TRACP Influences Th1 pathways by affecting dendritic cell function.

TRACP, a marker of osteoclasts, is also expressed by cells of the immune system. We identified a novel function for TRACP in the dendritic cell. DCs from TRACP knockout mice have impaired maturation and trigger reduced Th1 responses in vivo. We postulate that TRACP has an important role in the presentation of antigens to T cells. INTRODUCTION: TRACP is highly expressed by osteoclasts, activated macrophages, and dendritic cells (DCs). Knockout mice lacking TRACP have an intrinsic defect in osteoclastic resorption and macrophages that display abnormal immunomodulatory responses and cytokine secretion profiles. Our aim in this study was to investigate the significance of TRACP in the inductive phase of the immune response by examining dendritic cells from TRACP(-/-) mice. MATERIALS AND METHODS: Maturational state and function of leukocyte subsets in mice was assessed by flow cytometry. The ability of the immune system to respond to nonspecific activation and to specific antigen was assessed by delayed type hypersensitivity and the presence of isotype-specific serum antibody in vivo and T-cell proliferation and cytokine production in vitro. RESULTS: The ability of lipopolysaccharide (LPS) to upregulate MHC II and CD80 in DCs from TRACP(-/-) mice was reduced compared with wildtype mice, although production of IL-10 by DCs from TRACP-deficient animals was increased. T- and B-cell responses not involving antigen presentation (anti-CD3, TNP-ficoll) were normal in TRACP(-/-) mice, but responses to T-dependent antigens were impaired. Specifically, TRACP(-/-) mice had defective delayed hypersensitivity responses to picryl chloride and reduced proliferative responses to ovalbumin compared with wildtype mice. In response to ovalbumin, but not anti-CD3, T cells from TRACP(-/-) mice produced less interferon-gamma (IFN-gamma), but there was no difference in IL-4 production: TRACP(-/-) mice also produced less ovalbumin (OVA)-specific IgG2a after immunization. CONCLUSIONS: The finding that DCs from TRACP(-/-) mice have impaired maturation and defective Th1 responses shows that TRACP is important for polarizing responses in na?ve T cells to antigen-presented dendritic cells.     

Attainment of therapeutic fluoride levels in serum without major side effects using a slow-release preparation of sodium fluoride in postmenopausal osteoporosis

The bioavailability, biochemical effects, and safety of a slow-release preparation of sodium fluoride were examined. In 8 normal volunteers, a single administration of slow-release sodium fluoride (25 mg) caused a slow rise and gradual decline in serum fluoride concentration, thus avoiding sharp peaks produced by a rapid-release preparation. In 37 patients with postmenopausal osteoporosis, serum fluoride concentration was kept within the "therapeutic window" (95-100 ng/ml) during long-term intermittent sodium fluoride (slow-release) therapy (25 mg twice/day, given for 3 months in each 5-month cycle over five cycles). Serum fluoride was also kept within the therapeutic window in 64 patients who took sodium fluoride (slow release) continuously over 12 months. Serum osteocalcin concentration increased progressively during fluoride treatment (correlation coefficient of 0.88, p less than .001 for the relationship between serum osteocalcin and duration of therapy). Side effects to slow-release sodium fluoride therapy, assessed in 101 patients at two study sites, were minor and included diarrhea in 2 patients, nausea in 2 patients, abdominal pain and cramping in 2 patients, foot pain in 2 patients, and joint pain in 6 patients. Thus, slow-release sodium fluoride confers desired level of fluoride in serum, while providing safety of usage.     

Superior calcium bioavailability of effervescent potassium calcium citrate over tablet formulation of calcium citrate after Roux-en-Y gastric bypass

BackgroundCalcium supplementation is commonly recommended for patients after Roux-en-Y gastric bypass to avert bone loss. To test the hypothesis that effervescent (liquid) potassium-calcium-citrate (PCC) might be more bioavailable than a tablet formulation of calcium citrate (Citracal Petite), the present study compared a single dose response of the 2 compounds. The present study was conducted at the University of Texas Southwestern Medical School at Dallas.MethodsA total of 15 patients who had undergone Roux-en-Y gastric bypass were included in a 2-phase, crossover, randomized study comparing the single-dose bioavailability of PCC versus Citracal Petite. After following a restricted diet for 1 week, the participants ingested either a single dose of 400 mg elemental calcium as PCC or Citracal Petite. Sequential serum and urine samples were collected for a 6-hour period after the dose and analyzed for calcium, parathyroid hormone, and acid-base parameters.ResultsCompared with citracal petite, PCC significantly increased the serum calcium concentrations at 2, 3, and 4 hours after the oral load. The peak to baseline variation and increment in serum calcium (area under the curve) were significantly greater after PCC (P = .015 and P = .002, respectively). Concurrently, the baseline to nadir variation and decrement in serum parathyroid hormone (area over the curve) were significantly greater after PCC (P = .004 and P = .005, respectively). Moreover, compared with Citracal Petite, PCC caused a significantly greater increment in urinary citrate (P < .0001) and potassium (P = .0004) and a significantly lower increase in urinary ammonium (P = .045).ConclusionIn patients who have undergone Roux-en-Y gastric bypass, PCC was superior to Citracal Petite in conferring bioavailable calcium and suppressing parathyroid hormone secretion. PCC also provided an alkali load.     

Exaggerated natriuretic and calciuric responses to hydrochlorothiazide in renal hypercalciuria but not in absorptive hypercalciuria

Patients with hypercalciuria have been reported to have an exaggerated response to hydrochlorothiazide (HCTZ), implying a renal tubular defect in solute reabsorption. To determine whether this disturbance is generalized or unique to a particular pathogenetic type of hypercalciuria, we measured the increments in urinary sodium (delta Na), calcium (delta Ca), and magnesium after a 100-mg dose of oral HCTZ in 10 normal subjects and 31 patients with different types of hypercalciuric nephrolithiasis. Eleven patients with renal hypercalciuria had significantly greater delta Na (P less than 0.005) and delta Ca (P less than 0.005) than the normal subjects. Ten patients with absorptive hypercalciuria and 10 patients with fasting hypercalciuria without parathyroid stimulation had delta Na and delta Ca indistinguishable from those of normal subjects. In all groups, urinary HCTZ and basal 24-h urinary Na did not differ. The results suggest that the unique natriuretic and calciuric responses to HCTZ occur only in renal hypercalciuric patients with secondary hyperparathyroidism. The data support a renal tubular defect in renal hypercalciuric in contrast to other diagnostic categories of hypercalciuric nephrolithiasis.     

Bariatric Surgery and Effects on Calcium and Bone Metabolism

With the increasing epidemic of obesity in the United States as well as abroad, bariatric surgery has emerged as the most effective and sustained treatment for reduction. This treatment modality has been well recognized to diminish the risk of cardiovascular morbidity and mortality and ameliorate diabetes mellitus. However, with time, derangement in mineral metabolism has emerged as a major complication in this population. Population-based study has shown increased prevalence of bone fractures and kidney stone formation following bariatric surgery. The risk appears to be more specific after Roux-en-Y gastric bypass procedures, the most common surgical approach among this population. Over the past decade, there have been advances in the understanding of pathophysiologic mechanisms of both bone loss and kidney stone disease in these patients. The understanding of these underlying pathophysiologic mechanisms may lead to the development of drug therapies that ameliorate this complication. Unfortunately, at the present time, there is no hard data on any specific treatment showing decreased incidence of fragility fractures or kidney stone passage. However, some studies suggest that calcium and vitamin D supplementation may decrease bone loss and bone turnover, and as a result, increase bone mineral density in this population. However, there is concern with the development of kidney stone formation following such an approach. A novel treatment approach would be the use of effervescent potassium calcium citrate that not only prevents complications of bone loss but may diminish the risk of kidney stone formation. Despite preliminary results showing the effectiveness of this drug in the reduction in the parathyroid hormone, bone turnover, and improvement in the urinary saturation marker showing effectiveness against calcium oxalate and uric acid stones, there is no hard data available to support the effectiveness of this treatment in the reduction in fragility fractures or kidney stone incidence. Such studies to explore this effect must be considered in the future.     

Characterization of Plasmid-Mediated AmpC and Carbapenemases among Iranain Nosocomial Isolates of Klebsiella pneumoniae Using Phenotyping and Genotyping Methods

Objectives

Plasmid-mediated AmpC β-lactamases (PMABLs) and carbapenemases are emerging groups of antimicrobial-resistance determinants. The aims of the study were to evaluate the occurrence of PMABLs and carbapenemases in clinical isolates of Klebsiella pneumoniae and compare the test performance of various phenotypic methods for detection of these enzymes in Iran.

Methods

A total of 100 K. pneumoniae isolates were collected from clinical specimens obtained in Valiasr Hospital. AmpC production in all isolates was determined using the AmpC disk test, the cephamycin Hodge test, the AmpC Etest, and the boronic acid combined-disk test. In addition, carbapenemase production was determined using the modified Hodge test, the EDTA disk synergy test, and the boronic acid combined-disk test. The performances of various phenotypic methods were evaluated by the comparison of their results with polymerase chain reaction (PCR) method as the gold standard.

Results

Of the 100 isolates, 19 (19%) were demonstrated to harbor the PMABL-resistance gene by the multiplex PCR method. The PCR result indicated the presence of carbapenemase genes in 12 isolates. The performance of various phenotypic tests carried out for detection of carbapenemase-producing isolates varied widely, ranging in sensitivity from 30% to 100% and in specificity from 90.8% to 100%.

Conclusion

This is the first report of MOX-type AmpC β-lactamase and bla_GES in K. pneumoniae in Iran. A comparison of the phenotypic methods showed that a combination of cefoxitin plus boronic acid is optimal for detecting plasmid-mediated AmpC enzymes in K. pneumoniae, whereas the implementation of molecular methods is often complex, requires specially trained personnel, and is associated with higher costs.     

Short-term 1,25-dihydroxyvitamin D3 administration raises serum osteocalcin in patients with postmenopausal osteoporosis

In order to evaluate whether 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] could increase the serum concentration of osteocalcin (BGP) in patients with post-menopausal osteoporosis, we administered 2 micrograms/d of 1,25(OH)2D3 to 14 patients with biopsy proven osteoporosis for two weeks. An additional 13 age and sex-matched patients with osteoporosis received no drug and served as the control. Administration of 1,25(OH)2D3 significantly increased the serum concentration of 1,25(OH)2D from 31 +/- 2 SE to 56 +/- 5 pg/ml (p less than 0.01). Commensurate with the rise in 1,25(OH)2D was a significant increase in BGP from 3.9 +/- 0.6 to 6.4 +/- 0.9 ng/ml (p less than 0.001). There were no significant changes for these parameters in the control group. It is concluded that short term 1,25(OH)2D3 administration is effective in raising BGP concentrations in patients with post-menopausal osteoporosis.     

Post-renal transplantation hypophosphatemia

An understanding of the pathophysiologic mechanisms of post-renal transplant (PRT) bone disease is of important clinical significance. Although bone disease occurs after all solid organ transplantation, the cumulative skeletal fracture rate remains high in PRT subjects while reaching a plateau with other transplantations. One major difference in the pathophysiology of PRT bone disease is, perhaps, due to persistent renal phosphorus (Pi) wasting. Novel phosphaturic agents have recently been suggested to participate in the development of bone disease in PRT subjects. However, it is unclear as of yet whether these factors alone or in conjunction with excess parathyroid hormone (PTH) secretion play a key role in the development of negative Pi balance and consequent bone disease in this population. In this review, I present a natural history of PRT hypophosphatemia and persistent renal Pi leak, provide pathophysiologic insight into these developments, and discuss the difficulty in diagnosing these phenotypes in both adult and pediatric populations.