Molecular Targeted Therapy for the Bone Loss Secondary to Pyogenic Spondylodiscitis Using Medications for Osteoporosis: A Literature Review

Pyogenic spondylodiscitis can cause severe osteolytic and destructive lesions in the spine. Elderly or immunocompromised individuals are particularly susceptible to infectious diseases; specifically, infections in the spine can impair the ability of the spine to support the trunk, causing patients to be bedridden, which can also severely affect the physical condition of patients. Although treatments for osteoporosis have been well studied, treatments for bone loss secondary to infection remain to be elucidated because they have pathological manifestations that are similar to but distinct from those of osteoporosis. Recently, we encountered a patient with severely osteolytic pyogenic spondylodiscitis who was treated with romosozumab and exhibited enhanced bone formation. Romosozumab stimulated canonical Wnt/β-catenin signaling, causing robust bone formation and the inhibition of bone resorption, which exceeded the bone loss secondary to infection. Bone loss due to infections involves the suppression of osteoblastogenesis by osteoblast apoptosis, which is induced by the nuclear factor-κB and mitogen-activated protein kinase pathways, and osteoclastogenesis with the receptor activator of the nuclear factor-κB ligand-receptor combination and subsequent activation of the nuclear factor of activated T cells cytoplasmic 1 and c-Fos. In this study, we review and discuss the molecular mechanisms of bone loss secondary to infection and analyze the efficacy of the medications for osteoporosis, focusing on romosozumab, teriparatide, denosumab, and bisphosphonates, in treating this pathological condition.     

8-epi PGF2 alpha generation during coronary reperfusion. A potential quantitative marker of oxidant stress in vivo

BACKGROUND: Myocardial reperfusion is believed to be associated with free radical injury. However, indexes of oxidative stress in vivo have been limited by their poor specificity and sensitivity. Isoprostanes are stable products of arachidonic acid formed in a nonenzymatic, free radical-catalyzed manner. We have developed a sensitive and specific assay for one of these compounds, 8-epi prostaglandin (PG) F2 alpha. METHODS AND RESULTS: To address its utility as an index of oxidative stress during coronary reperfusion, we measured urinary levels by gas chromatography/mass spectrometry in a canine model of coronary thrombolysis, in patients with acute myocardial infarction treated with thrombolytic therapy, and in patients after elective coronary artery bypass surgery. Urinary 8-epi PGF2 alpha was unchanged after circumflex artery occlusion in a canine model of coronary thrombolysis (n = 13; 437.2 +/- 56.4 versus 432.7 +/- 55.2 pmol/mmol creatinine) but increased significantly (P < .05) immediately after reperfusion (553.8 +/- 64.7 pmol/mmol). Urinary levels were increased (P < .001) in patients (n = 12) with acute myocardial infarction given lytic therapy (265.8 +/- 40.8 pmol/mmol) compared with age-matched control subjects (n = 20; 91.5 +/- 11.8 pmol/mmol) and patients with stable coronary disease (n = 20; 95.7 +/- 6.3 pmol/mmol). Preoperative levels rose from 113.2 +/- 11.8 to 248.2 +/- 86.3 pmol/mmol at 30 minutes into revascularization to 332.2 +/- 82.6 pmol/mmol by 15 minutes after global myocardial reperfusion (P < .05) and dropped to 181.2 +/- 50.4 pmol/mmol at 30 minutes and 120.2 +/- 9.9 pmol/mmol at 24 hours after bypass surgery (n = 5). Corresponding changes in spin adduct formation, found with electron paramagnetic resonance, were noted in 2 patients. CONCLUSIONS: These data support the hypothesis that free radical generation occurs during myocardial reperfusion. Measurement of isoprostane production may serve as a noninvasive index of oxidative stress.     

Cortical blood flow response to hypercapnia during anaesthesia in Moyamoya disease

Cortical blood flow (CoBF) was measured continuously by the laser-Doppler method to evaluate the effect of hypercapnia on cortical blood flow during ten surgical procedures in ten young patients (mean +/- SD 9.3 +/- 6.4 yr) with Moyamoya disease. The CoBF was 42.8 +/- 13.4 (ml.100 g-1.min-1) during normocapnia (PaCO2 = 39.0 +/- 2.4 mmHg), and 38.7 +/- 14.4 during hypercapnia (PaCO2 = 47.1 +/- 2.5 mmHg). There was a decrease in CoBF with hypercapnia (P < 0.05) so that the normal CoBF response to hypercapnia was impaired during surgery in the patients with Moyamoya disease. He concluded that patients with Moyamoya disease have a precarious cerebral circulation and hypercapnia may be detrimental to the cortical circulation. This suggests that normocapnia is preferable to hypercapnia in patients with Moyamoya disease during anaesthesia.     

Acetazolamide challenge and technetium-99m-ECD versus iodine-123-IMP SPECT in chronic occlusive cerebrovascular disease

We compared the acetazolamide challenge test using 99mTc-ECD SPECT and 123I-IMP SPECT images in patients with chronic occlusive cerebrovascular disease. We also evaluated the usefulness of linearization correction for acetazolamide challenge test of 99mTc-ECD SPECT. METHODS: Twenty patients with unilateral chronic occlusive cerebrovascular disease (10 patients had middle cerebral arterial lesion and 10 had internal carotid lesion) were included in the study. Split-dose (a dose fractioning was 1:2), and sequential SPECT technique was used for 99mTc-ECD SPECT studies while only acetazolamide challenge test studies for 123I-IMP SPECT were performed. Permeability surface area product model (PS model) and back-diffusion model (Lassen's correction) were used for linearization correction of acetazolamide challenge with 99mTc-ECD SPECT. RESULTS: Six of 16 patients with reduced vasodilatory capacity in 123I-IMP SPECT were underestimated by 99mTc-ECD SPECT acetazolamide challenge test. Relative ECD uptake normalized by cerebellar uptake compared with IMP uptake showed a nonlinear relationship, indicating relatively less uptake in high flow range. The underestimations of limited vasodilatory capacity observed in 99mTc-ECD SPECT without linearization correction was modified by linearization algorithm. However, the effect of correction based on PS model was superior than that of Lassen's correction. The corrected 99mTc-ECD uptake ratio, based on PS model, and IMP uptake ratio demonstrated a better linear relationship than that of Lassen's correction. CONCLUSION: Technetium-99m ECD SPECT corrected based on the PS model is a better method of linearization for evaluating cerebrovascular reserve using acetazolamide challenge.     

Wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase, inhibits erythropoietin-induced erythroid differentiation of K562 cells

We report a large kindred in which a punctate palmoplantar keratoderma (PPK) is associated with malignancy, including Hodgkin's disease, renal, breast, pancreatic and colonic adenocarcinomas. The family was traced through four generations, and over 320 individuals were identified, of whom 49 had punctate PPK. The punctate PPK appeared to be inherited as an autosomal dominant trait with variable penetrance. Ten of the 43 adults (23%) with punctate PPK developed malignancies, and five of these developed before the age of 50. Of the 271 unaffected individuals, six (2%) have developed malignancies, one prior to the age of 50. The association of keratoderma and malignancy is discussed.     

Resonant-tunnelling hot-electron transistor (RHET) using a GaInAs/(AlGa)InAs heterostructure

A common-emitter current gain of 10 has been measured at 77 K for a 100 nm-base resonant-tunnelling hot-electron transistor (RHET) using a GaInAs/(AlGa)InAs heterostructure. The current gain for 25 nm-base RHETs has reached 25, which is the highest value yet reported for hot-electron transistors, and the collector current peak-to-valley ratio has reached 15.0 for the same device.     

Effects of cononsolvency on gelation of poly(vinyl alcohol) in mixed solvents of dimethyl sulfoxide and water

We studied the rates of gelation and phase separation of poly(vinyl alcohol) (PVA) solutions in mixtures of dimethyl sulfoxide (DMSO) and water at 25 °C and found that both the rates show a maximum at a volume fraction of DMSO φ_DMSO=0.60 while gelation was not observed either in pure DMSO or pure water, suggesting that water-DMSO is a cononsolvent system for PVA. On the basis of the data by Cowie [Can J Chem 36 (1961) 2240] we concluded that the 1:2 stable complex between one DMSO molecule and two water molecules is the main cause of this cononsolvency.     

Torque sensorless control in multidegree-of-freedom manipulator

A torque sensorless control for a multi-degree-of-freedom manipulator is described. In the method, two disturbance observers are applied to each joint. One is used to realize a robust motion controller. The other is used to obtain a sensorless torque controller. A robust acceleration controller based on the disturbance observer is shown. To obtain the sensorless torque control, it is necessary to calculate the reaction torque when the mechanical system performs a force task. The calculation method for the reaction torque is explained. Then the method is expanded to workspace force control in the multi-degree-of-freedom manipulator. Several experimental results are shown to confirm the validity of the proposed sensorless force controller