Mental stress ischemia: present status and future goals

Summary  A body of research published over the past 20 years has revealed much concerning the prevalence, pathophysiology, and prognosis associated with MSI while also providing promising approaches to improving event-free survival rates in those who have this form of ischemia. Although many important questions remain, we believe that the findings to date provide sufficient evidence for the planning, development, and execution of a large-scale clinical trial. Such a trial would provide for not only further testing of prognostic significance and treatment effects but also explorations into important remaining questions of pathophysiology while elaborating possible additional modalities for treatment. Our collective expertise in nuclear cardiology provides an opportunity to establish the diagnostic standardization, approach, and assessment of prognosis and treatment. We are in a position to be thought leaders of a complex clinical manifestation of ischemia that has substantial clinical impact. This work was supported by a VA Merit Review Grant award to Drs Burg and Soufer and by R01 awards (HL59619-01 and HL071116-01) from the National Heart, Lung, and Blood Institute to Dr Soufer.     

Therapeutic vaccination with papillomavirus E6 and E7 long peptides results in the control of both established virus-induced lesions and latently infected sites in a pre-clinical cottontail rabbit papillomavirus model

This study was performed to test the therapeutic efficacy of overlapping long E6 and E7 peptides, containing both CD4+ T-helper and CD8+ CTL epitopes, on CRPV-induced lesions, which is an appropriate pre-clinical model for HPV diseases, including recurrent respiratory papillomatosis (RRP). Therapeutic peptide vaccination was able to significantly control wart growth (p < 0.01) and abrogate latent CRPV infection (p = 0.0006) compared to controls. Vaccination was associated with a T(H)1 T cell response, as suggested by a strong DTH skin test, antigen-specific proliferation of PBMC and a minimal IgG antibody response. Thus, this study shows promise for treatment of RRP by vaccination with long peptides.     

Cervical adult rhabdomyoma presenting as a rapidly growing mass in a patient with diffuse large B-cell non-Hodgkin’s lymphoma

Background

Adult rhabdomyoma is a rare mesenchymal tumor, which generally grows slowly and is mainly localized in the head and neck area.

Patient and methods

We report the extraordinary case of a rapidly growing adult rhabdomyoma in a 73-year-old man. The patient was treated for diffuse large B-cell non-Hodgkin’s lymphoma with CHOP therapy (doxorubicin, cyclophosphamide, vincristine, and prednisone). Comparison of the respective computed tomography scans showed prominent enlargement of 35% in the tumor mass volume on the right side of the neck within 3 months. The tumor was highly suspicious for lymphoma. Surgical resection was performed.

Results

Histological examination revealed a tumor which was composed of tightly packed polygonal cells with a PAS-positive granular or vacuolated cytoplasm, occasionally with cross-striations. Immunohistochemically, the cells were positive for desmin, myogenin, Myo-D1, but negative for S-100. Due to these characteristic morphologies, adult rhabdomyoma was diagnosed.

Conclusion

This is the first report on an adult rhabdomyoma with a proven rapid enlargement. The possible pathomechanisms are discussed.     

Cervical adult rhabdomyoma presenting as a rapidly growing mass in a patient with diffuse large B-cell non-Hodgkin’s lymphoma

Background Adult rhabdomyoma is a rare mesenchymal tumor, which generally grows slowly and is mainly localized in the head and neck area.Patient and methods We report the extraordinary case of a rapidly growing adult rhabdomyoma in a 73-year-old man. The patient was treated for diffuse large B-cell non-Hodgkins lymphoma with CHOP therapy (doxorubicin, cyclophosphamide, vincristine, and prednisone). Comparison of the respective computed tomography scans showed prominent enlargement of 35% in the tumor mass volume on the right side of the neck within 3 months. The tumor was highly suspicious for lymphoma. Surgical resection was performed.Results Histological examination revealed a tumor which was composed of tightly packed polygonal cells with a PAS-positive granular or vacuolated cytoplasm, occasionally with cross-striations. Immunohistochemically, the cells were positive for desmin, myogenin, Myo-D1, but negative for S-100. Due to these characteristic morphologies, adult rhabdomyoma was diagnosed.Conclusion This is the first report on an adult rhabdomyoma with a proven rapid enlargement. The possible pathomechanisms are discussed.     

An improved organ culture for regeneration of pure autologous keratinocytes from small split-thickness skin specimens

BACKGROUND: Failure of autologous keratinocyte culture from small split-thickness skin specimens or contamination of the keratinocyte culture by melanocytes represents practical problems in basic medical research and clinical studies. PURPOSE: To establish a simple and reliable method of harvesting pure autologous keratinocytes from a small split-thickness skin specimen. METHODS: Split-thickness (0.3 mm) skin explants (1 x 2 mm) were firstly cultured in DMEM containing 10% FCS till formation of keratinocyte strips, then cultured in serum-free keratinocyte growth medium or cocultured with lethally irradiated 3T3 fibroblasts (J2) in a mixture of DMEM and Ham's F12 (DF) medium. RESULTS: Pure autologous keratinocyte culture is easily and reliably established by this organ culture technique. CONCLUSION: Culturing of skin explants in serum-free keratinocyte growth medium or coculturing of the skin explants with lethally irradiated 3T3 cells in DF medium is proved to be a useful, simple and reliable method of harvesting pure autologous keratinocytes from a small split-thickness skin biopsy.     

Intrathecal injection of GDNF and BDNF induces immediate early gene expression in rat spinal dorsal horn

Glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) are potent trophic factors for dorsal root ganglion cells. In addition, these factors are produced in subsets of dorsal root ganglion cells and transported anterogradely to their terminals in the superficial dorsal horn of the spinal cord, where they constitute the only source of GDNF and BDNF. We investigated the effect of 10 mug GDNF and BDNF injected by lumbar puncture on the expression of the immediate early gene (IEG) products c-Fos, c-Jun, and Krox-24 in the adult rat dorsal horn. In the dorsal horn of S1 spinal segments, GDNF and BDNF induced a strong increase in IEG expression, which was most pronounced in laminae I and II (2.9- to 4.5-fold). More distal from the injection site, in the dorsal horn of L1/L2 spinal segments, the increase in IEG expression was less pronounced, suggesting a concentration-dependent effect. In order to explain the effects of intrathecally injected GDNF, we investigated whether lumbo-sacral dorsal horn neurons expressed RET protein, the signal-transducing element of the receptor complex for GDNF. It was found that several of these neurons contained RET immunoreactivity and that some of the RET-labeled neurons had the appearance of nociceptive-specific cells, confirming their presumed role in pain transmission. Additionally, using double-labeling immunofluorescence combined with confocal microscopy, it was found that after intrathecal GDNF injection 35% of c-Fos-labeled cells were also labeled for RET. These results demonstrate that intrathecally administered GDNF and BDNF induce IEG expression in dorsal horn neurons in the adult rat, supposedly by way of their cognate receptors, which are present on these neurons. We further suggest that the endogenous release of GDNF and BDNF, triggered by nociceptive stimuli, is involved in the induction of changes in spinal nociceptive transmission as in various pain states.     

Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial

PURPOSE: The large and well-characterized population of acute myocardial infarction (AMI) patients studied in the recently completed Enhancing Recovery in Coronary Heart Disease (ENRICHD) multicenter clinical trial provides a unique opportunity to examine the importance of self-reported regular physical exercise in a large cohort of patients with a recent AMI who are depressed or report low levels of social support. METHODS: We prospectively examined the association between self-reported physical exercise and all-cause mortality and cardiovascular morbidity among 2078 men (N = 1175; 56.5%) and women (N = 903; 43.5%) with an AMI participating in the ENRICHD Trial. Six months after suffering an AMI, patients were surveyed about their exercise habits and were then followed for up to 4 yr. RESULTS: During an average 2 yr of follow-up, 187 fatal events occurred. Patients reporting regular exercise had less than half the events (5.7%) of those patients reporting they did not regularly exercise (12.0%). After adjustment for medical and demographic variables, the hazard ratio for fatal events was 0.62 (95% CI = 0.44-0.86, P = 0.004). The rate of nonfatal AMI among the exercisers was 6.5% compared with 10.5% who reported no regular exercise. After adjustment for covariates, the hazard ratio for nonfatal AMI was 0.72 (95% CI = 0.52-0.99, P = 0.044). CONCLUSIONS: The present findings demonstrate the potential value of exercise in reducing mortality and nonfatal reinfarction in AMI patients at increased risk for adverse events by virtue of their either being depressed or having low social support.     

Control of organ transplant-associated graft-versus-host disease by activated host lymphocyte infusions

BACKGROUND: Prolonged persistence of donor-derived T cells after organ transplantation has been proposed to improve long-term allograft survival. However, surviving transplant-derived T cells are also able to mediate devastating graft-versus-host disease (GvHD). Currently, GvHD after organ transplantation is usually refractory to conventional therapy and the disease outcome fatal. METHODS: Graft-reactive host T cells were generated ex vivo from a patient suffering from a severe and refractory liver-transplant-associated GvHD. To control GvHD, activated alloreactive host T cells were repetitively retransferred into the patient (activated host lymphocyte infusion [aHLI]). RESULTS: Adoptive transfer of ex vivo activated alloreactive host T cells (aHLI) led to the control and complete resolution of severe GvHD without inducing allograft rejection. CONCLUSIONS: aHLI opens a novel therapeutic window to control solid-organ transplant-associated GvHD while preserving allograft integrity.     

Bioreactor microcarrier cell culture system (Bio-MCCS) for large-scale production of autologous melanocytes

Restoration of cutaneous pigmentation can be achieved in stable vitiligo by autologous cultured melanocyte transplantation. It was the goal of this study to construct a bioreactor microcarrier cell culture system (Bio-MCCS) to produce autologous melanocytes in large scale. In this Bio-MCCS, porcine gelatin microbeads were used as microcarriers, spinning bottle as fermented tank. Autologous melanocytes were able to attach to and proliferate on the gelatin microbeads in serum-free melanocyte medium in the Bio-MCCS, reaching up to 24-fold the cells seeded on day 15 (MTT assay). These autologous melanocytes cultured on gelatin microbeads could leave the microbeads and proliferate on the bottom of tissue culture flasks. Although Pluronic F68 has been widely used to protect animal cells from hydrodynamic stress in animal cell bioreactors, Pluronic F68 at a concentration of 0.25-1.0% showed no significant protective effects on the autologous melanocytes cultured on the microbeads and subjected to mechanical stress in the Bio-MCCS. This Bio-MCCS using porcine gelatin microbeads as microcarriers enabled large-scale production of autologous melanocytes, offering a potential treatment for large-area stable vitiligo by direct administration of the melanocytes cultured on the gelatin microbeads to the vitiliginous site.