Two novel paradigms for the simultaneous assessment of conditioned taste aversion and food intake effects of anorexic agents

The conditioned taste aversion (CTA) is routinely used to assess the aversive consequences of anorexic agents, including potential pharmacological therapies for obesity. In a typical CTA paradigm, rats briefly sampling a novel tastant (e.g., saccharin) are acutely administered with toxin (e.g., lithium chloride, LiCl). After as few as one taste-toxin pairing, rats will reliably avoid the novel tastant. This paradigm is frequently used for the assessment of possible aversive consequences of drugs that are candidates for pharmacological therapies. The degree to which the drug supports development of a CTA is interpreted as an index of its aversive properties. Difficulties with previous work include the inability to assess affects on food intake and CTA simultaneously, particularly during chronic drug administration. We report here two novel CTA paradigms for the assessment of appetitive and aversive consequences of anorexic agents, simultaneously. In the first experiment, animals receive an intraoral infusion of a novel and highly palatable tastant immediately prior to administration of increasing doses of LiCl. In the second experiment, rats were implanted intraperitoneally with osmotic minipumps that chronically delivered a low dose of LiCl for 7 days. LiCl did not affect short or long term food intake in either experiment. However, LiCl did support the development of a CTA in both paradigms. These results suggest that both the appetitive and aversive consequences of anorexic agents can be assessed simultaneously during either acute or chronic drug administration.     

Care at the end of life: a novel curriculum module implemented by medical students.

End-of-life (EOL) and palliative care education in medical school curricula stand at a crossroads. Consensus has emerged that these topics merit systematic instruction throughout medical school training, yet curricula all too often consist of sporadic lectures focused on bioethics instead of clinical skills. The medical student authors identified a deficit in their curriculum, and designed and implemented an EOL curriculum module for their colleagues. In early 2000 the authors surveyed senior medical students about their experiences with EOL and palliative education, identifying deficits in clinical training and recommendations for interventions. They then designed a case-based educational module to teach EOL communication skills to medical students commencing clinical training. Faculty with national and local experience with EOL and palliative care reviewed the curriculum. Twelve of these faculty were oriented to the curriculum and then taught it in pairs to groups of 12 to 16 medical students in 2000 and 2001. The curriculum develops skills, attitudes, and knowledge relevant for communicating bad news and establishing treatment options in the EOL setting by utilizing trigger videos, group discussion, role plays, and case discussions. Approximately 75% of the 86 eligible students attended the module in 2000 and 2001. Feedback has guided the curriculum's refinement by the medical student authors. In addition, a standardized patient exercise, introduced in 2001, allowed students to reinforce the skills learned during the module.     

Diagnosis of gastrointestinal stromal tumors: A consensus approach

As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GISTs), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and the development of novel and effective therapy for GISTs using the receptor tyrosine kinase inhibitor STI-571, these tumors have become the focus of considerable attention by pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a source of confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity in diagnosis and a proposed scheme for estimating metastatic risk in these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term "benign" for any GIST, at least at the present time.     

Serological Survey of Toscana Virus Infections in a High-Risk Population in Italy

Toscana virus is the most important agent responsible for meningitis in central Italy. We report a serosurveillance study, using an immunoenzymatic assay, of 360 serum samples harvested from a high-risk population occupationally exposed to Toscana virus in two regions of Italy, Tuscany and Piedmont. The results indicates a seroprevalence of Toscana virus of 77.2% in the forestry workers, particularly in the Tuscany region. This fact is strictly correlated with the ecological niches specific for the survival of Toscana virus arthropod vector.     

Biosynthetic and regulatory role of lys9 mutants of Saccharomyces cerevisiae

Summary Derepression of lysine biosynthetic enzymes of Saccharomyces cerevisiae was investigated in lys9 auxotrophs which lack saccharopine reductase activity. Five enzymes (homocitrate synthase, homoisocitrate dehydrogenase, -aminoadipate aminotransferase, -aminoadipate reductase and saccharopine dehydrogenase) were constitutively derepressed in all lys9 mutants with up to eight-fold higher enzyme levels than in isogenic wild-type cells. Levels of these enzymes in lys2, lys14, and lys15 S mutants were the same or lower than those in wild-type cells. The regulatory property of lys9 mutants exhibited recessiveness to the wild-type gene in heterozygous diploids. Unlike the mating type effect, homozygous diploids resulting from crosses between lys9 auxotrophs exhibited even higher levels of derepressed enzymes than the haploid mutants. Addition of a higher concentration of lysine to the growth medium resulted in reduction of enzyme levels although they were still derepressed. These results suggest that lys9 mutants represent a lesion for the saccharopine reductase and may represent a repressor mutation which in the wild-type cells simultaneously represses unlinked structural genes that encode for five of the lysine biosynthetic enzymes.     

Fibrolamellar Carcinoma of Liver: A Primary Malignant Oncocytic Carcinoid?

Immunohistochemical and ultrastructural findings in two cases of fibrolamellar carcinoma of the liver and two cases of hepatocellular carcinoma of the common histologic type are described. Ultrastructural examination of both cases of fibrolamellar carcinoma revealed the presence of neurosecretory (NS) granules which were sparse in some cells and abundant in others. Many of the tumor cells had a distinct oncocytic appearance with abundant mitochondria. A portion of the glutaraldehyde-fixed neoplasm was processed for the uranaffin reaction (an ultrastructural cytochemical stain specific for the NS granules of neuroendocrine tissue). Abundant uranaffin-positive granules were found in the neoplastic cells of both cases of fibrolamellar carcinoma, whereas no uranaffin-positive granules were found in hepatocellular carcinoma of the common histologic type. There was no statistical difference in the mean diameter of the uranaffin-positive granules measured from both cases. Immunohisto-chemistry revealed the presence of neuron-specific enolase (NSE) and serotonin in one of the two cases of fibrolamellar carcinoma and no NSE staining in two cases of hepatocellular carcinoma of the common histologic type. These findings suggest that some liver tumors presenting histologically as fibrolamellar carcinoma may be neuroendocrine in nature.     

Recovery of function in cat visual cortex following prolonged deprivation

Summary Evidence that there is a critical period during which response characteristics of neurons in visual cortex of the cat may be influenced has been provided in several studies, which suggest that the period of influence is restricted to the first few months of life. Using a somewhat different experimental procedure, we have obtained evidence that cortical units retain plasticity long after the end of this period has passed. In our procedure prolonged visual deprivation was followed by exposure in a normal visual environment. The animals were maintained throughout the first year of life either in total darkness or in an enclosure illuminated intermittently by a strobe light. Following the period of deprivation, electrophysiologic recordings were taken from some of these animals. The remaining cats were permitted 6–12 months in a normally-illuminated environment prior to recording. Cats of the same age reared from birth in a normally lit environment were also recorded.Cortical neurons in cats deprived of any normal visual experience rarely show orientation selective responses. In animals allowed subsequent normal visual experience about one-half of the units studied exhibited this property. This level of response specificity is intermediate between that of normally-reared and recently-deprived animals. While most cortical units in normally-reared cats exhibit direction selectivity, this property is rarely observed in the recovery cats. A number of unit types which are rarely observed in either normal or totally deprived animals were encountered in cats that had normal exposure following prolonged deprivation. A convergent strabismus was observed, in contrast with the divergent strabismus often shown by cats immediately following prolonged visual deprivation. This shows that ocular alignment as well as cortical unit properties can remain plastic in the adult.Supported by NRC Grant No. A9939 and M.R.C. Grant No. MA5201 (to M.C.) and Grants from NIH and the Sloan Foundation (to A.H.).     

Expression of a calpastatin transgene slows muscle wasting and obviates changes in myosin isoform expression during murine muscle disuse

Muscle wasting is a prominent feature of several systemic diseases, neurological damage and muscle disuse. The contribution of calpain proteases to muscle wasting in any instance of muscle injury or disease has remained unknown because of the inability to specifically perturb calpain activity in vivo . We have generated a transgenic mouse with muscle-specific overexpression of calpastatin, which is the endogenous inhibitor of calpains, and induced muscle atrophy by unloading hindlimb musculature for 10 days. Expression of the transgene resulted in increases in calpastatin concentration in muscle by 30- to 50-fold, and eliminated all calpain activity that was detectable on zymograms. Muscle fibres in ambulatory, transgenic mice were smaller in diameter, but more numerous, so that muscle mass did not differ between transgenic and non-transgenic mice. This is consistent with the role of the calpain-calpastatin system in muscle cell fusion that has been observed in vitro . Overexpression of calpastatin reduced muscle atrophy by 30 % during the 10 day unloading period. In addition, calpastatin overexpression completely prevented the shift in myofibrillar myosin content from slow to fast isoforms, which normally occurs in muscle unloading. These findings indicate that therapeutics directed toward regulating the calpain-calpastatin system may be beneficial in preventing muscle mass loss in muscle injury and disease.     

The Turner syndrome research registry: Creating equipoise between investigators and participants

To address knowledge gaps about Turner syndrome (TS) associated disease mechanisms, the Turner Syndrome Society of the United States created the Turner Syndrome Research Registry (TSRR), a patient‐powered registry for girls and women with TS. More than 600 participants, parents or guardians completed a 33‐item foundational survey that included questions about demographics, medical conditions, psychological conditions, sexuality, hormonal therapy, patient and provider knowledge about TS, and patient satisfaction. The TSRR platform is engineered to allow individuals living with rare conditions and investigators to work side‐by‐side. The purpose of this article is to introduce the concept, architecture, and currently available content of the TSRR, in anticipation of inviting proposals to utilize registry resources.