Inhibition of calcineurin phosphatase activity in adult bone marrow transplant patients treated with cyclosporine A

In vitro studies have demonstrated that cyclosporine A (CsA) acts by inhibiting the phosphatase activity of calcineurin, an important mediator of T-cell activation. The relationship of CsA administration in vivo, calcineurin activity, and graft-versus-host disease (GVHD) has yet to be studied. The calcineurin activities of mononuclear cells isolated from 62 bone marrow transplant recipients and 12 normal volunteers were determined and analyzed with respect to administration of CsA, presence or absence of CsA in plasma, and presence or absence of GVHD. Of 62 patients, 33 were taking CsA and 29 were not. Early posttransplant (< 100 days), the calcineurin activity of patients on CsA was significantly lower than that of patients not on CsA (P = .0004) and than that of normal volunteers (P < .0001). Similarly, late posttransplant (> 100 days), the calcineurin activity of patients taking CsA was inhibited compared with normal volunteers (P < .05). The calcineurin activity of patients with acute GVHD who were taking CsA was lower than that of patients on CsA without acute GVHD matched for time posttransplant (P = .02). Calcineurin activity in patients on CsA with chronic GVHD was similar to those without chronic GVHD on drug. In conclusion, calcineurin activity is significantly suppressed by in vivo administration of CsA. The lower calcineurin activity of patients on CsA with acute GVHD suggests that CsA-resistant GVHD is not the result of inadequate suppression of calcineurin activity. These data suggest that if inhibition of calcineurin is the only physiologic target of CsA administration, simply increasing doses of CsA or treatment with other inhibitors of calcineurin, such as FK506, would not be expected to ameliorate GVHD.     

Interhospital transfer of the critically ill trauma patient: the potential role of a specialist transport team in a trauma system.

A specialist transfer team based in the regional intensive therapy unit (ITU) at the Western Infirmary, Glasgow, acts as a central interhospital retrieval team for Glasgow and the west of Scotland. The establishment of trauma systems has been proposed. This paper describes the activities of the specialist transfer team to illustrate the potential role of a central retrieval team within such a system.     

Characterizing the mitogenic effect of basic fibroblast growth factor in the adult rat striatum

The limited regenerative capacity of the adult central nervous system (CNS) renders it unable to fully recover from injury or disease. Although stem and progenitor cells have been shown to reside throughout the brain, in most regions they exist as quiescent cell populations and do not divide sufficiently to replace damaged or destroyed cells. In an effort to stimulate the proliferative capacity of these multipotent cells, we sought to determine the in vivo response of the adult CNS to an exogenous application of basic fibroblast growth factor (bFGF), a known mitogen to stem and progenitor cells. Specifically, we administered bFGF to the striatum of adult rats at varying concentrations (1, 10, 100, 1,000, or 10,000 ng/mL in saline) so as to establish a dose response curve for bFGF-induced cell proliferation. Forty-eight hours following bFGF administration, animals were injected with 5-bromodeoxyuridine to label dividing cells. Of the doses assessed, we found that 1,000 ng/mL bFGF generated the greatest proliferative response over that observed in animals given a control saline injection. Further, the proliferative response of the striatum to bFGF administration could be enhanced twofold by supplementing this growth factor with heparin sulfate, a factor that facilitates the binding of bFGF to its receptors. By determining the maturational fate of the proliferating cell population, we found that a significant proportion of newly generated cells resulting from bFGF administration differentiated into astrocytes. Collectively, these studies demonstrate the potential of bFGF to promote proliferation in the adult brain, which can be exploited to facilitate cell replacement therapies.     

A Multi-Institutional Phase II Trial of Preoperative Full-Dose Gemcitabine and Concurrent Radiation for Patients With Potentially Resectable Pancreatic Carcinoma

Background We report the results of a multi-institutional phase II trial that used preoperative full-dose gemcitabine and radiotherapy for patients with potentially resectable pancreatic carcinoma. Methods Patients were treated before surgery with three cycles of full-dose gemcitabine (1000 mg/m² intravenously), with radiation during the second cycle (36 Gy in daily 2.4-Gy fractions). Patients underwent surgery 4 to 6 weeks after the last gemcitabine infusion. Results There were 10 men and 10 women, with a median age of 58 years (range, 50–80 years). Nineteen patients (95%) completed therapy without interruption, and one experienced grade 3 gastrointestinal toxicity. The mean weight loss after therapy was 4.0%. Of 20 patients taken to surgery, 17 (85%) underwent resections (16 pancreaticoduodenectomies and 1 distal pancreatectomy). The complication rate was 24%, with an average length of stay of 13.5 days. There were no operative deaths. Pathologic analysis revealed clear margins in 16 (94%) of 17 and uninvolved lymph nodes in 11 (65%) of 17 specimens. One specimen contained no residual tumor, and three specimens revealed only microscopic foci of residual disease. With a median follow-up of 18 months, 7 (41%) of the 17 patients with resected disease are alive with no recurrence, 3 (18%) are alive with distant metastases, and 7 (41%) have died. Conclusions Preoperative gemcitabine/radiotherapy is well tolerated and safe when delivered in a multi-institutional setting. This protocol had a high rate of subsequent resection, with acceptable morbidity. The high rate of negative margins and uninvolved nodes suggests a significant tumor response. Preliminary survival data are encouraging. This regimen should be considered in future neoadjuvant trials for pancreatic cancer.     

SNAP-25 deficit and hippocampal connectivity in schizophrenia

Regional abnormalities of brain connectivity may be an important substrate for the expression of schizophrenia, a severe form of mental illness. Brain imaging and postmortem morphometric studies indicate hippocampal structure is abnormal in schizophrenia. To study molecular components of hippocampal connectivity the presynaptic proteins SNAP-25 and synaptophysin were assayed in postmortem samples. Immunocytochemical studies indicated reduced SNAP-25 immunoreactivity in schizophrenia compared to controls, particularly in the terminal fields of entorhinal cortex projections. Although there were no overall changes in synaptophysin immunoreactivity, in the granule cell layer of the dentate gyrus synaptophysin immunoreactivity was increased in schizophrenia. These results indicate that disconnection of a subset of hippocampal circuitry from the entorhinal cortex, as well as intrinsic changes in hippocampal connectivity, may contribute to the mechanism of illness in schizophrenia.