Prolactin modulates survival and cellular immune functions in septic mice

BACKGROUND: The immunomodulatory properties of the pituitary hormone prolactin have been demonstrated. It was proposed that prolactin is important in maintaining normal immune response in several pathological states. We investigated the effect of prolactin administration on the survival and cellular immune functions during systemic inflammation. MATERIALS AND METHODS: Male NMRI mice were subjected to laparotomy (LAP) or sepsis induced by cecal ligation and puncture (CLP). Mice were treated with either saline (LAP/saline; CLP/saline) or prolactin (LAP/PRL, CLP/RPL; 4 mg/kg s.c.). Survival of septic mice was determined 24 and 48 h after CLP. Forty-eight hours after the septic challenge, the proliferative capacity, cytokine release (IL-2, IL-6, IFN-gamma) and apoptosis of splenocytes were determined. Additionally, monitoring of circulating leukocyte distribution was performed (WBC; CD3+, CD4+, CD8+, B220+, NK1.1+, F4/80+ cells by FASCan). RESULTS: CLP was accompanied by a mortality of 47% and induced a decrease in splenocyte proliferation and apoptosis rate. Administration of prolactin significantly increased the mortality of septic mice (81%). This was paralleled by a further decrease of splenocyte proliferation and an increased splenocyte apoptosis. In addition, administration of prolactin augmented the sepsis-induced inhibition of IL-2 release, attenuated the sepsis-induced inhibition of IFN-gamma release, and did not affect the release of IL-6. However, prolactin did not affect the sepsis-induced changes of circulating leukocyte subpopulations. CONCLUSIONS: We conclude that prolactin has profound immunomodulatory properties and that administration of prolactin in pharmacological doses is associated with a decreased survival and an inhibition of cellular immune functions in septic mice.     

CD4+CD25+ regulatory T cells mediate acquired transplant tolerance

The Holy Grail of clinical organ transplantation is the safe induction of allograft tolerance. Transplant tolerance has been successfully induced in animal models. Since T cells play a pivotal role in graft rejection, modulating T cell function has been the primary focus of studies aimed at inducing transplant tolerance. Rodent models of transplant tolerance induction include central deletion and peripheral mechanisms involving activation-induced cell death (AICD), anergy, immune deviation, and production of regulatory T cells. These mechanisms are not mutually exclusive. Although clonal deletion and anergy limit self-reactive T cells in the thymus, these mechanisms alone are not sufficient for controlling self-reactive T cells in the periphery. There is now evidence that the adult animal harbors two functionally distinct populations of CD4(+) T cells; one mediates autoimmune disease and the other dominantly inhibits it. The latter cells express CD4, CD25 and CTLA-4. These thymus-derived T cells have recently been shown to mediate the induction and maintenance of transplant tolerance. These CD4(+)CD25(+) T cells are similar in origin, phenotype, and function to those that maintain natural self-tolerance and T cell homeostasis in the periphery. Against this background, is it possible that alloantigen specific regulatory T cells might be generated and expanded ex vivo before organ transplantation and then infused to induce long-term tolerance, perhaps without the need for chronic immunosuppression?     

Bone mineral density in pediatric transplant recipients

BACKGROUND: Reduced bone mass and fragility fractures are known complications after transplantation in adults. Far less is known about the skeletal effects of transplantation in children and adolescents. METHODS: This cross-sectional study examined the skeletal status of children (ages 9-18 years) who were at least 1 year post-cardiac (n=13), post-renal (n=8), or post-bone marrow (BMT; n=15) transplantation. Bone mass at total hip, femoral neck, spine (L2-4), and whole body (WB) was determined by dual energy x-ray absorptiometry and compared with age, sex, and ethnic-specific reference data. Standard deviations (z-scores) were calculated for both areal bone mineral density (BMD) and estimated volumetric bone density (bone mineral apparent density [BMAD]). RESULTS: Cardiac transplant patients had significantly lower BMD z-scores compared with the reference population at all skeletal sites. BMT recipients had significantly reduced BMD z-scores at total hip, spine, and WB. Kidney transplant patients had a significantly reduced WB BMD z-score only. Spine BMAD z-scores remained significantly reduced in cardiac and BMT subjects. Three of 36 patients had radiographic evidence of spinal fracture after transplantation. No correlation between steroid dosage and any measure of bone mass was observed. CONCLUSIONS: Cardiac and BMT recipients had reduced BMD at multiple skeletal sites, and renal transplant recipients had reduced WB BMD for age. Deficits in spine bone density persisted after correcting for small bone size using BMAD. Low bone density and the occurrence of vertebral fractures indicate that cardiac, renal, and bone marrow transplantation in children is associated with reduced bone health.     

Somatosensory evoked potential monitoring of lumbar pedicle screw placement for in situ posterior spinal fusion.

BACKGROUND CONTEXT: Somatosensory evoked potentials (SSEP) are commonly used to monitor the spinal cord and nerve roots during operative procedures that put those structures at risk. The utility of SSEPs to evaluate cauda equina and nerve root function during posterior spinal arthrodesis with pedicular fixation for degenerative lumbar disease has been reported anecdotally and remains controversial. PURPOSE: An institution-wide review of the ability of SSEP readings to monitor nerve function during posterior lumbar spinal arthrodeses with transpedicular fixation for degenerative lumbar spinal disorders was undertaken. STUDY DESIGN/SETTING: A retrospective review was undertaken. Patient history, preoperative physical examination, intraoperative anesthesia, SSEP records and the postoperative course were reviewed. METHODS: A total of 186 consecutive arthrodeses as described above were reviewed. Patients who had anterior procedures, spondyloreduction or scoliosis correction were excluded from the study. There were 76 male and 110 female patients. Five fellowship-trained spine surgeons placed a total of 888 pedicle screws. Sixty-five percent of the patients had a principal preoperative diagnosis of spinal stenosis with degenerative spondylolisthesis. Other common diagnoses were isthmic spondylolisthesis and degenerative scoliosis. Ninety-three percent of the cases involved decompressive laminectomy. Eight percent had posterior interbody fusions. All pedicle screws were placed without the assistance of fluoroscopy or stereotactic computer-assisted guidance. Screw position was evaluated intraoperatively with standard posteroanterior and lateral radiographs.Anesthetic agents compatible with SSEP monitoring were used in all patients. SSEP baseline readings were obtained in all patients in the operating room soon after induction of general anesthesia. An acute and sustained loss of 50% of the SSEP amplitude and/or increase by 10% of latency from baseline was considered to be pathologic. RESULTS: None of the 186 patients had significant SSEP changes. There were, however, 5 patients with postoperative radiculopathies distinct from their preoperative presentations. Early postoperative plain radiographs and computed assisted tomography (CAT) scans revealed malpositioned pedicle screws. Consequently, eight pedicle screws were either revised or removed. All patients had partial or full recovery of their new deficits after revision surgery. CONCLUSION: We conclude that the use of SSEPs in evaluating pedicle screw placement during lumbar arthrodesis is limited. In this setting, if monitoring is required, alternative methods with greater sensitivity and efficacy should be explored.     

Bone architecture and disc degeneration in the lumbar spine of mice lacking GDF-8 (myostatin).

GDF-8, also known as myostatin, is a member of the transforming growth factor-beta superfamily of secreted growth and differentiation factors that is expressed in vertebrate skeletal muscle. Myostatin functions as a negative regulator of skeletal muscle growth and myostatin null mice show a doubling of muscle mass compared to normal mice. We describe here morphology of the lumbar spine in myostatin knockout (Mstn(-/-)) mice using histological and densitometric techniques. The Mstn(-/-) mice examined in this study weigh approximately 10% more than controls (p<0.001) but the iliopsoas muscle is over 50% larger in the knockout mice than in wild-type mice (p<0.001). Peripheral quantitative computed tomography (pQCT) data from the fifth lumbar vertebra show that mice lacking myostatin have approximately 50% greater trabecular bone mineral density (p=0.001) and significantly greater cortical bone mineral content than normal mice. Toluidine blue staining of the intervertebral disc between L4-L5 reveals loss of proteoglycan staining in the hyaline end plates and inner annulus fibrosus of the knockout mice. Loss of cartilage staining in the caudal end plate of L4 is due to ossification of the end plate in the myostatin-deficient animals. Results from this study suggest that increased muscle mass in mice lacking myostatin is associated with increased bone mass as well as degenerative changes in the intervertebral disc.     

Strength of fixation of Ludloff metatarsal osteotomy utilizing three different types of Kirschner wires: a biomechanical study

Static biomechanical studies have demonstrated that the Ludloff shaft metatarsal osteotomy is significantly more stable than other commonly used proximal (basilar) osteotomies, such as the proximal crescentic and the proximal chevron. High average static bending failure moments have been recorded for the screw fixation Ludloff osteotomy construct. The objective of the current study was to find a reasonable alternative method of fixation in cases where a short osteotomy may not be amenable to adequate screw fixation and in cases where an inadvertent intraoperative fracture of the metatarsal occurs and subsequent screw fixation is precarious due to inadequate bone stock. A Ludloff osteotomy was performed on 24 matched pairs of cadaveric specimens to compare the strength of fixation of three different types of Kirschner wires (smooth, threaded, and SOC threaded). Biomechanical testing with plantar force was carried out, and failure load and stiffness were measured for each specimen. The current results indicate that the threaded pin construct provides adequate strength for fixation of the Ludloff osteotomy in the clinical setting.     

Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1

BACKGROUND: Previous linkage studies have suggested prostate cancer susceptibility genes located on chromosomes 1, 20, and X. Several putative prostate cancer candidate genes have also been identified including RNASEL, MSR1, and ELAC2. Presently, these linkage regions and candidate genes appear to explain only a small proportion of hereditary prostate cancer cases suggesting the need for additional whole genome analyses. METHODS: A genome-wide mode-of-inheritance-free linkage scan, using 405 genetic markers, was conducted on 175 pedigrees, the majority containing three or more affected individuals diagnosed with prostate cancer. Stratified linkage analyses were performed based on previously established criteria. RESULTS: Results based on the entire set of 175 pedigrees showed strong suggestive evidence for linkage on chromosome 17q (LOD = 2.36), with strongest evidence coming from the subset of pedigrees with four or more affected individuals (LOD = 3.27). Race specific analyses revealed strong suggestive evidence for linkage in our African-American pedigrees on chromosome 22q (LOD = 2.35). CONCLUSIONS: Genome-wide analysis of a large set of prostate cancer families indicates new areas of the genome that may harbor prostate cancer susceptibility genes. Specifically, our linkage results suggest that there is a prostate cancer susceptibility gene on chromosome 17 that is independent of ELAC2. Further research including combined analyses of independent genome-wide scan data may clarify the most important regions for future investigation.     

Sevelamer hydrochloride attenuates kidney and cardiovascular calcifications in long-term experimental uremia

BACKGROUND: In chronic renal failure (CRF), hyperphosphatemia and an elevated calcium-phosphate product are associated with vascular calcification and increased cardiovascular morbidity and mortality. Previous data have demonstrated that 3-month treatment of uremic rats with sevelamer was associated with less nephrocalcinosis compared to calcium carbonate (CaCO3), despite similar control of serum phosphorus, calcium-phosphorus product (Ca x P product), and secondary hyperparathyroidism. There was no evidence of aortic calcification after 3 months of uremia (J Am Soc Nephrol 13:2299-2308, 2002). The present studies explore the influence of sevelamer and CaCO3 on cardiovascular and kidney calcifications in long-term experimental uremia over 6 months. METHODS: Normal and 5/6 nephrectomized rats (U) were fed a high phosphorus (HP) diet for 6 months. Two phosphate binders, CaCO3 and sevelamer, were administered and their influence on hyperphosphatemia, secondary hyperparathyroidism, kidney/myocardial/aortic calcification, and renal function was compared. RESULTS: All uremic rats began the study with the same degree of renal failure. Sevelamer was as effective as CaCO3 in reducing serum phosphorus, Ca x P product, and attenuating secondary hyperparathyroidism. Despite similar serum cholesterol levels, rats in the U-HP + sevelamer group had markedly lower calcium deposition in the myocardium and aorta (myocardium, 72 +/- 4 microg/g wet tissue; aorta, 736 +/- 156 microg/g wet tissue) compared to rats in either the U-HP + CaCO3 group (myocardium, 179 +/- 48, P < 0.05; aorta, 1308 +/- 343, P < 0.05) or the U-HP group (myocardium, 98 +/- 10, NS; aorta, 2150 +/- 447, P < 0.05). Dual immunohistochemical analysis for calcium and endothelial cell markers demonstrated that myocardial calcium deposition was intravascular within capillaries. Furthermore, calcium deposition in the kidney of uremic rats treated with sevelamer (582 +/- 111 microg/g wet tissue) was lower than that found in uremic rats treated with CaCO3 (1196 +/- 180 microg/g wet tissue). Sevelamer-treated rats had less deterioration in renal function with an associated lower serum creatinine, higher creatinine clearance, and less proteinuria. There was no difference in overall mortality between the three experimental groups. CONCLUSION: In long-term experimental CRF, in addition to controlling serum phosphorus and secondary hyperparathyroidism as efficiently as CaCO3, treatment with the phosphate-binder sevelamer attenuates vascular and kidney calcification.     

Traditional cardiac risk factors in individuals with chronic kidney disease

Individuals with chronic kidney disease (CKD) are at increased risk for the development and progression of cardiovascular disease (CVD). The increased risk is due to a higher prevalence of both traditional risk factors as well as nontraditional risk factors. In this review we focus on individuals at all stages of CKD and discuss modifiable traditional risk factors, namely hypertension, dyslipidemia, diabetes mellitus and poor glycemic control, smoking, and physical inactivity. The prevalence of each risk factor and its relationship with CVD is described. Treatment recommendations are provided using evidence available from populations with CKD or evidence extrapolated from the general population when there are insufficient data on individuals with CKD.