From toxicological problem to therapeutic use: The discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug

NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4-hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.     

Inflammatory stimuli accelerate Sjögren's syndrome-like disease in (NZB x NZW)F1 mice

OBJECTIVE: This study was undertaken to determine whether induction of systemic inflammation accelerates the development of Sj?gren's syndrome (SS) in genetically susceptible mice. METHODS: Female (NZB x NZW)F1 mice were treated with either Freund's incomplete adjuvant (IFA) or phosphate buffered saline (PBS) at monthly intervals. Salivary gland function was monitored by measuring pilocarpine-induced saliva volume. Mice were killed at different time points and examined for sialadenitis and salivary gland-infiltrating cells. Sera were analyzed for autoantibodies to salivary gland antigens, nuclear antigens, and Ro60. RESULTS: While IFA-treated mice had significantly decreased salivary secretion 7 weeks after the initial treatment, salivary secretion did not decrease in PBS-treated controls until 17 weeks. At 7 weeks, the severity of sialadenitis and the number of T and B cells infiltrating the salivary glands did not differ between the 2 groups. However, at this time point IFA-treated mice showed significantly higher frequencies of CD11clow, B220+, Ly6C+, mouse PDCA-1+ dendritic cells (DCs) in the salivary glands. While levels of autoantibodies did not differ between the 2 groups at early time points, by late time points IFA-treated mice had higher levels. The gland dysfunction observed in IFA-treated mice at earlier time points did not correlate with the severity of sialadenitis or levels of autoantibodies. Instead, it was associated with increased frequency of plasmacytoid DCs in the gland. CONCLUSION: Our data suggest that generalized inflammatory stimuli can accelerate the development of SS-like disease in (NZB x NZW)F1 mice, and that gland dysfunction in SS can develop prior to the generation of a robust adaptive autoimmune response.     

Monoclonal antibody T101 in T cell malignancies: a clinical, pharmacokinetic, and immunologic correlation

Eight patients with cutaneous T cell lymphomas (CTCL) and five with various other T cell malignancies were treated with mouse monoclonal antibody (MoAb) T101. Doses of 1 to 500 mg were administered weekly over a two-hour period and resulted in one complete remission (convoluted T cell lymphoma) and one partial remission (CTCL). Remission duration was 6 weeks and 3 months, respectively. Frequent toxicities were pruritus, hives, flushing, and shortness of breath. Supraventricular arrhythmias and blood pressure instability were also observed. Complete targeting of peripheral blood T cells was achieved with 1 mg of MoAb in the nonleukemic patients (WBC less than 10,000/microL), and free, bioavailable antibody was present at the next (10-mg) dose level. Even higher doses resulted in substantial antibody excess that persisted for as long as 6 weeks. Serum concentrations of MoAb decreased with increasing number of peripheral blood T cells, and 25 to 35 mg of T101 were required for induction of antibody excess in leukemic patients. Excess antibody induced antigenic modulation, which was of consequence only if MoAb excess persisted to the next treatment. In the original treatment, the rapidly administered MoAb was able to target and remove peripheral blood T cells before the development of antigenic modulation. Antimouse antibodies developed in three patients. Their presence rendered further therapy ineffective and was associated with an anaphylactic reaction in one patient. Development of these antibodies could not be predicted by lymphoproliferative assays. In these assays, however, the T101 protein strongly stimulated the mononuclear cells of the patient who reached the only complete remission of this trial. Immunologic stimulation by the MoAb thus might have played a role in this patient's antitumor response. In summary, therapy with MoAb T101 was specific but only modestly efficacious. Rapid infusion of nonmodulating doses of antibody provided excellent targeting and removal of peripheral blood T cells and might be a valid approach in future trials with immunoconjugated T101.     

Can Stress Radiography of the Knee Help Characterize Posterolateral Corner Injury?

Background  

Conventional MRI is limited for characterizing the posterolateral corner of the knee due to the region’s anatomic variability and complexity; further, MRI is a static study and cannot demonstrate pathologic laxity. Stress radiography may provide additional information about instability.     

Power,effects, confidence,and significance: An investigation of statistical practices in nursing research

Objectives

To (a) assess the statistical power of nursing research to detect small, medium, and large effect sizes; (b) estimate the experiment-wise Type I error rate in these studies; and (c) assess the extent to which (i) a priori power analyses, (ii) effect sizes (and interpretations thereof), and (iii) confidence intervals were reported.

Design

Statistical review.

Data sources

Papers published in the 2011 volumes of the 10 highest ranked nursing journals, based on their 5-year impact factors.

Review methods

Papers were assessed for statistical power, control of experiment-wise Type I error, reporting of a priori power analyses, reporting and interpretation of effect sizes, and reporting of confidence intervals. The analyses were based on 333 papers, from which 10,337 inferential statistics were identified.

Results

The median power to detect small, medium, and large effect sizes was .40 (interquartile range [IQR] = .24–.71), .98 (IQR = .85–1.00), and 1.00 (IQR = 1.00–1.00), respectively. The median experiment-wise Type I error rate was .54 (IQR = .26–.80). A priori power analyses were reported in 28% of papers. Effect sizes were routinely reported for Spearman's rank correlations (100% of papers in which this test was used), Poisson regressions (100%), odds ratios (100%), Kendall's tau correlations (100%), Pearson's correlations (99%), logistic regressions (98%), structural equation modelling/confirmatory factor analyses/path analyses (97%), and linear regressions (83%), but were reported less often for two-proportion z tests (50%), analyses of variance/analyses of covariance/multivariate analyses of variance (18%), t tests (8%), Wilcoxon's tests (8%), Chi-squared tests (8%), and Fisher's exact tests (7%), and not reported for sign tests, Friedman's tests, McNemar's tests, multi-level models, and Kruskal–Wallis tests. Effect sizes were infrequently interpreted. Confidence intervals were reported in 28% of papers.

Conclusion

The use, reporting, and interpretation of inferential statistics in nursing research need substantial improvement. Most importantly, researchers should abandon the misleading practice of interpreting the results from inferential tests based solely on whether they are statistically significant (or not) and, instead, focus on reporting and interpreting effect sizes, confidence intervals, and significance levels. Nursing researchers also need to conduct and report a priori power analyses, and to address the issue of Type I experiment-wise error inflation in their studies.     

The Heartsink Patient: A Preliminary Study

Eight GPs identified 78 heartsink patients; in an open-endedinterview they were asked to explain why they regarded themin this way. A GP's definition of a heartsink patient was influencedby GP sex, practice location, and time of surgery, althoughthe number of participating GPs was too low to make any definiteassertions. Practitioners' anticipations of heartsink consultationswere generally over-exaggerated, with most of the encountersgoing better than expected. GPs expressed the view that thesepatients raised serious professional issues for them, whilstthere was also a dislike for these patients' personalities andbehaviour. Two levels of the heartsink state are hypothesized:one, a state of inertia, is when the heartsink patient has beena chronic high user of the primary health care system, and aGP has exhausted all avenues. The other is an acute situationwith those heartsink patients who have been low users of thesystem in the past. Recent, new events in these patients' liveshave raised an issue that is just as much to do with patientand doctor reaction to these events, as it is about findinga diagnosis or solution to the problem. We present the results and hypotheses to provoke further discussionand research.