Lipopolysaccharide binding protein inhibitory peptide protects against acetaminophen-induced hepatotoxicity.

Acetaminophen (APAP)-induced liver injury remains the main cause of acute liver failure in the United States. Our previous work demonstrated that LPS binding protein (LBP) knockout mice are protected from APAP-induced hepatotoxicity. LBP is known to bind avidly to LPS, facilitating cellular activation. In this study, we sought to specifically inhibit the interaction between LBP and LPS to define the role of this interaction in APAP-induced liver injury. The peptide LBPK95A was able to inhibit LBP-mediated LPS activation of RAW 267.4 cells in a dose-dependent manner in vitro. In vivo, C57Bl/6 mice were treated with either LBPK95A or vehicle control concurrently with the administration of APAP (350 mg/kg). Mice treated with LBPK95A had significantly lower serum aspartate aminotransferase and alanine aminotransferase levels. Morphometric analysis of the liver tissue showed significantly less liver injury in mice treated with LBPK95A. To assess whether the LBPK95A altered glutathione depletion and APAP metabolism, we measured total glutathione levels in the liver after APAP. We found no difference in the glutathione levels and APAP-adduct formation between LBPK95A vs. vehicle control both at baseline and after APAP. In conclusion, our results support the hypothesis that LBP-induced liver injury after APAP is due to its ability to mediate activation by endogenous LPS. Our results suggest that blocking LBP-LPS interactions is a potential therapeutic avenue for the treatment of APAP-induced liver injury.

[Biochemical bone resorption markers during the healing of osteoporotic fractures]. / Biochemische Knochenresorptionsmarker in der Heilungsphase osteoporotischer Frakturen.

BACKGROUND: This study investigated the progression and clinical relevance of biochemical resorption marker values during fracture healing in osteoporosis. PATIENTS AND METHODS: In 44 patients with distal radius fractures and 29 patients without fractures, the blood and urine concentrations of pyridinoline (PYD), deoxypyridinoline (DPD), N-telopeptides (NTx), and bone sialoprotein (BSP) were recorded on the day of trauma as well as during further progression. All postmenopausal patients underwent bone density measurement. Accordingly, patients were divided into premenopausal, postmenopausal osteoporotic, and postmenopausal nonosteoporotic groups. RESULTS: Between the groups, PYD, DPD, and NTx showed significant differences in their initial values. However, their further relative progression was primarily affected by the chosen therapy. CONCLUSION: Bone resorption markers can diagnostically point to osteoporosis and are significant parameters in fracture healing.

Diagnosis of osteoporosis with vitamin k as a new biochemical marker.

Osteoporosis is a metabolic bone disease characterized by reduced bone quality and quantity. As a consequence, patients are at risk for fractures, subsequent immobility, and higher mortality especially among elder patients. Because of the high incidence of complications and the associated financial burden for the health system, new parameters for diagnostic and therapeutic purposes are urgently needed. In this regard, research focused on vitamin K as a biochemical bone marker has provided promising results. Vitamin K represents an important enzyme-cofactor for the posttranslational modification and activation of several proteins involved in bone metabolism. Vitamin K has been proven to be a valuable diagnostic as well as therapeutic parameter especially in osteoporosis. Patients with osteoporosis have been shown to have decreased levels of vitamin K. Further, regular intake of vitamin K may increase bone mineral density (BMD), thereby lowering the fracture risk. Yet vitamin K alone may not sufficiently indicate the mineral status of the bone. However, the usefulness of a combination of several biochemical bone markers as improved surrogate markers of bone metabolism has been shown recently. Therefore, this review will focus on the significance and importance of vitamin K for bone metabolism. Beyond this, aspects on the current and prospective use of vitamin K as well as other newly developed biochemical bone markers will be discussed.

Posteromedial approach to proximal tibia for corticotomy in callus distractions.

Corticotomy of the tibia using Ilizarov's anterolateral approach is used routinely for callus distraction. This method is associated with impaired callus formation and delayed healing because of marginal soft tissue covering and blood supply to the proximal tibia. We presumed a newly designed posteromedial approach would result in less callus defects and improved healing. In this prospective, randomized study, 31 patients had callus distraction using an anterolateral approach or the newly designed posteromedial approach. Callus formation was assessed radiographically and histologically. Callus defects were classified using serial radiographs. Biopsy specimens were taken from high-grade defect (Grades 3-4) zones to examine the osteogenic potential. Radiographic evaluation showed 13 callus defects; 12 occurred after the anterolateral approach and only one occurred after the posteromedial method. Although low-grade defects (Grades 1-2) healed spontaneously, biopsy specimens taken from Grades 3-4 defects revealed no osteogenic potential and requiring operative revision. Because of low soft tissue covering and impaired blood supply to the anterior tibia during surgical exposure for corticotomy, less callus formation occurred after the anterolateral approach compared with the posteromedial approach. We recommend the less invasive posteromedial approach to reduce callus defects and impaired healing in callus distraction of the proximal tibia.

Biochemical bone markers are useful to monitor fracture repair.

UNLABELLED: Biochemical bone markers reflect bone metabolism but little is known regarding their usefulness during fracture repair. Reduced bone mineral density may influence fracture healing. We hypothesized that low bone mineral density results in decreased levels of bone markers during the acute phase of fracture healing, especially in women who are postmenopausal. We also addressed the question of different fracture types and locations resulting in different levels of bone markers. Urinary levels of N-terminal cross-linked telopeptide, deoxypyridinoline, and pyridinoline were measured preoperatively and postoperatively in patients with hip fractures, distal forearm fractures, and in 25 control subjects. Bone mineral density was determined using quantitative computed tomography of the spine. Patients with low bone mineral density, especially women who were postmenopausal, had greater concentrations of N-terminal cross-linked telopeptide when compared with patients with normal bone mineral density or men. Patients with pertrochanteric fractures had greater concentrations than patients with femoral neck fractures, as did patients with hip fractures compared with patients with fractures of the distal forearm. These results suggest that levels of bone markers increase during fracture healing despite low bone mineral density and that different fracture types and locations result in different levels of bone markers. LEVEL OF EVIDENCE: Prognostic study, Level I (high quality prospective study-all patients were enrolled at the same time with > or = 80% of followup of enrolled patients). See the Guidelines for Authors for a complete description of levels of evidence.

Vitamin K in combination with other biochemical markers to diagnose osteoporosis.

The significance of a multiparametric classification approach of vitamin K is analysed to differentiate premenopausal (CTRL), postmenopausal non-osteoporotic (nOSP) and osteoporotic (OSP) women. Data records of women between 28 and 74 years of age were used for evaluation. Bone mineral density was determined by quantitative computed tomography of the lumbar spine using the T-score to diagnose osteoporosis. Vitamin K and biochemical markers of bone formation and resorption--alkaline phosphatase (AP), bone alkaline phosphatase (bAP), osteocalcin (OC), undercarboxylated osteocalcin (ucOC), procollagen type I carboxyterminal propeptide (PICP), pyridinoline (PYD), deoxypyridinoline (DPD), N-terminal cross-linked telopeptide of type I collagen (NTx) and bone sialo protein (BSP)--were analysed in all women on days 1 and 42. Vitamin K was significantly lower in the OSP group versus nOSP and CTRL. The odds ratio results revealed the following: vitamin K, 16.7; PYD, 7.5; NTx, 6.0; DPD, 2.7; and ucOC, 2.7. Vitamin K represented a sensitivity rate of 64% and a specificity rate of 82%. In the receiver operating curve analysis, vitamin K reached the highest area under curve (AUC) score. The combination of vitamin K and AP, bAP and PYD resulted in increased AUC scores (>0.9). The parameter combination of vitamin K/PYD and vitamin K/bAP demonstrated a sensitivity rate of 75-88%, with a specificity rate of more than 82%. The data suggests that a combination of vitamin K with other biochemical bone indices might be a useful tool for assessing bone metabolism, especially in metabolic bone diseases such as osteoporosis.