Acinar pattern of mammary Paget's disease: a case report.

Mammary Paget's disease (MPD) is an uncommon in situ neoplasm of the nipple-areolar complex and surrounding skin. It is almost always associated with mammary ductal carcinoma in situ (DCIS), high-grade or invasive carcinoma, usually of ductal origin. MPD has only rarely been described in association with specialized forms of breast carcinoma. We report an unusual case of an acinar pattern of MPD with low-grade cytological atypia, associated with invasive papillary carcinoma and micropapillary DCIS of the lactiferous ducts, in an 83-year-old woman. Most cases of MPD are characterized by intraepidermal spread of discohesive glandular epithelial cells with high-grade nuclear atypia. A predominant acinar pattern of MPD is extremely uncommon and, to our knowledge, has not been formally reported. The histological features and differential diagnosis are discussed.

Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation.

Cerebral vasospasm is a common, formidable, and potentially devastating complication in patients who have sustained subarachnoid hemorrhage (SAH). Despite intensive research efforts, cerebral vasospasm remains incompletely understood from both the pathogenic and therapeutic perspectives. At present, no consistently efficacious and ubiquitously applied preventive and therapeutic measures are available in clinical practice. Recently, convincing data have implicated a role of inflammation in the development and maintenance of cerebral vasospasm. A burgeoning (although incomplete) body of evidence suggests that various constituents of the inflammatory response, including adhesion molecules, cytokines, leukocytes, immunoglobulins, and complement, may be critical in the pathogenesis of cerebral vasospasm. Recent studies attempting to dissect the cellular and molecular basis of the inflammatory response accompanying SAH and cerebral vasospasm have provided a promising groundwork for future studies. It is plausible that the inflammatory response may indeed represent a critical common pathway in the pathogenesis of cerebral vasospasm pursuant to SAH. Investigations into the nature of the inflammatory response accompanying SAH are needed to elucidate the precise role(s) of inflammatory events in SAH-induced pathologies.

Human mesenchymal stem cells transduced with recombinant bone morphogenetic protein-9 adenovirus promote osteogenesis in rodents.

The present study was undertaken to determine whether ex vivo bone morphogenetic protein-9 (BMP-9) gene therapy using human mesenchymal stem cells (hMSCs) can induce endochondral bone formation in athymic nude rats. An in vitro study was initially performed on hMSCs to evaluate morphological changes and osteoblastic differentiation induced by replication-defective adenovirus type 5 with the cytomegalovirus promoter and either the BMP-9 (Ad-BMP-9) or beta-galactosidase (Ad-beta-gal) gene. In vivo, athymic nude rats received an injection (10(6) hMSCs transduced with recombinant adenovirus at 50 PFU/cell) into the anterior thigh musculature: Ad-BMP-9 on the left and Ad-beta-gal (control) on the right. Computed tomography scans and histological analysis were obtained 7, 14, 28, 42, 56, and 84 days postinjection. In vitro, human mesenchymal stem cells treated with Ad-BMP-9 (50 PFU/cell) showed signs of differentiation, whereas hMSCs treated with 250 and 1250 PFU/cell showed cytotoxicity. In vivo, computed tomography and histological analysis clearly demonstrated ectopic bone at hMSC/Ad-BMP-9 treatment sites, whereas the hMSC/Ad-beta-gal treatment sites showed no evidence of osteogenesis. None of the animals showed clinical evidence of toxicity. Ex vivo gene therapy with hMSC/BMP-9 may be efficacious for promoting bone formation for a variety of bone pathologies and certainly warrants further investigations.

Chronic endothelin antagonism restores cerebrovascular function in diabetes.

OBJECTIVE: Diabetes profoundly alters vascular function and is a risk factor for cerebrovascular disease. Diabetes increases myogenic tone and decreases responsiveness to adenosine triphosphatase (ATP)-sensitive K(+) (K(ATP)) channel openers and endothelium-dependent vasodilators. The mechanism(s) by which diabetes impairs cerebrovascular function remain obscure. In the present study, the effects of the potent vasoactive peptide endothelin-1 on myogenic tone and endothelium-dependent and potassium channel-mediated vasodilation in middle cerebral arteries from diabetic and nondiabetic rats were investigated. METHODS: Twenty-eight Wistar rats were divided into four experimental groups (n = 7 per group): control (C), control treated with bosentan (an endothelin A/B receptor antagonist) (CB), diabetic (D), and diabetic bosentan-treated (DB). Diabetes was induced with streptozotocin (D and DB groups), after which chronic bosentan treatment was initiated (CB and DB groups). Middle cerebral arteries were mounted in a pressure myograph, and myogenic responses were recorded. In addition, endothelium-dependent and -independent responses and the effects of the K(ATP) channel opener pinacidil were examined. RESULTS: Cerebral arteries from the diabetic and nondiabetic rats constricted in response to graded pressure increases. Maximum myogenic responses (percent constriction at 60 mm Hg) were significantly greater in the D group (38 +/- 3% versus 25 +/- 3% in C; P < 0.02). The enhanced myogenic tone in the D group was completely prevented by bosentan treatment (DB, 23 +/- 5% versus D; P < 0.003) without an effect on the CB group. In addition, bosentan treatment improved endothelium-dependent vasomotion and improved K(ATP)-mediated vasodilation in the DB group (P < 0.001). CONCLUSION: These data describe, for the first time, the interaction between endothelin-1, myogenic tone, and endothelial function in diabetes. Chronic endothelin antagonism restores cerebrovascular function in this model of diabetes and has global implications for the management of cerebrovascular disease in diabetes.

Will improved understanding of the pathophysiological mechanisms involved in acute spinal cord injury improve the potential for therapeutic intervention?

At the dawning of the present decade, deemed appropriately the Decade of the Spine, acute spinal cord injury lingers as a formidable disorder affecting society. The enormous physical, emotional and socioeconomic impact of acute spinal cord injury on society is well known. Consequently, intensive clinical and laboratory research efforts have focused on furthering contemporary understanding of the mechanisms involved in primary and secondary injury following spinal cord injury. Additionally, research has been devoted to investigations concerning the treatment of acute spinal cord injury using a myriad of strategies, some of which involve rational targeting of known pathophysiological mechanisms. A recent surge of studies endeavoring to dissect the cellular and molecular mechanisms involved in the development and perpetuation of acute spinal cord injury appear particularly promising as a basis for identifying candidate pathways of injury for therapeutic manipulation. Meritorious investigations examining changes in gene expression, especially pertaining to pathways of cell death and inflammation, are increasingly reported. Molecular therapies harnessing knowledge gleaned from the aforementioned groundwork, including stem cell transplantation, likely represent the future direction of treatment for acute spinal cord injury. The Decade of the Spine is poised to be a phase of advancement in the treatment of acute spinal cord injury and the importance of further elucidation of underlying pathophysiological mechanisms to targeted, rational therapy will likely become clearly evident.

Ex vivo bone morphogenetic protein-9 gene therapy using human mesenchymal stem cells induces spinal fusion in rodents.

OBJECTIVE: Ex vivo gene therapy with the use of human mesenchymal stem cells (hMSCs) and bone morphogenetic protein (BMP) genes provides a local supply of precursor cells and a supraphysiological dose of osteoinductive molecules that may promote bone formation in patients with inadequate hMSC populations because of age, osteoporosis, metastatic bone disease, iatrogenic depletion, or other metabolic derangements. This study was undertaken to evaluate the efficacy of ex vivo gene therapy with the use of hMSCs and the BMP-9 gene to promote spinal fusion in the rat. METHODS: Sixteen athymic nude rats were treated with hMSCs transduced with recombinant, replication-defective Type 5 adenovirus containing the cytomegalovirus promoter and either the BMP-9 (Ad-BMP-9) or the beta-galactosidase (Ad-beta-gal) gene. Ad-beta-gal served as the control. Each animal received a percutaneous, paraspinal injection of 10(6) hMSCs transduced with 50 plaque-forming units/cell adenovirus in the lumbar region, with Ad-BMP-9 on the left and Ad-beta-gal on the right. At 8 weeks postinjection, computed tomographic scans of the lumbosacral spine were obtained, and the lumbosacral spine specimens were examined histologically. RESULTS: Both computed tomographic studies and histological analysis clearly demonstrated large volumes of ectopic bone at the Ad-BMP-9-transduced hMSC injection sites, resulting in successful spinal fusion and no evidence of nerve root compression or local or systemic toxicity. The contralateral regions that were treated with Ad-beta-gal-transduced hMSCs showed no evidence of osteogenesis. CONCLUSION: The results of this study suggest that hMSC and BMP-9 ex vivo gene therapy may be useful in inducing spinal fusion as well as other related procedures and certainly warrants further clinical development.

Pharmacokinetics and protein binding of mycophenolic acid in stable lung transplant recipients.

Mycophenolate mofetil (MMF) use is increasing in solid organ transplantation. Mycophenolic acid (MPA), the active metabolite of MMF, is highly protein bound and only free MPA is pharmacologically active. The average MPA free fraction in healthy adult individuals, stable renal transplant recipients, and heart transplant recipients is approximately 2 to 3%. However, no data are currently available on MPA protein binding in stable lung transplant recipients and little is known regarding MPA's pharmacokinetic characteristics after lung transplantation. The purpose of this study was to characterize the pharmacokinetic profile and protein binding of MPA in this patient population. Seven patients were entered into the study. On administration of a steady-state morning MMF dose, blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 8, 9, 10, and 12 hours post-dose. Total MPA concentrations were measured by a validated HPLC method with UV detection and followed by ultrafiltration of pooled samples for free MPA concentrations. Area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), trough concentration (Cmin), free fraction (f), and free MPA AUC were calculated by traditional pharmacokinetic methods. Patient characteristics included; 3 males and 4 females, an average of 4.4 years post-lung transplant (range, 0.3-11.5 yr), mean (+/- SD) age of 50 +/- 10 years and weight 69 +/- 20 kg. Mean albumin concentration was 37 +/- 3 g/L and serum creatinine was 142 +/- 49 micromol/L. All patients were on cyclosporine and prednisone. MMF dosage ranged from 1 to 3 g daily (35.5 +/- 14.1 mg/kg/d; range, 15.2-60.0 mg/kg/d). Mean (+/- SD) AUC was 45.78 +/- 18.35 microg.h/mL (range, 16.56-74.22 microg.h/mL), Cmax was 17.37 +/- 7.69 microg/mL (range, 4.92-26.63 microg/mL), Tmax was 1.2 +/- 0.4 hours (range, 1.0-2.0 h), Cmin was 3.12 +/- 1.41 microg/mL (range, 1.47-4.82 microg/mL), f was 2.90 +/- 0.56% (range, 2.00-3.40%), and free MPA AUC was 1.29 +/- 0.50 microg.h/mL (range, 0.54-1.88 microg.h/mL). This is the first study to determine these pharmacokinetic characteristics of MPA in the lung transplant population. Further studies should focus on identification of MMF dosing strategies that optimize immunosuppressive efficacy and minimize toxicity in lung allograft recipients.