Amyloid-beta causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons.

Elevation of intracranial soluble amyloid-beta (Abeta) levels has been implicated in the pathogenesis of Alzheimer's disease (AD). Intracellular events in neurons, which lead to memory loss in AD, however, remain elusive. Humanin (HN) is a short neuroprotective peptide abolishing Abeta neurotoxicity. Recently, we found that HN derivatives activate the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. We here report that an HN derivative named colivelin completely restored cognitive function in an AD model (Tg2576) by activating the JAK2/STAT3 axis. In accordance, immunofluorescence staining using a specific antibody against phospho- (p-) STAT3 revealed that p-STAT3 levels in hippocampal neurons age-dependently decreased in both AD model mice and AD patients. Intracerebroventricular administration of Abeta1-42 downregulated p-STAT3 whereas passive immunization with anti-Abeta antibody conversely restored hippocampal p-STAT3 levels in Tg2576 mice, paralleling the decrease in the brain Abeta burden. Abeta1-42 consistently modulated p-STAT3 levels in primary neurons. Pharmacological inhibition of the JAK2/STAT3 axis not only induced significant loss of spatial working memory by downregulating an acetylcholine-producing enzyme choline acetyltransferase but also desensitized the M(1)-type muscarinic acetylcholine receptor. Thus, we propose a novel theory accounting for memory impairment related to AD: Abeta-dependent inactivation of the JAK2/STAT3 axis causes memory loss through cholinergic dysfunction. Our findings provide not only a novel pathological hallmark in AD but also a novel target in AD therapy.

Insulin-like growth factor I (IGF-I) protects cells from apoptosis by Alzheimer's V642I mutant amyloid precursor protein through IGF-I receptor in an IGF-binding protein-sensitive manner.

It has been found that insulin-like growth factor I (IGF-I) exerts cytoprotection against Abeta amyloid-induced neuronal cell death. Deposits of Abeta amyloid are one of the pathological hallmarks of Alzheimer's disease (AD). Here, we examined whether IGF-I exerts protective activity against cell death induced by a familial AD (FAD)-linked mutant of amyloid precursor protein (APP), and we found that IGF-I protected cells from toxicity of FAD-associated V642I mutant of APP in multiple cell systems. IGFBP-3 blocked this action of IGF-I, but not of des(1-3)IGF-I, which was as active as IGF-I in the presence of IGFBP-3. The data also demonstrated that the IGF-I receptor (IGF-IR) mediates the protective activity of IGF-I. The antagonizing function of the IGF-I/IGF-IR system against V642I-APP, which is further antagonized by IGFBP-3, provides a molecular clue to the understanding of AD pathophysiology and to the establishment of potential therapy for AD.

Circulating levels of soluble Fas ligand and soluble Fas in patients with chronic obstructive pulmonary disease.

Fas- and tumour necrosis factor (TNF) receptor-mediated apoptosis are known to be two principal apoptotic mechanisms in humans. Although there are several distinctions between these two systems, in vitro studies have demonstrated similar hypoxic activation and a functional relationship. Since patients with chronic obstructive pulmonary disease (COPD) show chronic hypoxaemia and the activation of the TNF-alpha system, we investigated whether these pathophysiological changes influence the Fas-Fas ligand system. We measured the circulating soluble Fas ligand (sFas-L) level, an inducer of apoptosis, and the soluble Fas receptor (sFas) level, an inhibitor of apoptosis, in 34 COPD patients and 35 age-matched healthy controls. In addition, we investigated the relationships between the levels of sFas-L or sFas and clinical variables including the TNF-alpha system; circulating TNF-alpha and soluble TNF-receptor (sTNF-Rs: sTNF-R55 and R75) levels, in the COPD patients. Although circulating TNF-alpha, sTNF-R55 and R75 levels were significantly higher in the COPD patients than in the healthy controls, serum level of sFas-L (Fisher's exact probability test; P = 0.26) and plasma level of sFas [COPD patients vs. controls; mean (SD); 3.74 (0.63) vs. 3.67 (0.48) ng/ml; P = 0.89) were not increased in the COPD patients. There was no significant correlation between the levels of sFas-L or sFas and clinical variables in COPD patients. These results suggest that the Fas-Fas ligand system does not independently play an important role in the pathophysiology of patients with COPD.

[Circulatory effects of stellate ganglion block and high thoracic epidural block].

A comparative study of the circulatory effects of stellate ganglion block (SGB) and high thoracic epidural block (TEB) was conducted in 11 patients. Although blood pressure and heart rate showed no significant changes even after SGB, they both decreased significantly following TEB. The blood flow in the common carotid artery (CCA) increased markedly at 5 minutes after performing SGB, and at 20 minutes it reached its peak value of 163.5 +/- 7.8%, and the increase remained significant up to 75 minutes. On the other hand, it increased significantly from 5 minutes after performing TEB and reached its peak of 122.2 +/- 7.6% at 15 minutes, and this increase remained significant up to 60 minutes. In comparing these two nerve blocks, the blood flow in the CCA showed a more marked increase following SGB than after TEB from 5 to 60 minutes after performing. The blood flow rate in the CCA increased markedly from 5 minutes after performing SGB, reached its peak of 139.1 +/- 11.3% at 20 minutes, and this increase remained significant up to 60 minutes thereafter. After performing TEB no significant changes were observed. In comparing SGB and TEB, from 5 to 60 minutes after performing, the rate became markedly faster after SGB than after TEB. The vascular diameter of the CCA from 5 minutes after performing SGB showed a slight but significant enlargement, and at 20 minutes it reached its maximum of 111.7 +/- 3.0%, and this significant enlargement persisted up to 60 minutes. From 10 minutes after performing TEB, it showed a slight but significant enlargement.(ABSTRACT TRUNCATED AT 250 WORDS)

[Anesthetic considerations for hepatic resection using veno-venous bypass].

Anesthetic experience of 4 cases of hepatic resection using veno-venous bypass was reported. Non-forced bypass (passive shunt) was used in case 1. Hepatic resection was performed while supporting hemodynamic stability during the subsequent anhepatic phase using pump-driven veno-venous bypass (active shunt) in case 2-4. Various problems arose in each case. In the non-forced bypass case, hypotension during the bypass created a problem; whereas, hypothermia was pronounced during bypass in the pump-driven bypass cases. Massive transfusion due to bleeding, hypocalcemia, and unintentional hypothermia after veno-venous bypass precipitated heart failure. Attention should therefore be directed toward, (1) preparation for massive transfusion, (2) measurement and correction of the plasma calcium ion concentration, (3) maintenance of body temperature, and (4) hemodynamic control with a Swan-Ganz catheter and an inferior vena cava catheter. Extracorporeal bypass using a pump-driven veno-venous bypass (Bio-pump) and splanchnic decompression system via the portal system appear to be advantageous.

[Aortic pulse wave velocity in patients with coronary atherosclerosis--a comparison with coronary angiographic findings].

This study was conducted to investigate the relationship between aortic pulse wave velocity (PWV) and coronary atherosclerosis. We measured PWV in 105 subjects (84 males and 21 females; age 59 +/- 0.5) who received coronary angiographic examination (CAG). PWV was measured by simultaneous recording of pulse waves from the left carotid and the left femoral arteries, electrocardiogram and phonocardiogram. The subjects were classified into 4 groups according to the number of major coronary arteries having stenosis, that is, N group with normal CAG, 1 vessel disease (VD) group, 2VD group and 3VD group. The PWV value was significantly greater only in 3VD group (n = 10, age 63 +/- 3.6, PWV 10.0 +/- 0.88 m/sec) than that in N group (n = 18, age 53 +/- 2.0, PWV 8.0 +/- 0.34 m/sec). No significant difference was observed between PWV value in N group and that in all patients with coronary artery stenosis (n = 87, age 60 +/- 2.0, PWV 8.9 +/- 0.2 m/sec). To further investigate the relationship between PWV values and CAG findings, we used a CAG score which means the sum of the points assigned to each coronary artery segment (American Heart Association) according to the severity of stenosis (0, 1, 2, 3, and 4 for normal, less than 49% stenosis, 50 to 74% stenosis, 75 to 99% stenosis, and complete occlusion, respectively). The PWV values significantly correlated with the CAG score and also with age by a simple regression analysis. Multivariate analysis, however, revealed that PWV values did no longer correlate with CAG score. PWV values still significantly correlated with age.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin type V receptor activates c-Jun N-terminal kinases via Galpha(12) family G proteins.

Somatostatin is a neurotransmitter with diverse effects including anti-proliferation in a wide range of normal and neoplastic cells, and occasionally growth stimulatory and neurotrophic actions. Stress-activated protein kinase or c-Jun N-terminal kinase (SAPK/JNK) can also induce growth arrest and occasionally growth stimulation. However, the relationship between somatostatin and SAPK/JNK is less clear. Here we report that the binding of somatostatin to the somatostatin receptor type V (SSTR5) upregulates SAPK/JNK activity. We also show that this activation is mediated by Galpha(12) and Galpha(13). This study demonstrates that SSTR5 is the heptahelical receptor that activates SAPK/JNK via the G(12) family G proteins.

[Coronary bypass surgery in patients 70 years of age and older].

Twenty-six patients 70 years of age and older who underwent elective coronary artery bypass grafting were analyzed. These patients were compared with 76 patients under 70 years of age. The results obtained were as follows. The aged group had significantly greater incidences of preoperative pulmonary and renal complications. Preoperative cardiac function in the aged group was not different from that in the younger one. The incidence of left main trunk stenosis among the aged group (31%) was twice that in the younger one (15%). Then mean number of grafts was 3.0 in both groups. There were no significant differences in the operation time, anoxic arrest time, and extracorporeal circulation time between these two groups. Although the operative mortality rate in the aged group (11.5%) was higher than that (2.6%) in the younger one, the difference was not significant. Postoperative cerebral, respiratory and renal complications were more common in the aged group. However, the incidences of these complications were not different between these two groups. Surgical mortality and morbidity were improved in the latter half of the patients of the aged group, in whom only one operative death was observed and there was no life-threatening postoperative complication. Symptomatic improvements in survivors were remarkable. Thus, we conclude that coronary artery bypass grafting can be performed with acceptable risk in patients 70 years of age and older.

Impaired hyperemic response of forearm vessels in patients with coronary artery disease. A non-invasive evaluation.

The blood flow velocity of the right brachial artery was measured noninvasively by pulsed Doppler flowmetry in 50 patients with angina pectoris. Reactive hyperemia was induced by a 2-minute occlusion of the artery by a tourniquet. We assessed the peak velocity ratio (PVR) and 50% recovery time (RT) which were defined as the ratio of maximal to baseline systolic peak velocity and as the interval from the resumption of arterial flow to 50% decline of the increased systolic peak velocity, respectively. Multiple regression analysis for determinants of PVR and 50% RT was performed with 7 variables which were age, sex, hypertension, diabetes mellitus, smoking, total cholesterol level, and the number of diseased coronary arteries. Multiple R was 0.649 (p < .01) for PVR and 0.682 (p < .01) for 50% RT. There were significant inverse correlations between PVR and the number of diseased vessels (t-value; -3.34), hypertension (-2.43) and smoking (-2.38). The 50% RT was inversely correlated with the number of diseased vessels (t-value; -4.45), feminine gender (-2.75) or smoking (-2.12). Stepwise regression analysis revealed that the number of diseased vessels was the only significant variable for the determination of PVR or 50% RT. An impairment of reactive hyperemia at the forearm vessel correlated with the severity of coronary artery disease in patients with angina pectoris. This finding suggests the presence of some identical mechanisms which are detrimental to both vascular beds. Observation of the hyperemic response at the brachial artery will provide a clue for noninvasive estimation of the extent of coronary artery disease.

[A case of coexisting descending thoracic aortic aneurysm and atypical aortic coarctation treated successfully by surgery using the thromboexclusion method].

The thromboexclusion method was successfully applied to a 43-year-old male with aortitis syndrome. Preoperative aortogram showed a fusiform aneurysm of the descending aorta just below the left subclavian artery and atypical coarctation of the descending aorta distal to this aneurysm. Pressure gradient across the stenosis was about 70 mmHg. The technique of flow reversal and thromboexclusion was performed in this patient because of severe calcification in the aortic arch and the entire descending aorta. A long extra-anatomical bypass between the ascending aorta and the infrarenal abdominal aorta was made, and a permanent aortic clamp was placed across the aorta at the left subclavian artery. Hypertension in the arm disappeared immediately after the operation, and postoperative catheterization revealed no pressure gradient between the ascending and the abdominal aorta. Computed tomogram performed 18 days after the operation and aortogram done 44 days postoperatively disclosed thrombi formation in the aneurysm.

Neuronal cell apoptosis by a receptor-binding domain peptide of ApoE4, not through low-density lipoprotein receptor-related protein.

Since an apolipoprotein E4 (ApoE4) peptide composed of the low-density lipoprotein (LDL) receptor-related protein (LRP)-binding domain [ApoE4(141-149)(2) or ApoE(141-155)(2)] exerts neurotoxicity in primary neurons and neuronal cell lines, it has been controversial whether these effects are mediated by LRP. Here, we examined whether ApoE4(141-149)(2)-induced toxicity is mediated by LRP in a neuronal cell system where ApoE4 toxicity is mediated by LRP: serum-deprived F11 neuronal cells. In these cells, where ApoE4 exerted toxicity by apoptosis in a manner sensitive to both caspase inhibitors and pertussis toxin (PTX), ApoE4(141-149)(2) also caused cell death by apoptosis but in a caspase-inhibitor-resistant, PTX-resistant manner. ApoE4(141-149)(2)-induced death was not inhibited by antisense oligonucleotides to LRP. Therefore, we conclude that ApoE4(141-149)(2) is able to exert neurotoxicity without involving LRP.

Hydrogen peroxide enhances shedding of type I soluble tumor necrosis factor receptor from pulmonary epithelial cells.

Reactive oxygen intermediates (ROIs) are among the important mediators in the pathogenesis of lung diseases in which tumor necrosis factor (TNF) plays a pivotal role. However, the effects of ROIs on the TNF- TNF receptor system remain unclear. Effects of hydrogen peroxide on the shedding of soluble tumor necrosis factor receptor (sTNF-R) were investigated in a pulmonary epithelial cell line (A549) using enzyme-linked immunoassay. A549 cells spontaneously released type I sTNF-R (sTNF-RI) into the culture medium. Hydrogen peroxide accelerated the release of sTNF-RI from the A549 cells time- and dose- dependently. Stimulated release of sTNF-RI by hydrogen peroxide or phorbol myristate acetate (PMA) was inhibited by pretreatment with the intracellular hydroxyl radical scavengers dimethyl sulfoxide and dimethyl thiourea. A synthetic metalloproteinase inhibitor (KB-R8301) inhibited not only spontaneous release of sTNF-RI but also shedding enhanced by hydrogen peroxide and PMA. Preincubation with a protein kinase C inhibitor, calphostin C, downregulated the hydrogen peroxide- or PMA-induced shedding of sTNF-RI. Neither genistein, a tyrosine kinase inhibitor, nor H-89, a protein kinase A inhibitor, inhibited shedding of sTNF-RI by hydrogen peroxide and PMA. Although the surface expression of TNF-R assessed by 125I-TNF specific binding was decreased in the presence of hydrogen peroxide or PMA, TNF-RI mRNA transcript levels remained unchanged. These results show that hydrogen peroxide is involved in the activation of metalloproteinase and protein kinase C responsible for the shedding of sTNF-RI. Accordingly, ROIs may alter TNF action by enhanced shedding of sTNF-RI and reducing its surface receptor expression.