such as dextropropoxyphene and codeine were disregarded. It was found that there was a strong positive association between heavy analgesic intake and chronic gastric ulcer with a relative risk of 29.5. The association was most marked in female patients (relative risk = 51.8). The involvement of aspirin-containing and acetaminophen-containing drugs was of similar significance with relative risk of 17.3 and 24.4, respectively. Aspirin alone was the least frequently ingested. The association was only partly related to painful nonulcer health problems and to ulcer pain. No association was found between chronic duodenal ulcer and analgesic intake. The strong association found between gastric ulcer and heavy analgesic intake does not, per se, necessarily indicate a causal relationship.

Patterns of dyspepsia during the course of duodenal ulcer.

Dyspepsia patterns during the course of duodenal ulcer (DU) were examined in terms of the number of consecutive months that patients experienced dyspepsia either intermittently or continuously, or were dyspepsia-free. The patients (n = 224) were community-based. After ulcer healing, they were evaluated every 3 months for less than or equal to 7 years. Antiulcer agents were prescribed at the physicians' discretion. We analyzed the data on a patient-month basis using a 2-state Markov chain model. The fitted mean number of consecutive months with dyspepsia and the number of months dyspepsia-free were, respectively, 1.7 and 14 in patients on antiulcer agents, and 1.5 and 9 in patients not taking them. On average, patients experienced dyspepsia during 15% of months studied if they were on antiulcer agents, and during 20% of months if not. Regardless of antiulcer therapy, dyspepsia periods were lengthened by age, especially greater than 60 years; male sex; widowhood/divorce/separation; increasing acetaminophen use; and increasing length of time since initial onset of ulcerlike dyspepsia. Dyspepsia-free periods were lengthened by age greater than 70 years, and shortened by widowhood/divorce/separation and increasing cigarette consumption. These results suggest that dyspepsia occurs for less than or equal to 20% of the time in DU patients on about a yearly basis. The least dyspepsia may be expected in patients neither widowed, divorced, nor separated, in whom length of time since the initial onset of ulcerlike dyspepsia does not exceed 7 years, and who neither smoke nor use analgesics regularly.

Some factors associated with mortality in perforated peptic ulcer: a case-control study.

This study examined the associations of individual coexisting illnesses, septicaemia, intra-abdominal abscess, marital status, smoking and alcohol use, with mortality following perforation of peptic ulcer without pre-operative evidence of haemorrhage. Patients who died in hospital following ulcer perforation (cases; n = 300) were compared with patients who survived following ulcer perforation (controls; n = 276). The controls were frequency-matched to the cases on age, sex and perforation site. Data were analysed by logistic regression. Cardiac, respiratory, cerebrovascular, renal, liver and malignant diseases, and septicaemia and intra-abdominal abscess were associated with mortality and the coexisting illnesses were significantly increased in cases compared to controls both on admission and at the end of hospital stay. During hospitalization, the odds of pneumonia decreased in cases, otherwise there was little change in strengths of associations over this period. Being widowed or never married was positively associated with mortality, and moderate alcohol use was negatively associated. In conclusion, this study identifies several coexisting illnesses, septicaemia and intra-abdominal abscess as risk factors for mortality following ulcer perforation. The results suggest that, with little exception, the same level of mortality risk is associated with coexisting illnesses whether the beginning or end of hospital stay is used as the index time point.

Trends in peptic ulcer mortality in Sydney from 1971 to 1987.

Gastric and duodenal ulcer (GU,DU) mortality in Western countries has varied over time by age and sex. Temporal variation raises the question of whether these ulcers have an environmental etiology. Using death certificate data, we investigated peptic ulcer mortality time trends from 1971 to 1987 in Sydney, Australia, and whether ulcer mortality and overall mortality in Sydney were similar with regard to time trends and associations with demographic and environmental factors. In men in all age groups and in women age < 65, GU and DU mortality decreased. In women age > or = 70, GU mortality remained constant and DU mortality increased. Average age at ulcer death increased: from 1971 to 1987, ulcer deaths at age > or = 70 rose from 52 to 80% of all ulcer deaths. In men who died at age 30-54, GU and DU mortality decreased relative to overall mortality. In women who died at age > or = 55, DU mortality increased relative to overall mortality. Compared with overall mortality, the ulcer mortality rate was affected more adversely by lower social class and lack of the marriage tie, and smoking rates tended to correlate more strongly with GU mortality. The greater-than-expected decrease in GU and DU mortality in younger men and the increase in DU mortality in elderly women suggest important changes in as yet unidentified environmental risk factors for ulcer mortality within the young adult male and elderly female general populations.

Life events and chronic duodenal ulcer: a case control study.

The frequency of life events during the two years before an exacerbation of ulcer in a duodenal ulcer population was compared with the frequency of these events over the same time period in an age-sex matched probability sample of the community population. The mean number of events and the associated distress and life change scores were similar for both groups. When events were categorised into areas of activity, such as health, bereavement, family and social life, change of residence, etc. and were further classified on the basis of desirability, separation from persons, and problem chronicity, only one significant difference was found between patients and controls-more patients changed residence (p=0.0005). Frequency distributions of the number of events and the distress and life change scores were similar for both groups. Concerning individual events, the only significant differences in frequency were that more patients changed residence in Sydney (p=0.006) and more controls had a child leave home for reasons other than marriage (p=0.03). Patients and controls experienced the same four most frequent events. Among patients, no correlation existed between age and either the number of events experienced or distress and life change scores. Among controls, age was negatively correlated with the number of events experienced (p=0.0004) and the life change scores (p<0.003). It is concluded, therefore, that an excess of stress, as measured by the number of life events experienced and by distress and life change scores associated with these events, does not appear to be a risk factor for the exacerbation of chronic duodenal ulcer.

Phenylthiocarbamide taste sensitivity in chronic peptic ulcer.

Ability to taste phenylthiocarbamide is genetically determined and has been investigated as a possible genetic marker for disease. This study examined phenylthiocarbamide taste sensitivity in gastric and duodenal ulcer disease. The study sample included 164 patients with gastric ulcer, 134 with duodenal ulcer, and 299 community controls. Eight concentrations of phenylthiocarbamide in distilled water were obtained by binary serial dilution. The lowest concentration distinguished by taste from distilled water defined taste threshold. Bimodality of threshold distributions distinguished nontasters from tasters. Comparisons of patients with controls gave odds ratios of nontaste in gastric ulcer and duodenal ulcer of, respectively, 0.7 (P greater than 0.1) and 1.3 (P greater than 0.03). The power of detecting at least a twofold difference between patients and controls in the odds of nontaste was 80%. Nontaste was more common in duodenal than in gastric ulcer patients (odds ratio = 2.0, P = 0.02). Taste sensitivity was unassociated with other genetic factors related to ulcer--ABO blood group, secretor status, and serum pepsinogen 1 level. The difference between gastric and duodenal ulcer patients in the ability to taste phenylthiocarbamide may be genetic; however, this study's inability, despite substantial power, to detect at least a twofold difference between patients and controls suggests that if phenylthiocarbamide taste sensitivity is a genetic factor in peptic ulcer, the relationship is weak.