Constitutive secretion of the granule chymase mouse mast cell protease-1 and the chemokine, CCL2, by mucosal mast cell homologues

BACKGROUND: The mucosal mast cell (MMC) granule-specific beta-chymase, mouse mast cell protease-1 (mMCP-1), is released systemically into the bloodstream early in nematode infection before parasite-specific IgE responses develop and TGF-beta1 induces constitutive release of mMCP-1 by homologues of MMC in vitro. Intraepithelial MMC may also express the chemokine CCL2 (monocyte chemotactic protein-1) during nematode infection but the expression of this chemokine by MMC homologues has not been investigated. OBJECTIVE: To investigate the expression and to compare the mechanisms of constitutive release of the chymase, mMCP-1, and the chemokine, CCL2. METHODS: MMC homologues were generated by culturing bone marrow cells in the presence of TGF-beta1, IL-3, IL-9 and stem cell factor (SCF). The intracellular distribution of mMCP-1 and CCL2 was examined by confocal microscopy. The involvement of the Golgi complex and of protein synthesis in the constitutive release of mMCP-1 and CCL2 was investigated using the Golgi-disrupting agent brefeldin A and cycloheximide to block protein synthesis. Secreted analytes were quantified by ELISA. RESULTS: mMCP-1 colocalized with Golgi matrix protein 130 but was most abundant in the granules, whereas CCL2 was not found in the granules but appeared to be located uniquely in the Golgi complex. Extracellular release of mMCP-1 was significantly inhibited ( approximately 40%) by cycloheximide and by the Golgi-disrupting agent brefeldin A, indicating both continuous protein synthesis and transportation via the Golgi complex are required for optimal mMCP-1 secretion. A similar but more marked inhibitory effect with both compounds was demonstrated on the constitutive secretion of CCL2. CONCLUSION: The culture conditions that promote mMCP-1 expression and release by MMC homologues also promote the expression and release of CCL2. Constitutive release involves de novo protein synthesis and requires a functional Golgi complex, suggesting that similar mechanisms of extracellular secretion operate for both mediators.     

Ziprasidone in the treatment of mania in bipolar disorder

Ziprasidone is an atypical antipsychotic with a unique receptor-binding profile. Currently, ziprasidone is approved by the US Food and Drug Administration for the acute treatment of psychosis in schizophrenia and mania in bipolar disorder. When compared to certain other atypical antipsychotics, ziprasidone appears to have a relatively benign side effect profile, especially as regards metabolic effects eg, weight gain, serum lipid elevations and glucose dysregulation. Taken together, these data suggest that ziprasidone may be a first line treatment for patients with bipolar mania. However, ziprasidone is a relatively new medication for which adverse events after long-term use and/or in vulnerable patient populations must be studied. Unstudied areas of particular importance include the efficacy and safety of ziprasidone in the treatment of bipolar depression and relapse prevention of mania as, well as in the subpopulations of pregnant women, the elderly and pediatric patients. The emergence of mania in patients taking ziprasidone is another topic for further study.     

Smoking delays chondrogenesis in a mouse model of closed tibial fracture healing.

Smoking delays the healing process and increases morbidity associated with many common musculoskeletal disorders, including long bone fracture. In the current study, a murine model of tibial fracture healing was used to test the hypothesis that smoking delays chondrogenesis after fracture. Mice were divided into two groups, a nonsmoking control group and a group exposed to cigarette smoke for 1 month prior to surgical tibial fracture. Mice were euthanized at 7, 14, and 28 days after surgery. The outcomes measured were immunohistochemical staining for type II collagen protein expression as a marker of cartilage matrix and proliferating cell nuclear antigen (PCNA) staining to measure proliferation at the site of injury. Toluidine blue staining and histomorphometry were used to quantify areas of cartilaginous and noncartilaginous fracture callus. Radiographs were analyzed for evidence of remodeling after injury. At day 7 after injury, mice exposed to cigarette smoke had a smaller fracture callus with less cartilage matrix compared to controls. Proliferation was present at high levels in both groups at this time point, but proliferating cells had a more immature morphology in the smoking group. At day 14, chondrogenesis was more active in smokers compared to controls, while a higher percentage of bone was present in the control animals. At day 28, X-ray analysis revealed a larger fracture callus remaining in the smoking animals. Together, these findings show that the chondrogenic phase of tibial fracture healing is delayed by smoking. This study represents, to our knowledge, the first analysis of molecular and cellular mechanisms of healing in a smoking mouse fracture model.     

Spinal injuries in children

We reviewed 47 children with spinal injuries. Three distinct patterns of injury were observed: subluxations and dislocations without a fracture (type 1), spinal cord injury without radiographic abnormality (type 2), and spinal fractures which may be associated with subluxation or dislocation (type 3), The neurological recovery was poor in complete lesions associated with type 2 injuries.     

Neurologic Evaluation of Infant and Adult Rats before and after Sciatic Nerve Blockade

Background: Only limited data exist comparing differences in sensory function and responses to neural blockade in infant and adult rats. Therefore, the authors sought (1) to compare baseline thermal, proprioceptive, and postural responses in infant, adolescent, and adult rats; and (2) to compare the effects of sciatic nerve blockade on thermal, proprioceptive, and postural responses in infant, adolescent, and adult rats.

Methods: Infant, adolescent, and adult rats were evaluated for proprioceptive, thermal, and mechanical nociceptive and motor function before and after sciatic blockade using a detailed neurologic examination.

Results: Mechanical and thermal nociception were present in all rats, starting from age 1 day. The withdrawal reflex latency to pinch was rapid at all ages, whereas that reaction to thermal stimulus depended on both age and temperature. In contrast, the tactile placing response and hopping response were absent at birth and developed completely during the first 10 days of life. The extensor postural thrust was absent in the first 2 weeks of life and developed variably during the first 50 days of life. Sciatic blockade duration is shorter in infant rats than in adult rats receiving the same dose per kilogram. A brief halothane general anesthetic at the time of sciatic injection in infant or adult rats does not alter the duration of blockade.