Clinical impact of amyloid PET using 18F-florbetapir in patients with cognitive impairment and suspected Alzheimer’s disease: a multicenter study

Annals of Nuclear Medicine - Amyloid positron emission tomography (PET) can reliably detect senile plaques and fluorinated ligands are approved for clinical use. However, the clinical impact of...     

Successful catheter ablation of ventricular tachycardia originating from the idiopathic saccular apical left ventricular aneurysm

Left ventricular (LV) aneurysm has been recognized to frequently become a substrate of ventricular tachyarrhythmias. We report a case of a 66-year-old woman with symptomatic sustained monomorphic ventricular tachycardia (SMVT) originating from saccular apical LV aneurysm without definite underlying diseases. We performed catheter ablation using electroanatomical and conventional bipolar potential mapping. During SMVT, we found an area of fragmented potential -40 ms preceding the earliest wide QRS complex in the area of the apical LV aneurysm. Radiofrequency applications were delivered to this area. Since then, SMVT was no longer inducible by programmed electrical stimulation. The patient has remained free of VT recurrences during a subsequent 12-month follow-up period.     

Irritant-induced cyclooxygenase-2 is involved in the defense mechanism of the gastric mucosa in mice

Background. Endogenous and exogenous prostaglandins (PGs) have been shown to contribute to reducing the gastric injury caused by irritants given subse-quently. The aim of this study was to clarify whether cyclooxygenase-2 (COX-2) protein induced by pretreatment was involved in the prevention of subsequent ethanol-caused gastric injury in mice. Methods. Mice were pretreated with acidified ethanol or saline and then COX-2 protein expression in the stomach was immunohistochemically determined every 8 h. Mice were administered 95% ethanol 24 h after the acidified ethanol pretreatment, and gastric mucosal damage was evaluated macroscopically and histologically. The effects of NS-398 or indomethacin on the 95% ethanol-caused damage were also examined. Results. Acidified ethanol pretreatment induced COX-2 protein expression in lamina propria macrophages of the gastric mucosa, with a peak level 24 h after the pretreatment. The 95% ethanol treatment caused gastric mucosal damage. The degree of the damage was not different between mice pretreated with acidified ethanol and those pretreated with saline. However, NS-398 aggravated the ethanol-caused damage only in mice pretreated with acidified ethanol, while indomethacin aggravated the damage, evaluated histologically, irrespective of the pretreatment. Conclusions. Pretreatment-induced COX-2, in addition to COX-1, seemed to be involved in the defense mechanism through minimizing the damage caused by a subsequent irritant. Received: October 16, 2000 / Accepted: September 14, 2001     

Associations of hypertension and its complications with variations in the xanthine dehydrogenase gene

Hyperuricemia and oxidative stress participate in the pathophysiology of hypertension and its complications. Xanthine dehydrogenase (XDH) produces urate and, in its oxidase isoform, reactive oxygen species. Here we have studied whether or not the genetic variations in XDH could be implicated in hypertension and its complications. By sequencing the promoter region and all exons of XDH in 48 subjects, we identified three missense mutations (G172R, A932T, N1109T) in a heterozygous state in addition to 34 variations, including 15 common single nucleotide polymorphisms (SNPs). The three missense mutations and eight common SNPs (11488C>G, 37387A>G, 44408A>G, 46774G>A, 47686C>T, 49245A>T, 66292C>G, and 69901A>C) were genotyped in 953 hypertensive Japanese subjects and in 1,818 subjects from a general Japanese population. Four hypertensive patients with rare missense mutations (G172R or N1109T) in homozygous form had severe hypertension. Multivariate logistic regression analysis showed a significant association of three SNPs with hypertension in men: 47686C>T (exon 22, odds ratio [OR]: 1.52, p = 0.047) and 69901A>C (intron 31, OR: 3.14, p = 0.039) in the recessive model, and 67873A>C (N1109T) (exon 31, OR: 1.84, p = 0.018) in the dominant model. After full adjustment for all confounding factors, only one polymorphism (69901A>C) was found to be associated with carotid atherosclerosis in the dominant model (p = 0.028). Multiple logistic regression analysis showed that one SNP (66292C>G) was significantly associated with chronic kidney disease (CKD: estimated creatinine clearance < 60 ml/min) in the recessive model (p = 0.0006). Our results suggest that genetic variations in XDH contribute partly to hypertension and its complications, including atherosclerosis and CKD.     

Genotype and phylogenetic characterization of hepatitis B virus among multi-ethnic cohort in Hawaii

AIM: Hepatitis B virus (HBV) genomes in carriers from Hawaii have not been evaluated previously. The aim of the present study was to evaluate the distribution of HBV genotypes and their clinical relevance in Hawaii. METHODS: Genotyping of HBV among 61 multi-ethnic carriers in Hawaii was performed by genetic methods. Three complete genomes and 61 core promoter/precore regions of HBV were sequenced directly. RESULTS: HBV genotype distribution among the 61 carriers was 23.0% for genotype A, 14.7% for genotype B and 62.3% for genotype C. Genotypes A, B and C were obtained from the carriers whose ethnicities were Filipino and Caucasian, Southeast Asian, and various Asian and Micronesian, respectively. All cases of genotype B were composed of recombinant strains with genotype C in the precore plus core region named genotype Ba. HBeAg was detected more frequently in genotype C than in genotype B (68.4% vs 33.3%, P<0.05) and basal core promoter (BCP) mutation (T1762/A1764) was more frequently found in genotype C than in genotype B. Twelve of the 38 genotype C strains possessed C at nucleotide (nt) position 1858 (C-1858). However there was no significant difference in clinical characteristics between C-1858 and T-1858 variants. Based on complete genome sequences, phylogenetic analysis revealed one patient of Micronesian ethnicity as having C-1858 clustered with two isolates from Polynesia with T-1858. In addition, two strains from Asian ethnicities were clustered with known isolates in carriers from Southeast Asia. CONCLUSION: Genotypes A, B and C are predominant types among multi-ethnic HBV carriers in Hawaii, and distribution of HBV genotypes is dependent on the ethnic background of the carriers in Hawaii.     

Granulocytapheresis (GCAP) for severe alcoholic hepatitis-A preliminary report.

AIM: To evaluate the efficacy of granulocytapheresis therapy in alcoholic hepatitis. METHODS: We attempted to trap leukocytes in the peripheral circulation using the granulocytapheresis (GCAP) technique in patients with severe alcoholic hepatitis who showed a marked elevation of peripheral leukocytes. Corticosteroids were co-administered. RESULTS: The Maddrey's indices for these patients varied between 42 and 117 and MELD scores for alcoholic hepatitis (Mayo) ranged from 20 to 44. Survival rate was 50% (3/6), which is better than the results reported recently for similar patients in a national survey (29%). The effect of GCAP was reflected in decreases in interleukin-6 and interleukin-8 levels as well as in serum concentrations of soluble intercellular adhesion molecule. White blood cell counts were not affected. In the surviving patients, the Maddrey's indices and MELD scores for alcoholic hepatitis varied between 49 and 67, and 20 and 22, respectively, showing that GCAP is effective in patients with disease of moderate severity. Hemolytic anemia occurred in one patient after GCAP therapy. Other events such as pancreatitis, pneumonia, and cerebral hemorrhage were considered to be related to the alcoholic hepatitis itself. CONCLUSION: GCAP therapy deserves further evaluation as a new therapeutic modality for a moderately severe alcoholic hepatitis.     

Interleukin-3, -5, and Granulocyte Macrophage Colony-Stimulating Factor Induce Adhesion and Chemotaxis of Human Eosinophils via p38 Mitogen-Activated Protein Kinase and Nuclear Factor κB

Hematopoietic cytokines such as interleukin (IL)-3, IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF) play a fundamental role in eosinophil functions in allergic asthma. The intracellular signal transduction mechanisms of these cytokines regulating the activation of eosinophils have been potential therapeutic targets. We investigated the roles of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) in IL-3, IL-5, and GM-CSF-induced adhesion, morphological changes, and subsequence transmigration of human eosinophils. IL-3, IL-5, and GM-CSF could augment the phosphorylation of p38 MAPK and nucleus translocation of NF-κB in eosinophils. cDNA expression arrays demonstrated that the gene expression levels of several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), α6, β2 integrin (CD18), and CD44 were upregulated by these cytokines. Results from functional assays showed that adhesion of eosinophils onto airway epithelial cells was enhanced after IL-3 and IL-5 but not GM-CSF stimulation. These cytokines could markedly induce shape change and augment the transmigration of eosinophils. Moreover, administration of either p38 MAPK inhibitor, SB 203580, or proteasome inhibitor, N-cbz-Leu-Leu-leucinal (MG-132), could inhibit the cytokine-induced adhesion, shape change, and transmigration of eosinophils. Together, our findings suggest that IL-3, IL-5, and GM-CSF regulated the adhesion and chemotaxis of human eosinophils through shared signaling pathways involving both p38 MAPK and NF-κB. Our results therefore shed light on the further development of more effective agents for allergic and inflammatory diseases.     

Immunomodulatory Activities of HERBSnSENSES™ Cordyceps — in Vitro and in Vivo Studies

The commercially available HERBSnSENSES? Cordyceps (HSCS) belongs to a cultivated strain of Cordyceps sinensis whose immunomodulatory activities has been renowned in traditional Chinese medicine (TCM) for centuries. The present report is the first that describes its immunomodulatory features through a series of in vitro and in vivo experiments. We measured, in peripheral blood mononuclear cells the in vitro effects of HSCS on the gene expression of cytokines and cytokine receptors, cytokine release, and surface expression of cytokine receptors using cDNA expression array, cytometric bead array (CBA), and immunoflorescence staining, respectively, as well as macrophage phagocytosis and monocyte production of H₂O₂ using flow cytometry. Sixty female BALB/c mice were fed with either HSCS (40 mg/kg/day) or water consecutively for 14 days. Proliferation, cytokine liberation, and CD3/4/8 expression of splenic cells were measured using 5-bromo-2′-deoxyuridine proliferation ELISA, CBA, and cytometry immunoflorescence staining, respectively. In vitro results demonstrated that HSCS induced the production of interleukin(IL)-1β, IL-6, IL-10 and tumor necrosis factor alphaα from PBMC, augmented surface expression of CD25 on lymphocytes, and elevated macrophage phagocytosis and monocyte production of H₂O₂. In vivo results showed that HSCS did not induce splenomegaly and cytokine overliberation. Our results possibly provide the biochemical basis for future clinical trials.     

Temporal Prediction Signals for Periodic Sensory Events in the Primate Central Thalamus

Prediction of periodic event timing is an important function for everyday activities, while the exact neural mechanism remains unclear. Previous studies in nonhuman primates have demonstrated that neurons in the cerebellar dentate nucleus and those in the caudate nucleus exhibit periodic firing modulation when the animals attempt to detect a single omission of isochronous repetitive audiovisual stimuli. To understand how these subcortical signals are sent and processed through the thalamocortical pathways, we examined single-neuron activities in the central thalamus of two macaque monkeys (one female and one male). We found that three types of neurons responded to each stimulus in the sequence in the absence of movements. Reactive-type neurons showed sensory adaptation and gradually waned the transient response to each stimulus. Predictive-type neurons steadily increased the magnitude of the suppressive response, similar to neurons previously reported in the cerebellum. Switch-type neurons initially showed a transient response, but after several cycles, the direction of firing modulation reversed and the activity decreased for each repetitive stimulus. The time course of Switch-type activity was well explained by the weighted sum of activities of the other types of neurons. Furthermore, for only Switch-type neurons the activity just before stimulus omission significantly correlated with behavioral latency, indicating that this type of neuron may carry a more advanced signal in the system detecting stimulus omission. These results suggest that the central thalamus may transmit integrated signals to the cerebral cortex for temporal information processing, which are necessary to accurately predict rhythmic event timing.SIGNIFICANCE STATEMENT Several cortical and subcortical regions are involved in temporal information processing, and the thalamus will play a role in functionally linking them. The present study aimed to clarify how the paralaminar part of the thalamus transmits and modifies signals for temporal prediction of rhythmic events. Three types of thalamic neurons exhibited periodic activity when monkeys attempted to detect a single omission of isochronous repetitive stimuli. The activity of one type of neuron correlated with the behavioral latency and appeared to be generated by integrating the signals carried by the other types of neurons. Our results revealed the neuronal signals in the thalamus for temporal prediction of sensory events, providing a clue to elucidate information processing in the thalamocortical pathways.     

Peripheral nerves are involved in hypomyelinating leukodystrophy-3 caused by a homozygous AIMP1 variant

IntroductionAminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their correct tRNAs. Bi-allelic truncating variants in the AIMP1 gene have been associated with hypomyelinating leukodystrophy-3 (HLD3; MIM 260600), which is characterized by hypomyelination, microcephaly, seizures and decreased life expectancy. Although peripheral nerve involvement has been assumed for HLD3, no compelling evidence is available to date.Case reportThe case was a first-born Filipino male. He showed profound developmental delay, failure to thrive, and spasticity in his limbs. At three months of age he developed refractory epilepsy. Serial magnetic resonance imaging (MRIs) showed profound myelination delay and progressive cerebral atrophy. He showed abnormal nerve conduction studies. Genetic testing revealed a homozygous pathogenic variant in the AIMP1 gene (NM_004757.3: c.115C > T: p.Gln39*). The parents were heterozygous for the same variant.ConclusionHere, we report a patient with a homozygous nonsense AIMP1 variant showing peripheral neuropathy as well as HLD3. Our case suggests that AIMP1 plays a pivotal role in the peripheral nerve as well as the central nervous system.