Heterogeneity of posterior limbic perfusion in very early Alzheimer's disease

PURPOSE: This study was designed to quantify the heterogeneity of cerebral perfusion on SPECT images in elderly controls and Alzheimer's disease (AD) patients in mild stage using a three-dimensional fractal analysis (3D-FA). MATERIAL AND METHOD: Seventy-five patients with possible and probable AD based on the NINCDS/ADRDA criteria, and thirty-one elderly controls underwent 99mTc-HMPAO SPECT scanning. Dementia severity was assessed using the clinical dementia rating (CDR). Patients with CDR scores of 0.5 (n=33) were classified as "very early" and those with CDR 1 (n=42) as "early". We delineated the SPECT images using 2 cutoffs (35% and 50% cutoffs of the maximal voxel radioactivity) and measured the number of voxels in the areas included by the contours obtained with each cutoff level. The fractal dimension (FD) was calculated by relating the logarithms of cutoff level and the number of voxels. Posterior limbic images were reconstructed at 30 degrees positive to the coronal plane, and posterior limbic FD was calculated. RESULT: Posterior limbic FD for early AD, very early AD, and control groups were 1.03+/-0.16, 1.02+/-0.17, and 0.87+/-0.14 (P=0.001 versus early AD group, P=0.001 versus very early AD). Use of the posterior limbic FD and the ratio of posterior limbic FD to total FD separated very early AD patients from controls with a sensitivity of 76% and a specificity of 81%. CONCLUSION: 3D-FA indicated significant differences in the heterogeneity of CBF distribution between patients with AD in mild stage and elderly controls. Posterior limbic FD may be useful for easily and objectively distinguishing patients with very early AD from aging people.     

A critical role of CpG motifs in a murine peritonitis model by their binding to highly expressed toll-like receptor-9 on liver NKT cells

BACKGROUNDS: Toll-like receptor (TLR)-9 plays a critical role in the recognition of the CpG motifs, which is frequently observed in bacterial DNA. To date, there have not been any reports regarding the role of bacterial DNA in the systemic circulation on the development of sepsis. METHODS: We examined the expression of TLR-9 in the liver and spleen in a murine peritonitis model (CLP mice). We also measured the cytokine response of mononuclear cells (MNCs) from normal and CLP mice to CpG oligodeoxynucleotides (ODN) in vitro and in vivo. RESULTS: TLR-9 expression on F4/80(+) and NK1.1(+)CD3epsilon(+) cells in the liver of CLP mice was elevated compared to sham-operated mice. With regard to cytokine production, we found that CpG ODN markedly stimulated the production of inflammatory cytokines by murine macrophages and liver MNCs. The intravenous injection of CpG ODN in mice that underwent CLP 12h earlier led to their increased cytokine production and their increased mortality. In addition, the depletion of NK/NKT cells contributed to improve their survival rate. CONCLUSIONS: Our results suggest that, in patients with overwhelming bacterial infection, bacterial DNA may induce liver toxicity that is mediated by liver NKT cells and macrophages that express high levels of TLR-9.     

Carbonyl side-chain of catechol compounds is a key structure for the suppression of copper-associated oxidative DNA damage in vitro

Catechol is possibly carcinogenic to humans (International Agency for Research on Cancer, IARC). The key mechanism could include its oxidative DNA-damaging effect in combination with reductive–oxidative metals like Cu. We found that DNA damage was suppressed by introducing an α-carbonyl group to catechol at C4-position to produce carbonyl catechols. During the oxidative DNA-damaging process, catechols but not carbonyl catechols were oxidized to o-quinone; however, coexisting Cu(II) was reduced to Cu(I). Carbonyl catechols were possibly arrested at the oxidation step of semiquinones in the presence of Cu(II). Cu(I)-binding to DNA was stronger than Cu(II)-binding, on the basis of the circular dichroism spectral change. None of the carbonyl catechols induced such change, suggesting sequestration of Cu(I) from DNA. Solid-phase extraction experiments and spectrophotometric analyses showed the formation of semiquinone chelates with Cu(I). Thus, chelate formation could explain the suppression mechanism of the Cu–catechol-dependent DNA damage by terminating the reduction–oxidation cycle. Structural modifications such as introducing an α-carbonyl group to catechol at C4-position would contribute to reducing the risk and improving industrial and medical potentials of aromatic/phenolic compounds sustaining our daily lives.     

Next-day residual sedative effect after nighttime administration of an over-the-counter antihistamine sleep aid, diphenhydramine, measured by positron emission tomography

Antihistamines often are self-administered at night as over-the-counter (OTC) sleep aids, but their next-day residual sedative effect has never been evaluated using a reliable quantitative method such as positron emission tomography (PET). We performed a double-blind, placebo-controlled, crossover study in which we evaluated the residual effect the next day after nighttime administration of diphenhydramine, a commonly used OTC sleep aid, in terms of brain H? receptor occupancy (H?RO) measured using 11C-doxepin-PET. We also compared the results of diphenhydramine with those of bepotastine, a second-generation antihistamine. Eight healthy adult male subjects underwent PET measurement the morning (11:00) after random oral administration of diphenhydramine (50 mg), bepotastine (10 mg), or placebo the night before (23:00). Binding potential ratios and H?ROs were calculated in different brain regions of interest such as the cingulate gyrus, frontotemporal cortex, and cerebellum. Subjective sleepiness and plasma drug concentration also were measured. Calculation of binding potential ratios revealed significantly lower values for diphenhydramine than for bepotastine or placebo in all regions of interest (P < 0.01). Cortical mean H?RO after diphenhydramine treatment was 44.7% compared with 16.6% for bepotastine treatment (P < 0.01). Subjective sleepiness was not significantly different among the subjects treated with each test drug or the placebo. In conclusion, the next-day residual sedative effect after nighttime administration of the OTC sleep aid diphenhydramine was verified for the first time by direct PET measurement of H?RO. Taking into account the possible hangover effect of OTC antihistamine sleep aids, care needs to be taken during their administration.     

Comparison of Autologous Hematopoietic Cell Transplantation and Chemotherapy as Postremission Treatment in Non-M3 Acute Myeloid Leukemia in First Complete Remission

IntroductionA number of randomized trials in patients with AML in CR1 have been conducted and they showed that auto-HCT improves RFS but not OS, compared with chemotherapy. However, because these trials have had compliance problems, the value of auto-HCT still has not been clearly established.Patients and MethodsUsing a database of 2518 adult patients with AML in CR1, we retrospectively analyzed the outcome of auto-HCT and compared it with intensive nonmyeloablative chemotherapy using landmark analyses.ResultsIn 103 auto-HCT recipients, OS and RFS at 3 years from treatment were 65% and 57%, respectively. Multivariate analysis showed that unfavorable risk cytogenetics and entry into CR1 after 2 courses of induction treatment predicted a poor outcome. Because the median time interval between CR1 and auto-HCT was 153 days, landmark analyses at 5 months after CR1 were performed to compare 1290 patients who received chemotherapy alone (median age, 52 years; range, 16-70) with 103 who received auto-HCT (median age, 48 years; range, 16-67). Auto-HCT improves 3-year RFS (58% vs. 37%; P < .001) but not OS compared with chemotherapy alone. Among patients with unfavorable risk cytogenetics or those who required 2 courses to reach CR1, there was no significant difference in RFS between the 2 groups.ConclusionAuto-HCT can be considered as a postremission therapy for AML patients with favorable or intermediate risk cytogenetics who achieve CR1 after a single course of induction treatment.     

Expression of beta-adrenergic receptor up-regulation is mediated by two different processes

Mechanisms of up-regulation of beta-adrenergic receptors (beta-ARs) induced by sustained exposure to 10(-8) M nadolol, a non-selective beta-AR antagonist, were examined using mouse cerebrocortical neurons. Nadolol dose- and time-dependently increased [3H]CGP-12177 bindings to the particulate fractions. This increase occurred 6 h and attained its plateau 12 h after the exposure, whereas beta1- and beta2-AR mRNA significantly increased 24 h and attained their plateaus 3 days after the exposure. Scatchard analysis revealed that the increased bindings were due to increase of receptor density. The [3H]CGP-12177 bindings to beta1- and beta2-ARs increased both 12 h and 5 days after the exposure. Although cycloheximide (CHX) decreased the bindings with or without nadolol, the extent of increase of the bindings induced by nadolol was not affected by CHX. Actinomycin D (AD) with nadolol showed no affects on the bindings 12 h after nadolol exposure, while AD treated 6 h after nadolol exposure significantly reduced the bindings 48 h after nadolol exposure. During 24 h after nadolol exposure, the increase in proteins of beta1- and beta2-ARs in the neuronal membrane was due to the increased receptor protein translocation from cytosol to membrane. These results indicate that the up-regulation of beta-ARs induced by nadolol is mediated by, at least, two different processes, one is increase in translocation of receptor proteins from cytosol to membrane with no changes in synthesis of receptor proteins and their mRNA and another is dependent on receptor protein synthesis with increased synthesis of their mRNA.     

Primary biomarkers in cerebral spinal fluid obtained from patients with influenza-associated encephalopathy analyzed by metabolomics

In order to search for the specific biomarkers of patients with influenza-associated encephalopathy this article analyzed all metabolites in cerebrospinal fluid (CSF) by using metabolome analysis. In all metabolites, the peaks of two molecular weights, 246.0092 and 204.0611, were significantly higher than those in other diseases including influenza without convulsion (p < .05). The peak of a molecular weight 228.0247 in all of the patients except one was less than that in other patients. These results indicate that the new metabolites detected in CSF would be primary markers for the diagnosis of influenza-associated encephalopathy.     

Intrathecal upregulation of granulocyte colony stimulating factor and its neuroprotective actions on motor neurons in amyotrophic lateral sclerosis

To investigate cytokine/chemokine changes in amyotrophic lateral sclerosis (ALS), we simultaneously measured 16 cytokine/chemokines (interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony stimulating factor [G-CSF], macrophage chemoattractant protein-1 [MCP-1], and macrophage inflammatory protein-1beta) in cerebrospinal fluid (CSF) and sera from 37 patients with sporadic ALS and 33 controls using a multiplexed fluorescent bead-based immunoassay. We also conducted immunohistochemical analyses from 8 autopsied ALS cases and 6 nonneurologic disease controls as well as cell culture analyses of relevant cytokines and their receptors. We found that concentrations of G-CSF and MCP-1 were significantly increased in ALS CSF compared with controls. In spinal cords, G-CSF was expressed in reactive astrocytes in ALS cases but not controls, whereas G-CSF receptor expression was significantly decreased in motor neurons of spinal cords from ALS cases. Biologically, G-CSF had a protective effect on the NSC34 cell line under conditions of both oxidative and nutritional stress. We suggested that G-CSF has potentially neuroprotective effects on motor neurons in ALS and that downregulation of its receptor might contribute to ALS pathogenesis. On the other hand, MCP-1 correlated with disease severity, which may aggravate motor neuron damage.     

Upregulation of vascular growth factors in multiple sclerosis: correlation with MRI findings

Vascular permeability changes precede the development of demyelinating lesions in multiple sclerosis (MS), and vessel wall thickening and capillary proliferation are frequently seen in autopsied MS lesions. Although vascular growth factors are critical for inducing such vascular changes, their involvement in MS has not been extensively studied. Thus, we examined the involvement of various vascular growth factors in MS according to their clinical phase and subtype. We measured serum levels of vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (FGF) and platelet-derived growth factors (PDGFs)-AA, -AB and -BB in 50 patients with MS (27 opticospinal MS and 23 conventional MS patients) and 33 healthy controls using sandwich enzyme immunoassays. Correlations between growth factor changes and brain and spinal cord MRI findings were then analyzed. Serum VEGF concentrations were significantly higher in MS patients in relapse than in controls (p = 0.0495) and in MS patients in remission (p = 0.0003), irrespective of clinical subtype. Basic FGF was significantly increased in conventional MS patients, but not opticospinal MS patients compared with controls (p = 0.0291), irrespective of clinical phase. VEGF at relapse showed a significant positive correlation with the length of spinal cord lesions on MRI (r = 0.506, p = 0.0319). The results suggest that an increase in serum VEGF concentration might be involved in MS relapse and the formation of longitudinally extensive spinal cord lesions.