The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy.

BACKGROUND: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. METHODS: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. RESULTS: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. CONCLUSION: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers.

Projecting cancer incidence and mortality using Bayesian age-period-cohort models.

BACKGROUND: We present a practical application of an age-period-cohort model in a Bayesian frame-work for making cancer-burden projections. METHODS: Second degree autoregressive smoothing was used on the age, period and cohort effects for estimating future incidence and mortality. RESULTS: We are able to demonstrate the feasibility, flexibility and strengths of this approach. Compared with previously used methods, it performed better for providing point estimates when past trends continued into the future. However, the extremely wide credible intervals need careful interpretation. DISCUSSION: Part of the uncertainty is attributable to the possible inadequacy of the model and not necessarily relevant in the prediction of what would happen if the present trends continue into the future.

Measurement error in epidemiology: the design of validation studies I: univariate situation.

It is becoming standard practice in epidemiology to adjust relative risk estimates to remove the bias caused by non-differential errors in the exposure measurement. Estimation of the correction factor is often based on a validation study incorporating repeated measures of exposure, which are assumed to be independent. This assumption is difficult to verify and often likely to be false. We examine the effect of departures from this assumption on the correction factor estimate, and explore the design of validation studies using two or even three different types of measurement of exposure, where assumption of independence between the measures may be more realistic. The value of good biomarker measures of exposure is demonstrated even if they are feasible to use only in a validation study.

Medical practitioners and their practices in acute diarrhea.

PIP: A study conducted in the Pediatric Outpatient Department of the Institute of Medical Sciences in Srinagar, India, assessed the acute diarrhea management strategies of various categories of health care practitioners. Of the total of 1030 infants enrolled at private clinics or other health units, 71.7% were treated by general practitioners and chemists, 11.6% saw hospital residents, and 16.7% were treated by pediatricians. Antidiarrheal and antispasmodic preparations were given to most infants, either alone (46.8%) or in conjunction with oral rehydration therapy (ORT) (45.4%). Only 4.1% of infants received ORT alone. 87.2% of pediatricians selected a combination of drugs and ORT. Both qualified and unqualified practitioners provided drugs such as lopermaide (57.9%), pipenzolate (2.1%), metoclopramide (13.7%), and steroids (2.5%). All categories of health workers prescribed marketed ORT preparations containing insufficient sodium; only 23.7% of cases received home-made sugar-salt solution. Parents in India express a preference for the use of drugs and parenteral fluids in acute diarrhea, and most practitioners appear to gear their practices to this preference. Education of both parents and health professionals about the adequacy of ORT in most cases of acute diarrhea is needed to prevent electrolyte imbalances, iatrogenic hazards, and the emergence of multidrug-resistant strains of microorganisms.^ieng

The correction of risk estimates for measurement error.

PURPOSE: The methods available for the correction of risk estimates for measurement errors are reviewed. The assumptions and design implications of each of the following six methods are noted: linear imputation, absolute limits, maximum likelihood, latent class, discriminant analysis and Gibbs sampling. METHODS: All methods, with the exception of the absolute limits approach, require either repeated determinations on the same subjects with use of the methods that are prone to error or a validation study, in which the measurement is performed for a number of persons with use of both the error-prone method and a more accurate method regarded as a "gold standard". RESULTS: The maximum likelihood, latent class and absolute limits methods are most suitable for purely discrete risk factors. The linear imputation methods and the closely related discrimination analysis method are suitable for continuous risk factors which, together with the errors of measurement, are usually assumed to be normally distributed. CONCLUSIONS: The Gibbs sampling approach is, in principle, useful for both discrete and continuous risk factors and measurement errors, although its use does mandate that the user specify models and dependencies that may be very complex. Also, the Bayesian approach implicit in the use of Gibbs sampling is difficult to apply to the design of the case-control study.

Repeat measurement of case-control data: corrections for measurement error in a study of ischaemic stroke and haemostatic factors.

BACKGROUND: Haemostatic factors are suspected to be involved in the aetiology of cerebrovascular events. METHODS: In a case-control study of 105 cases of transient ischaemic attack and minor ischaemic stroke, and 241 controls, data were available on levels of the haemostatic factors-von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI), tissue plasminogen activator (TPA) and factor VII (FVII). These are subject to measurement error and within-person fluctuation of true levels, which may bias relative risk estimates. For all subjects, two determinations were performed on the same blood sample, which allowed estimation of pure measurement error. For estimation of within-person fluctuation, levels were measured from a repeat blood sample on 81 of the controls one year later. RESULTS: The pure measurement error accounted for a very small proportion of the total variation in all cases. Uncorrected for within-person fluctuation, the odds ratio estimates associated with exceeding the median of vWF, PAI, TPA and FVII respectively were 1.88, 0.87, 1.30 and 0.93. After correction for within-person fluctuation odds ratios were 3.56, 0.80, 1.41 and 0.91. Because the PAI determination was not robust to storage conditions, it was estimated that 75% of the variation in this factor was within-person rather than between-persons. Thus, estimates of relative risk relation to PAI cannot be regarded as reliable in this study. CONCLUSIONS: It is likely that elevated levels of vWF are associated with increased risk of ischaemic stroke, but interpretation must be tentative, due to relatively large within-person fluctuation of vWF levels.

Correction of risk estimates for measurement error in epidemiology.

Epidemiologists are under considerable pressure to acknowledge the presence of measurement error in the determination of risk factors. Repeatability and validation studies are often prescribed in conjunction with epidemiological studies. We describe some practical uses for repeatability and validation study data, in terms of correcting risk estimates for measurement error. Commonly available methods are described, with their advantages and shortcomings. A user-friendly computer program to carry out the analyses described accompanies the paper.