Increases in adipose and total body weight,but not in lean body mass,associated with subcutaneous administration of Sonic hedgehog‐Ig fusion protein to mice

Sonic hedgehog (Shh) is a member of a family of proteins that are involved in embryonic development. The receptor signaling pathways for Shh persist in adults and stimulation of this pathway has shown therapeutic efficacy in animal models of neurodegeneration/regeneration. This study was conducted to evaluate the safety of repeat dose administration of an IgG fusion protein of Shh (Shh‐Ig) in adult mice. Routine toxicology evaluations were performed. In addition, body composition analysis was conducted by densitometry. Shh‐Ig treatment caused a significant increase in body weight gain relative to controls and a slight increase in liver and spleen weights. The increase in body weight could be largely accounted for by an increase in body fat. The treatment‐related increases in body weight were reversible upon cessation of treatment. Shh‐Ig treatment produced no significant changes in clinical chemistry or hematology. There were no gross or histomorphologic findings in any tissue except for skin and spleen. Microscopic findings in the skin were limited to minimal to slight local epidermal hyperplasia at the sc injection site and increased thickness of the fat layer. In the spleen a slight increase in extramedullary hematopoiesis was seen. This finding is possibly a secondary response following inflammation at the injection site in some animals due to the administration of a foreign protein. This study showed that Shh‐Ig administration was well tolerated. The most significant finding was a reversible increase in body weight. Drug Dev. Res. 57:107–114, 2002. © 2002 Wiley‐Liss, Inc.     

Genome regulation in mammalian cells

A theory is presented proposing that genetic regulation in mammalian cells is at least a two-tiered effect; that one level of regulation involves the transition between gene exposure and sequestration; that normal differentiation requires a different spectrum of genes to be exposed in each separate state of differentiation; that the fiber systems of the cell cytoskeleton and the nuclear matrix together control the degree of gene exposure; that specific phosphorylation of these elements causes them to assume a different organizational network and to impose a different pattern of sequestration and exposure on the elements of the genome; that the varied gene phosphorylation mechanisms in the cell are integrated in this function; that attachment of this network system to specific parts of the chromosomes brings about sequestration or exposure of the genes in their neighborhood in a fashion similar to that observed when microtubule elements attach through the kinetochore to the centromeric DNA; that one function of repetitive sequences is to serve as elements for the final attachment of this fibrous network to the specific chromosomal loci; and that at least an important part of the calcium manifestation as a metabolic trigger of different differentiation states involves its acting as a binding agent to centers of electronegativity, in particular proteins and especially phosphorylated groups, so as to change the conformation of the fiber network that ultimately controls gene exposure in the mammalian cell. It would appear essential to determine what abnormal gene exposures and sequestrations are characteristic of each type of cancer; which agonists, if any, will bring about reverse transformation; and whether these considerations can be used in therapy.     

Relationships of physical job tasks and living conditions with occupational injuries in coal miners

This study assessed the relationships of job tasks and living conditions with occupational injuries among coal miners. The sample included randomly selected 516 underground workers. They completed a standardized self-administred questionnaire. The data were analyzed via logistic regression method. The rate of injuries in the past two years was 29.8%. The job tasks with significant crude relative risks were: power hammer, vibrating hand tools, pneumatic tools, bent trunk, awkward work posture, heat, standing about and walking, job tasks for trunk and upper/lower limbs, pain caused by work, and muscular tiredness. Logistic model shows a strong relationship between the number of job tasks (JT) and injuries (adjusted ORs vs. JT 0-1: 2.21, 95%CI 1.27-3.86 for JT 2-6 and 3.82, 2.14-6.82 for JT>or=7), and significant ORs>or=1.71 for face work, not-good-health-status, and psychotropic drug use. Musculoskeletal disorders and certain personality traits were also significant in univariate analysis. Therefore job tasks and living conditions strongly increase the injuries, and occupational physicians could help workers to find remedial measures.     

Adrenalectomy decreases amino-acid transport in hepatocytes

The effect of adrenalectomy on basal and hormone-stimulated amino-acid transport in liver was investigated by measuring the uptake of α-aminoisobutyric acid in freshly isolated rat hepatocytes. Adrenalectomy resulted in a 50% decrease m the transport capacity of hepatocytes; this change was accounted for by a diminution in the V_max of a low affinity component of transport and specifically affected the A-transport system. Cortisone therapy fully restored the capacity of hepatocytes to transport amino acids. Sensitivity and responsiveness of hepatocytes from adrenalectomized animals to insulin, glucagon and dexamethasone, tested for the capacity of these hormones to stimulate AIB transport in vitro, were essentially identical with that of hepatocytes from control rats. The results support the concept of a positive (stimulatory) role of glucocorticoids in vivo, in the regulation of ammo acid transport in the liver.     

PET imaging in the surgical management of pediatric brain tumors

Objective The present article illustrates whether positron-emission tomography (PET) imaging may improve the surgical management of pediatric brain tumors (PBT) at different steps. Materials and methods Among 400 consecutive PBT treated between 1995 and 2005 at Erasme Hospital, Brussels, Belgium, we have studied with ¹⁸ F-2-fluoro-2-deoxy-D-glucose (FDG)–PET and/or L-(methyl-¹¹C)methionine (MET)–PET and integrated PET images in the diagnostic workup of 126 selected cases. The selection criteria were mainly based on the lesion appearance on magnetic resonance (MR) sequences. Cases were selected when MR imaging showed limitations for (1) assessing the evolving nature of an incidental lesion (n = 54), (2) selecting targets for contributive and accurate biopsy (n = 32), and (3) delineating tumor tissue for maximal resection (n = 40). Whenever needed, PET images were integrated in the planning of image-guided surgical procedures (frame-based stereotactic biopsies (SB), frameless navigation-based resections, or leksell gamma knife radiosurgery). Results Like in adults, PET imaging really helped the surgical management of the 126 children explored, which represented about 30% of all PBT, especially when the newly diagnosed brain lesion was (1) an incidental finding so that the choice between surgery and conservative MR follow-up was debated, and (2) so infiltrative or ill-defined on MR that the choice between biopsy and resection was hardly discussed. Integrating PET into the diagnostic workup of these two selected groups helped to (1) take a more appropriate decision in incidental lesions by detecting tumor/evolving tissue; (2) better understand complex cases by differentiating indolent and active components of the lesion; (3) improve target selection and diagnostic yield of stereotactic biopsies in gliomas; (4) illustrate the intratumoral histological heterogeneity in gliomas; (5) provide additional prognostic information; (6) reduce the number of trajectories in biopsies performed in eloquent areas such as the brainstem or the pineal region; (7) better delineate ill-defined PBT infiltrative along functional cortex than magnetic resonance imaging (MRI); (8) increase significantly, compared to using MRI alone, the number of total tumor resection and the amount of tumor tissue removed in PBT for which a total resection is a key-factor of survival; (9) target the resection on more active areas; (10) improve detection of tumor residues in the operative cavity at the early postoperative stage; (11) facilitate the decision of early second-look surgery for optimizing the radical resection; (12) improve the accuracy of the radiosurgical dosimetry planning. Conclusions PET imaging may improve the surgical management of PBT at the diagnostic, surgical, and post-operative steps. Integration of PET in the clinical workup of PBT inaugurates a new approach in which functional data can influence the therapeutic decision process. Although metabolic information from PET are valid and relevant for the clinical purposes, further studies are needed to assess whether PET-guidance may decrease surgical morbidity and increase children survival.     

Low local recurrence rate without postmastectomy radiation in node-negative breast cancer patients with tumors 5 cm and larger

PURPOSE: To assess the need for adjuvant radiotherapy following mastectomy for patients with node-negative breast tumors 5 cm or larger. METHODS AND MATERIALS: Between 1981 and 2002, a total of 70 patients with node-negative breast cancer and tumors 5 cm or larger were treated with mastectomy and adjuvant systemic therapies but without radiotherapy at three institutions. We retrospectively assessed rates and risk factors for locoregional failure (LRF), overall survival (OS), and disease-free survival (DFS) in these patients. RESULTS: With a median follow-up of 85 months, the 5-year actuarial LRF rate was 7.6% (95% confidence interval, 3%-16%). LRF was primarily in the chest wall (4/5 local failures), and lymphatic-vascular invasion (LVI) was statistically significantly associated with LRF risk by the log-rank test (p=0.017) and in Cox proportional hazards analysis (p=0.038). The 5-year OS and DFS rates were 83% and 86% respectively. LVI was also significantly associated with OS and DFS in both univariate and multivariate analysis. CONCLUSIONS: This series demonstrates a low LRF rate of 7.6% among breast cancer patients with node-negative tumors 5 cm and larger after mastectomy and adjuvant systemic therapy. Our data indicate that further adjuvant radiation therapy to increase local control may not be indicated by tumor size alone in the absence of positive lymph nodes. LVI was significantly associated with LRF in our series, indicating that patients with this risk factor require careful consideration with regard to further local therapy.