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.     

EEG spectral abnormalities and psychosis as predictors of cognitive and functional decline in probable Alzheimer's disease

We examined whether either psychotic features (e.g., delusions and hallucinations) or EEG abnormalities are associated with more rapid progression of Alzheimer's disease (AD). AD patients with psychosis have exhibited more EEG abnormalities than those without psychosis, and both abnormal EEG and psychosis have been noted to be predictors of functional and cognitive decline in AD. Ninety-five probable AD patients participating in a longitudinal study of dementia had an EEG and a semistructured psychiatric interview at baseline. Using EEG spectral analysis, we classified records as normal/abnormal based on the parasagittal mean frequency. Patients with abnormal EEGs were more functionally (e.g., Blessed Rating Scale for activities of daily living) and cognitively (e.g., Mini-Mental State) impaired than patients with normal EEG. AD patients with psychosis were only more functionally impaired than patients without psychosis. A two-factor analysis showed no interaction between abnormal EEG and psychosis. In addition, using a Cox proportional hazard model adjusted for age and education, the presence of an abnormal EEG or psychotic symptom at study entry was associated with higher risk of reaching severe cognitive and functional impairment during follow-up. Neither abnormal EEG nor the presence of psychosis predicted death. These results indicate that both abnormal EEG and psychosis are independent predictors of disease progression but not of physical survival.     

Triple check for antigen specificity of B cells during germinal centre reactions

Somatic hypermutation of the immunoglobulin variable genes during germinal reactions might permit the expansion of B-cell clones with unwanted (e.g. autoreactive) specificity. Here, Ernst Lindhout and colleagues propose three antigen-specific checkpoints that ensure the appropriate antigen specificity of activated B cells is maintained by regulating the activation, selection and further differentiation of B cells.     

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.     

Paget's disease of the breast in a man without underlying breast carcinoma

A case of histologically confirmed Paget's disease of the breast in a 72 year old man, without underlying breast carcinoma, is reported. This report raises questions about the pathogenesis of this condition and suggests that Paget's disease is an independent, intraepidermal carcinoma rather than a direct extension of intraductal carcinoma of the breast to the nipple and areola.     

Prostaglandin synthase-1 and prostaglandin synthase-2 are coupled to distinct phospholipases for the generation of prostaglandin D2 in activated mast cells

Aggregation of IgE cell surface receptors on MMC-34 cells, a murine mast cell line, induces the synthesis and secretion of prostaglandin D2 (PGD2). Synthesis and secretion of PGD2 in activated MMC-34 cells occurs in two stages, an early phase that is complete within 30 min after activation and a late phase that reaches a maximum about 6 h after activation. The early and late phases of PGD2 generation are mediated by prostaglandin synthase 1 (PGS1) and prostaglandin synthase 2 (PGS2), respectively. Arachidonic acid, the substrate for both PGS1 and PGS2, is released from membrane phospholipids by the activation of phospholipases. We now demonstrate that in activated mast cells (i) secretory phospholipase A2 (PLA2) mediates the release of arachidonic acid for early, PGS1-dependent synthesis of PGD2; (ii) secretory PLA2 does not play a role in the late, PGS2-dependent synthesis of PGD2; (iii) cytoplasmic PLA2 mediates the release of arachidonic acid for late, PGS2-dependent synthesis of PGD2; and (iv) a cytoplasmic PLA2-dependent step precedes secretory PLA2 activation and is necessary for optimal PGD2 production by the secretory PLA2/PGS1-dependent early pathway.     

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.