Content Uniformity and Dose Uniformity: Current Approaches,Statistical Analyses,and Presentation of an Alternative Approach,with Special Reference to Oral Inhalation and Nasal Drug Products

This article reviews current and proposed approaches to content uniformity testing. In addition, the article proposes an approach that allows regulatory agencies and compendia to clearly state allowable consumer risk. Further, the article suggests that producers be allowed to control producer risk through selection of numbers of units and testing tiers. The approach facilitates risk communication to practitioners and patients/consumers, which is impeded with current approaches, and reduces regulatory and compendial burden.     

A Pseudomonas syringae type III effector suppresses cell wall-based extracellular defense in susceptible Arabidopsis plants

Bacterial effector proteins secreted through the type III secretion system (TTSS) play a crucial role in causing plant and human diseases. Although the ability of type III effectors to trigger defense responses in resistant plants is well understood, the disease-promoting functions of type III effectors in susceptible plants are largely enigmatic. Previous microscopic studies suggest that in susceptible plants the TTSS of plant-pathogenic bacteria transports suppressors of a cell wall-based plant defense activated by the TTSS-defective hrp mutant bacteria. However, the identity of such suppressors has remained elusive. We discovered that the Pseudomonas syringae TTSS down-regulated the expression of a set of Arabidopsis genes encoding putatively secreted cell wall and defense proteins in a salicylic acid-independent manner. Transgenic expression of AvrPto repressed a similar set of host genes, compromised defense-related callose deposition in the host cell wall, and permitted substantial multiplication of an hrp mutant. AvrPto is therefore one of the long postulated suppressors of an salicylic acid-independent, cell wall-based defense that is aimed at hrp mutant bacteria.     

Recovery of upper-extremity strength in complete and incomplete tetraplegia: a multicenter study

OBJECTIVE: To examine upper-extremity motor recovery of subjects with tetraplegia with both complete and incomplete injuries, to predict which patients and at what time they would recover a motor level. DESIGN: Prospective, multicenter clinical study of upper-extremity motor recovery in subjects with acute traumatic spinal cord injury. SETTING: Three regional spinal cord injury centers. SUBJECTS: One hundred sixty-seven individuals with acute traumatic tetraplegia (144 males [86%], and 23 females [14%]) between the ages of 15 and 75 years (mean age, 35.5 yrs). METHODS: Subjects were examined and classified using sequential manual muscle tests performed on admission, 72 hours, 1, 2, and 3 weeks, and 1, 2, 3, 6, 12, 18, and 24 months postinjury. C5 biceps, C6 extensor carpi radialis, C7 triceps, and C8 flexor digitorum profundus were evaluated using a 0-5 scale. Analyses of the right motor levels used a series of logistic regression models, and for multiple measurements on each subject, models were estimated using generalized estimating equations. RESULTS: The analysis for recovery of the biceps for the C4 group showed 70% of complete compared with 90% of incomplete injuries recovered (p < .001); of the extensor carpi radialis in the C5 group, 75% complete and 90% incomplete recovered (p < .002); and of the triceps in the C6 group, 85% of complete and 90% of incomplete injuries recovered (p < .16). CONCLUSION: Predicting future potential for upper-extremity motor recovery and for independence in self-care in groups of patients at a specific motor level is possible within the first week of injury.     

Subject-by-Formulation Interaction in Bioequivalence: Conceptual and Statistical Issues

Purpose. The FDA has proposed replacing the current averagebioequivalence criterion with population and individual bioequivalence criteriathat consider variances in addition to the difference of averages. Oneof these variances in the individual bioequivalence criterion measuressubject-by-formulation interaction, the extent to which thetest-reference difference varies from person to person. This paper discussesconceptual and statistical issues raised in various publications andpresentations with respect to the presence and estimation of such aninteraction. Methods. We focus on the importance of subject-by-formulationinteraction, an understanding of what is a large interaction, and theassessment of the magnitude of this interaction in bioequivalence studies.Simulation studies, examples from the literature, and data from FDAfiles are used to demonstrate the magnitude of the interaction and itsdistribution under various conditions. Results. The concept of a large interaction is tied to the concept of alarge mean difference. We suggest that an interaction greater than0.15 is a conservative criterion for a large interaction. Magnitudes ofestimated interaction are affected by variability, sample size, and theselection of data sets that pass average bioequivalence. Conclusions. Examples of substantial interactions are beginning toappear. More data is needed before reaching definitive conclusionsregarding the frequency and importance of observed interactions.     

Colorectal hemangioma: radiologic findings

The authors correlated radiographs with the clinical and histologic data of 12 patients with colorectal hemangioma. All patients presented with rectal bleeding, which was chronic in seven. Phleboliths were also visible in seven cases, which correlated with chronic bleeding in five. On barium studies, three masses were soft and three produced rigid narrowing. The atypical features of rigid luminal narrowing, which might mimic a carcinoma, and hypovascularity correlated with chronic bleeding or visible phleboliths, which suggest the correct diagnosis of colorectal hemangioma.     

A new statistical procedure for testing equivalence in two-group comparative bioavailability trials

The clinical problem of testing for equivalence in comparative bioavailability trials is restated in terms of the proper statistical hypotheses. A simple t-test procedure for these hypotheses has been developed that is more powerful than the methods based on usual (shortest) and symmetric confidence intervals. In this note, this new procedure is explained and an example is given, including the method for sample size determination.     

Das Verhalten von Blutdruck und Stromzeitvolumen in der Pfortader bei intraabdomineller Drucksteigerung

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