Predominant factors associated with bone loss in liver transplant patients - after prolonged post-transplantation period

INTRODUCTION: Osteoporosis is a major cause of morbidity in liver transplant recipients and is associated with multiple factors. OBJECTIVES: To evaluate bone mineral density (BMD), bone turnover and calcium-regulating hormones in 29 patients (17 men, 12 women) 2-12 yrs following liver transplantation for non-alcoholic liver diseases. RESULTS: Fifteen patients (52%) were on immunosuppressive treatment with tacrolimus and 14 (48%) with cyclosporine. Eleven patients (38%) were currently on prednisone, 18 patients (62%) had stopped glucocorticoid treatment 6 months to 11 yrs prior to the study. Nineteen patients (65.5%) had decreased BMD according to WHO criteria, 17 (58.2%) at the femoral neck, 13 (44.8%) at the lumbar spine. Nineteen patients (65.5%) had a subnormal (<15 ng/mL) serum level of 25 (OH) D3. These patients had significantly lower BMD at the femoral neck (p = 0.02). Femoral neck BMD negatively correlated with serum parathyroid hormone level (p = 0.06, r = -0.35), length of the post-transplantation period (p = 0.025, r = -0.416) and duration of glucocorticoid treatment (p = 0.029, r = -0.406), regardless of its cumulative dose. Symptomatic fractures were less frequent in tacrolimus treated patients than in cyclosporine users (p = 0.03). CONCLUSIONS: Decreased BMD is frequent following liver transplantation and is affected by vitamin D deficiency, cyclosporine use, and the duration of glucocorticoid therapy, but not by its cumulative dose. Achievement and maintenance of optimal vitamin D status and shortening of glucocorticoid treatment period may have a favorable effect on bone preservation.     

Bone density in axial and appendicular skeleton in patients with lactose intolerance: influence of calcium intake and vitamin D status

BACKGROUND: Lactose intolerance (LI) is a common enzymatic insufficiency, manifesting by poor tolerance of dairy products, leading to low calcium intake and poor calcium absorption from dairy products. These changes might lead to an impairment of bone metabolism [1]. OBJECTIVES: To evaluate the impact of LI on quantitative bone parameters in axial and appendicular skeletal sites. To assess the impact of calcium intake from dairy and non-dairy nutritional sources, calcium regulating hormones and bone turnover on quantitative bone parameters in LI patients. METHODS: We evaluated calcium intake and bone status in sixty-six patients with LI, 49 women and 17 men, aged 20 to 78. Bone mass was assessed at the lumbar spine (LS), total hip (TH) and femoral neck (FN) by dual-energy x-ray absorptiometry (DEXA) and at the radius, tibia, phalanx by quantitative ultrasound. Serum calcium, albumin, inorganic phosphate, calcium regulating hormones and markers of bone turnover were evaluated. RESULTS: Total daily calcium intake was below the recommended by the American Dietetic Association [2] in all study participants (mean 692 mg/day +/- 162). Elevated level of urinary deoxypyridinoline crosslinks (DPD) was observed in 63 (96%) patients and was negatively correlated with total daily calcium intake (r = -0.998, p = 0.025) and with nondairy calcium intake (r = -0.34, p = 0.015). Parathyroid hormone (PTH) level in the upper third of normal range (45-65 ng/L) was observed in 11 (17%) patients. Parathyroid hormone (PTH) was inversely correlated with total calcium intake (r = -0.4, p = 0.001), dairy calcium intake (r = -0.83, p = 0.05), non-dairy calcium intake (r = -0.29, p = 0.043), 25OHD(3) serum level (r = -0.3, p = 0.007) and positively correlated with bone turnover markers (deoxypyridinoline crosslinks [DPD], r = 0.36, p = 0.01 and bone specific alkaline phosphatase [BSAP] r = 0.36, p = 0.01). Decrease in quantitative bone parameters compared to age-matched controls was observed in the axial and in the appendicular skeleton in men and in postmenopausal women: mean z-score for LS -0.87 +/- 0.22 and -1.32 +/- 0.65, p = 0.004 and 0.015, tibia -1.15 +/- 0.53 and -0.44 +/- 0.044, p < 0.001 and 0.27, phalanx -0.98 +/- 0.22 and -0.52 +/- 0.98, p < 0.001. We observed decrease in bone mass in patients with serum PTH in the upper tertile of normal range in the FN (z-score -0.57 +/- 0.6 versus -0.03 +/- 0.9, p = 0.025), TH (-0.51 +/- 0.96 versus 0.04 +/- 0.9, p = 0.05) and radius (-1.84 +/- 0.27 versus -0.07 +/- 1.61, p = 0.025, respectively). z-scores in FN and TH positively correlated with serum 25OHD(3) level (r = 0.31, 0.29; p = 0.014, 0.019). In postmenopausal women serum 25OHD(3) level correlated also with LS z-scores (r = 0.52, p = 0.004); FN and TH z-scores negatively correlated with DPD level (r = -0.51, p = 0.02 and r = -0.55, p = 0.04). CONCLUSION: LI state may lead to increased bone turnover and decreased bone mass especially in men and postmenopausal women. Impaired vitamin D status and low calcium intake may be deleterious to bone in this condition.     

Differential expression of galectin-3 in pituitary tumors

Galectin-3 (Gal-3), a beta-galactoside-binding protein, has been implicated in a variety of biological functions, including cell proliferation and differentiation, tumor cell adhesion, angiogenesis, apoptosis, tumor progression, and metastasis. We investigated the role of Gal-3 in the development and progression of pituitary tumors. Immunohistochemical and Western blot analysis of normal and neoplastic human pituitaries showed that only lactotroph (PRL) and corticotroph (ACTH) hormone-producing cells and tumors expressed Gal-3. Gal-3 was present in 24 of 38 (63.2%) PRL adenomas, 5 of 6 (83.3%) PRL carcinomas, 19 of 41 (46.3) ACTH adenomas, and 7 of 8 (87.5%) ACTH carcinomas, but not in 112 other pituitary adenomas and carcinomas. Pituitary folliculo-stellate cells, which have macrophage-type functions in the anterior pituitary, also expressed Gal-3. Hyperplastic and neoplastic pituitaries from p27(Kip1) (p27)-null mice, which produce mainly ACTH, showed increased Gal-3 expression levels compared with control mice. Treatment with transforming growth factor beta1, which regulates pituitary cell proliferation, reduced Gal-3 as well as p27 expression levels in cultured HP75 pituitary cells and Gal-3 in cultured pituitary cells from p27-null mice, suggesting that p27 is not necessary for the inhibitory effects of transforming growth factor beta1 on the cell cycle in the pituitary. The role of Gal-3 in pituitary cell function was examined by RNA interference experiments. Inhibition of Gal-3 gene expression by RNA interference decreased HP75 cell proliferation and increased apoptosis. These results indicate that Gal-3 has an important role in pituitary cell proliferation and tumor progression.     

Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity

The cytokine interleukin-1 (IL-1) is produced by peripheral immune cells as well as glia and neurons within the brain; it plays a major role in immune to brain communication and in modulation of neural, neuroendocrine, and behavioral systems during illness. Although previous studies demonstrated that excess levels of IL-1 impaired memory processes and neural plasticity, it has been suggested that physiological levels of IL-1 are involved in hippocampal-dependent memory and long-term potentiation (LTP). To examine this hypothesis, we studied IL-1 receptor type I knockout (IL-1rKO) mice in several paradigms of memory function and hippocampal plasticity. In the spatial version of the water maze test, IL-1rKO mice displayed significantly longer latency to reach a hidden platform, compared with wild-type controls. Furthermore, IL-1rKO exhibited diminished contextual fear conditioning. In contrast, IL-1rKO mice were similar to control animals in hippocampal-independent memory tasks; i.e., their performance in the visually guided task of the water maze and the auditory-cued fear conditioning was normal. Electrophysiologically, anesthetized IL-1rKO mice exhibited enhanced paired-pulse inhibition in response to perforant path stimulation and no LTP in the dentate gyrus. In vitro, decreased paired-pulse responses, as well as a complete absence of LTP, were observed in the CA1 region of hippocampal slices taken from IL-1rKO mice compared with WT controls. These results suggest that IL-1 contributes to the regulation of memory processes as well as short- and long-term plasticity within the hippocampus. These findings have important implications to several conditions in humans, which are associated with long-term defects in IL-1 signaling, such as mutations in the IL-1 receptor accessory protein-like gene, which are involved in a frequent form of X-linked mental retardation.     

Reproducibility of visual activation in functional magnetic resonance imaging at very high field strength (4 Tesla)

PURPOSE: The reproducibility of functional magnetic resonance imaging (fMRI) has been studied on 1.5 Tesla (T) (high field strength) scanners. We report the reproducibility of visual activation in fMRI at 4 T (very high field strength). METHODS: Five healthy subjects were scanned twice in the same session with a 4 T scanner during binocular flashing visual stimulation. The activated areas during the first and second acquisition were compared.RESULTS: Activation of the visual cortex was observed in all subjects and activation of lateral geniculate nucleus was also detected in four subjects. The ratio of overlapping activated voxels in the first and second acquisition was 0.81 +/- 0.05. CONCLUSIONS: Reproducibility of visual activation using fMRI at 4 T was found to be acceptable, and the results from 4T scanners show a reliability similar to those at 1.5 T.     

Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo

Considerable research effort is currently being directed towards understanding the mechanisms mediating the antiproliferative effects of non-steroidal anti-inflammatory drugs (NSAIDs) and, more recently, of cyclooxygenase (COX)-2 inhibitors as well. A key question is whether NSAIDs (excluding sulindac) exert their anticarcinogenic effects in vivo by a mechanism that is dependent on their capacity to inhibit COX activity. Some studies with cultured tumor cells in vitro have argued against such a linkage, showing that NSAIDs inhibit cell replication and/or augment apoptosis only at concentrations that exceed those required to inhibit COX activities 10- to 100-fold. The significance of these results for the observed anticarcinogenic effects of NSAIDs in vivo has not yet been evaluated. We addressed this question by comparing, for the same tumor cells, the effects of the NSAID indomethacin on cell growth parameters when the cells were grown in culture to the effects seen in the in vivo growing tumor in the mouse. Indomethacin added to cultured Lewis lung carcinoma cells exerted a potent antiproliferative effect ((3)H thymidine assay) and reduced cell viability (MTT[3-(4,5-dimethyl(thiazol-2-yl)-2,5 diphenyl tetrazolium bromide] assay) at low doses (10-20 microM) in parallel with its inhibitory effect on cellular cyclooxygenase. These effects of indomethacin appeared to arise from a clear antiproliferative shift in the profile of the cell cycle parameters towards a reduced percentage of cells at the S and G(2)/M phases, together with an increased percentage of cells at the G(1) phase. Significantly, similar results were seen when indomethacin was given in vivo at the low dose of 2 mg per kg/day, which blocked blood platelet COX activity and at the same time produced a delay in tumor growth initiation and attenuation of apparent primary tumor growth as well as growth of lung metastases. These results thus provide strong support for the notion that COX inhibition is a major determinant in the antitumorigenic effect of indomethacin in vivo.     

High-level handwashing compliance in a community teaching hospital: a challenge that can be met!

Handwashing is the most important and least expensive measure for preventing the transmission of hospital-acquired infection. Compliance, however, rarely exceeds 40%, even in intensive care units. The present study evaluated the effectiveness of the authors' infection control programme in relation to handwashing compliance of healthcare workers. Ten nursing students observed 300 uninformed staff members and recorded their handwashing practices throughout the working day. The observations were categorized by profession, gender, age, hospital unit and type of delivered care. In 1035 opportunities that required handwashing, the overall compliance was 76%. Healthcare workers washed hands before (68%) and after patient care (80%). Females complied more than males (69 vs. 80%, P<0.0001) and nurses more than physicians (81 vs. 69%, P<0.001). In intensive care units, overall compliance exceeded 97%, while in other wards and in the emergency departments, it approximated 61%. More handwashing was observed during the evening shift compared with the morning shift (P=0.02). Despite the high compliance, only 30% washed their hands for the required 10-20s. In conclusion, compliance with handwashing in the authors' institution is the highest reported to date, and reflects the intensive and incessant educational infection control programme.