Incidence of BK with Tacrolimus Versus Cyclosporine and Impact of Preemptive Immunosuppression Reduction

Our purposes were to determine the incidence of BK viruria, viremia or nephropathy with tacrolimus (FK506) versus cyclosporine (CyA) and whether intensive monitoring and discontinuation of mycophenolate (MMF) or azathioprine (AZA), upon detection of BK viremia, could prevent BK nephropathy. We randomized 200 adult renal transplant recipients to FK506 (n = 134) or CyA (n = 66). Urine and blood were collected weekly for 16 weeks and at months 5, 6, 9 and 12 and analyzed for BK by polymerase chain reaction (PCR). By 1 year, 70 patients (35%) developed viruria and 23 (11.5%) viremia; neither were affected independently by FK506, CyA, MMF or AZA. Viruria was highest with FK506-MMF (46%) and lowest with CyA-MMF (13%), p = 0.005. Viruria >/= 9.5 log(10) copies/mL was associated with a 3-fold increased risk of viremia and a 13-fold increased risk of sustained viremia. After reduction of immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction or graft loss. No BK nephropathy was observed. Choice of calcineurin inhibitor or adjuvant immunosuppression, independently, did not affect BK viruria or viremia. Viruria was highest with FK506-MMF and lowest with CyA-MMF. Monitoring and preemptive withdrawal of immunosuppression were associated with resolution of viremia and absence of BK nephropathy without acute rejection or graft loss.     

Expression of type-X collagen in osteoarthritis

The present study was undertaken to examine how osteoarthritis affects the expression of type-X collagen, a hypertrophic chondrocyte-specific collagen in articular cartilage. A well characterized sheep polyclonal antiserum, as well as three mouse monoclonal antibodies against canine type-X collagen, was used to immunolocalize type-X collagen in human and canine joints. Its expression in osteoarthritic cartilage was altered in several locations. In the canine osteoarthritic joints, type-X collagen increased in and just above the zone of calcified cartilage and was present diffusely throughout the calcified matrix. In both the human and canine cartilage, type-X collagen was localized around cell clones in the transitional zone of cartilage. This is surprising, since that region of the cartilage does not calcify and one of the proposed roles of type-X collagen is in mineralization. Thus, the osteoarthritic process may damage the matrix in the superficial layer and induce changes leading to the expression of the hypertrophic chondrocyte phenotype.     

Image-directed percutaneous biopsies with a biopsy gun

Core tissue for histologic study is believed by many pathologists to be more diagnostic than material from needle aspiration. Recently, a biopsy "gun" has been introduced, which simplifies core biopsies. With this device, 182 biopsies of multiple anatomic sites were performed with ultrasonic, computed tomographic, and fluoroscopic guidance and 18-gauge needles. High-quality histopathologic specimens were obtained in 177 of the biopsies, and diagnostic target tissue was obtained in 167. Only three significant complications occurred: one bleeding complication that required transfusion and two cases of pneumothorax that necessitated placement of chest tubes. The biopsy gun eliminated the disjointed movements of conventional "skinny" needle biopsies, and none of the samples demonstrated significant "crush" artifact or obscuring blood, problems that are commonly associated with manual biopsy techniques. Patient discomfort was decreased with this system compared with that of manual biopsies, and the total procedure time was reduced. Because of these distinct advantages, the authors now use the biopsy gun exclusively for all percutaneous biopsies and recommend that other institutions consider the use of this biopsy method.     

Increased elastin production in experimental granulomatous lung disease.

In the normal, healthy lung, elastin production is restricted to periods of development and growth. However, elastin expression in the adult lung has been observed in some forms of pulmonary injury, including pulmonary fibrosis. Here, we report that elastin production is significantly increased within precise interstitial compartments of the lung in an experimental model of granulomatous lung disease. An increase in the number and volume of elastic fibers within the alveolar walls was apparent on histological examination of Verhoeff-van Gieson-stained sections of silicotic rat lungs. Quantitation of mature elastin cross-links indicated that silicosis was accompanied by a 17-fold increase in lung elastin content when compared with values from saline-treated controls. In situ hybridization for tropoelastin mRNA revealed that elastin production was absent from granulomatous lesions yet was prominent at nonfibrotic alveolar septal tips, where a high density of elastic fibers is seen in the normal lung. Immunohistochemistry indicated tropoelastin was being expressed by alpha-smooth muscle actin-containing cells. Transforming growth factor-beta was immunolocalized to granulomatous regions of the silicotic lung but was absent from regions showing increased tropoelastin expression. These data indicate that the reinitiation of tropoelastin gene expression is associated with granulomatous lung disease, and this expression leads to the aberrant accumulation of mature elastin in the lung.     

EEG and evoked potential changes during gas- and liquid-breathing dives to 1000 msw

To test the hypothesis that compression in helium gas and compression without gas (hydrostatic compression) both produce the same neurological symptoms of high pressure nervous syndrome (HPNS), groups of 4 to 5 dogs were exposed to one of the following: (a) a 2-h surface control breathing He-O2 gas; (b) compression to 700-1000 msw breathing He-O2 gas; (c) a 2-h liquid-breathing control [ventilation with warmed (38 degrees C), oxygenated fluorocarbon liquid, FC-80]; and (d) "near hydrostatic" compression to 700-1000 msw while being ventilated with liquid from a sealed reservoir. Power spectra obtained from scalp-recorded EEG signals revealed a significant compression-related shift of power from the normally dominant 5-8 Hz band to the 8-11 Hz band. This effect was greatest at 600 msw and occurred equally in both dive groups. At very high pressures (greater than 900 msw) power in this 6-10 Hz range became reduced whereas 16-22 Hz activity increased as the EEG flattened. Somatosensory evoked potentials (SEPs) were elicited by subdermal electrical stimulation in the foreleg (n = 120). The latency of P1 (approximately 31 ms) did not change in any group; transmission time to cortex was unaltered by time or pressure. However, the "late-wave" P4 (approximately 250 ms) was slowed by 32-35 ms at 1000 msw in both groups (P less than 0.003 in He-O2). Since these main symptoms were provoked equally in both He-O2 and FC-80 dive groups, helium pressure did not play a significant role in the etiology of HPNS in this animal model. It is concluded that the HPNS is primarily a result of excessive pressure per se or rate of change of pressure per se.     

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta?=??0.0264, p value?=?3.5?×?10^–8) in the discovery panel and was replicated in replication panel (beta?=??0.07, p value?=?0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value?=?1.4?×?10^–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

     

Osteosarcomatosis

A review of the 690 cases of osteosarcoma in the radiographic file of the Armed Forces Institute of Pathology revealed 29 cases of "osteosarcomatosis" (multiple skeletal sites of osteosarcoma). Fifteen of these patients were 18 years old and under and manifested rapidly appearing, usually symmetric, sclerotic metaphyseal lesions. The remaining 14 patients were more than 18 years old and had fewer, asymmetric sclerotic lesions. In most patients (28 of 29), a radiographically dominant skeletal tumor was seen. Pulmonary metastases occurred in the majority of patients and were detected at the same time as the bone lesions. These 29 patients were studied with regard to demographic data and skeletal distribution and radiographic appearance of their lesions. As a result of the findings, a metastatic origin from a primary dominant osteosarcoma is favored over a multifocal origin as the basis for osteosarcomatosis. Osteosarcomatosis is more commonly encountered in the mature skeleton than has been previously recognized.