Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.

The poor state of Aboriginal and Torres Strait Islander health has been documented in many ways, most obviously by comparing the relatively higher age‐specific mortality and morbidity rates. This paper demonstrates the use of acute hospital separation data as a way to identify potential deficiencies in providing appropriate primary health care services for Aboriginal and Torres Strait Islander populations. It does so by using ‘ambulatory sensitive conditions’: those conditions (and procedures) for which high‐quality appropriate primary health services deliverable under ideal circumstances are thought to potentially reduce or eliminate the need for hospitalisation. Potential or realised access to primary care is not analysed directly using primary health service data. In this study, 1993–94 acute hospital separation data from NSW, Queensland, South Australia, Western Australia and the Northern Territory were used to calculate separation rates and odds ratios for Aboriginal and Torres Strait Islander and non‐Aboriginal and Torres Strait Islander populations. Age‐specific acute hospital separation rates for ambulatory sensitive conditions were 1.7 to 11 times higher for the Aboriginal and Torres Strait Islander populations studied. This supports clinical contentions that much Aboriginal and Torres Strait Islander morbidity and mortality is preventable and that further consideration is needed to service delivery reform at all levels in the health system and the distribution of funding.

No abstract

Image analysis is now routinely employed as a tool in toxicologic pathology to help quantitate end points of efficacy and safety. It is regarded as a proficient and a sensitive technique to generate numerical data that can be easily interrogated for statistical evaluation. Traditional semiquantitative pathology scoring on the other hand is sometimes regarded as less accurate due to the limitations of the scoring systems employed and the day-to-day variations often noted between pathologists. We therefore decided to generate an optimized histochemical staining and image analysis protocol to compare the accuracy of semiquantitative scoring with computerized image analysis. In order to achieve this, we describe a standardized protocol for staining and image analysis that eliminates or minimizes as many sources of error as possible. The results of this experiment demonstrate that despite consistent variations in scoring between two independent pathologists, correlation with image analysis data of 0.91 to 0.95 (Spearman's Rho test) was achieved. These data indicate that either image analysis or traditional semiquantitative scoring can generate accurate data. As a result of this, it appears that it is equally safe to employ either method dependent upon the complexity and the practicality of the task at hand provided that the experimental conditions are rigorously optimized and rigidly adhered to.

No abstract