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We present the first Fermi Large Area Telescope (LAT) catalog of long-term $\gamma$-ray transient sources (1FLT). This comprises sources that were detected on monthly time intervals during the first decade of Fermi-LAT operations. The monthly time scale allows us to identify transient and variable sources that were not yet reported in other Fermi-LAT catalogs. The monthly datasets were analyzed using a wavelet-based source detection algorithm that provided the candidate new transient sources. The search was limited to the extragalactic regions of the sky to avoid the dominance of the Galactic diffuse emission at low Galactic latitudes. The transient candidates were then analyzed using the standard Fermi-LAT Maximum Likelihood analysis method. All sources detected with a statistical significance above 4$\sigma$ in at least one monthly bin were listed in the final catalog. The 1FLT catalog contains 142 transient $\gamma$-ray sources that are not included in the 4FGL-DR2 catalog. Many of these sources (102) have been confidently associated with Active Galactic Nuclei (AGN): 24 are associated with Flat Spectrum Radio Quasars; 1 with a BL Lac object; 70 with Blazars of Uncertain Type; 3 with Radio Galaxies; 1 with a Compact Steep Spectrum radio source; 1 with a Steep Spectrum Radio Quasar; 2 with AGN of other types. The remaining 40 sources have no candidate counterparts at other wavelengths. The median $\gamma$-ray spectral index of the 1FLT-AGN sources is softer than that reported in the latest Fermi-LAT AGN general catalog. This result is consistent with the hypothesis that detection of the softest $\gamma$-ray emitters is less efficient when the data are integrated over year-long intervals., Comment: 41 pages, 17 figures, 7 tables; Accepted by ApJS on 24 May 2021; Contact Authors: I. Mereu, S. Cutini, E. Cavazzuti, G. Tosti

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19–2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11–1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01–2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24–2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

著者人数: 43名, Accepted: 2005-06-15, 資料番号: SA1003415000

Membrane cofactor protein (MCP) of the C system is a widely distributed regulatory molecule with C3b/C4b binding and factor I-dependent cofactor activity. A rabbit polyclonal antibody was raised against purified human MCP, and it was found to also immunoprecipitate C4b-binding protein (C4bp). Other related complement regulatory proteins, factor H, C3b/C4b receptor, and decay-accelerating factor, were not recognized by this polyclonal antibody to MCP. The cross-reactive epitope was sensitive to reduction with 2-ME and about 3% of the anti-MCP antibody reacted with C4bp. The amino-terminal 48,000-Da, chymotryptic fragment of C4bp was recognized by the antibody to MCP. This fragment of C4bp contains a seven-amino acid peptide that is identical, in its sequence and its location in the third short consensus repeat, to one found in MCP. Two polyclonal antibodies to C4bp, one raised to native and the other to reduced C4bp, did not cross-react with MCP. In addition to this one-way cross-reaction with C4bp, a protein with a m.w. of approximately 60,000 (p60) was found in two of three C4bp preparations that also cross-reacted with antiserum to MCP. p60 was present in trace quantities in the C4bp preparation and was successfully isolated from plasma by C3b affinity chromatography. Its Mr was distinct from that of MCP and other known C3b/C4b binding proteins. Furthermore, p60 was isolated by two different procedures and such material possessed no detectable cofactor activity. Based on these results, p60 is a plasma C3b-binding protein that shares epitopes with C4bp and MCP, and is probably not a soluble form of MCP.

We obtained a unique CD46 cDNA, STc/CY4, from the human testis, the predicted amino acid sequence of which suggested the presence of a novel isoform of CD46. This message was present predominantly in the testis, and the predicted isoform possessed a short (11 amino acids) transmembrane section (TM) and an unidentified cytoplasmic tail (CY). When expressed in Chinese hamster ovary (CHO) cells, this CD46 isoform underwent no O-glycosylation and was mostly retained in the endoplasmic reticulum. This unusual behaviour of the new isoform was due in part to the short TM and the unusual sequences of the CY. The molecular mass of this isoform was 42,000, approximately 20,000 smaller than conventional CD46. These properties of the STc/CY4 isoform were similar to those of sperm CD46. The only difference between sperm CD46 and the STc/CY4 isoform expressed on CHO cells was that only the latter possessed N-linked sugars of high mannose types. Since the STc/CY4 isoform may behave like sperm CD46 in cellular localization and post-translational modification, studies of sperm-egg interassociation were performed using hamster eggs and CHO cell clones expressing various isoforms including the STc/CY4. Rosette formation was seen most effectively between hamster eggs and STc/CY4-expressing CHO cells. These results infer that O-glycosylation perturbs CD46-mediated sperm-binding to eggs and thus sperm CD46 lacking O-linked sugars can serve as an adhesion molecule. The possible role of CD46 in fertilization and the structural differences between sperm and conventional CD46 are discussed.

We have characterized a C3a receptor on guinea-pig macrophages by 125I-C3a binding and functional responses. Scatchard analysis applied to the 125I-C3a binding to guinea-pig macrophages revealed the existence of two receptor classes; a high-affinity class with approximately 0.63 x 10(5) binding sites/cell with a Kd = 2.7 nM, and a relatively low-affinity class with approximately 1.2 x 10(5) binding sites/cell with a Kd = 51 nM. The binding of C3a to macrophages was totally blocked when there was an excess of C3a. C3a triggered a transient intracellular Ca2+ ([Ca2+]i) mobilization in macrophages, which was accompanied by homologous desensitization. C3a was also capable of generating O2- from macrophages. The C3a-induced Ca2+ response and O2- generation were not detected in the pertussis toxin-treated macrophages, suggesting that G proteins are coupled with the C3a receptors of macrophages. Although the C3a-induced O2- generation was inhibited by staurosporine, it was more resistant to staurosporine than phorbol 12-myristate-13-acetate (PMA)-induced O2- generation, suggesting that a protein kinase distinct from protein kinase C may be associated with the C3a receptor.

A case describing a huge, suprasellar germinoma with subfrontal extension that produced striking emaciation of the patient as an initial symptom is discussed. Diagnosis of germinoma was made on the basis of a computed tomography scan and cytology of the ventricular fluid. The tumor responded well to radiation treatment, which may indicate that it is not always necessary to reduce tumor bulk by direct surgical intervention before radiation therapy.

Fluosol-DA, 20%, was intravenously infused in 28 patients suffering from cerebrovascular disease, and, was found to be effective in 60% of the cases with vasospasm and in 80% of the cases with stenosis and/or occlusion of the artery. Administration of the solution increases r-CBF by 10.1 to 37.9% when measured by either intra-arterial injection or inhalation of 133Xe. However, an increase of arterial oxygen tension appears to have little effect on r-CBF after administration of the solution. The increase of r-CBF caused by Fluosol-DA, 20%, may be due not only to the lowering viscosity of the mixed blood but also to its direct effect on dilating cerebral vessels.

Human arterial walls obtained from intracranial and extracranial sites were studied with regard to the change in stiffness, elastic modulus, dimension and microstructure with age. The stiffness parameter calculated directly from the relationship between transmural pressure and wall diameter was proposed to express the stiffness of a vascular wall comprehensively. On the other hand, the incremental elastic modulus was utilized as a parameter which represents the intrinsic elastic properties of wall material itself. It was found that the intracranial arteries below middle age are significantly stiff, and have higher incremental elastic moduli and wall stresses compared with the extracranial arteries. The elastic properties as well as wall dimensions of intracranial and extracranial arteries showed different trends with age. These mechanical and morphological features of intracranial arteries were considered to be important factors which contribute to the initiation and development of some cerebro-vascular diseases.

In 24 patients suffering from cerebrovascular diseases, alteration of the cerebral blood flow was investigated by means of the 133Xe clearance technique before and after the intravenous infusion of perfluorochemical suspension (Fluosol-DA, 20%, 10 ml/kg). Since perfluorochemicals exhibit high solubilities for not only oxygen but other kinds of gases, the partition coefficient of Xe (lambda tb) is considered to change depending on the amount of perfluorochemicals contained in the blood (Fct). The solubilities of Xe in the perfluorochemicals contained in the solution were then measured by gas chromatography to obtain an equation for lambda tb: lambda tb = 1.50/(Hct/100 + 12.48Fct/100 + 0.95). The cerebral blood flow was found to increase significantly by 10.1% in the lesional hemisphere and by 10.8% in the healthy one. The cortical small artery with a diameter between 0.1 and 0.2 mm appeared to dilate by 13% after its administration. From these results, the decrease of blood viscosity and some vasodilating effect of the solution might be responsible for the increase of the cerebral blood flow.

新しく開発された自動挿入圧一定式歯周ポケット測定器 (Probie J. Morita製) とコンピューターを連動して, 歯周病患者の全顎全歯面 (1歯当り6点) のプロービングデプスをコンピューターチャーティングし, 次の結果を得た。1) 全顎の全歯面の歯肉 (縁) レベル, プロービングデプス, アタッチメントレベル, 歯肉退縮のコンピューターチャーティングが簡単に, かつ適確に迅速に測定出来た。2) 全顎全歯面のプロービングデプスのチャーティングと印字記録に要する時間は, それぞれ10分19秒と20分23秒であった。以上のことから歯周病の診査, 診断, 予後判定, 治療の再評価において, 自動化したポケット測定器Probieを使用して, プロービングデプスをコンピューターチャーティングすることは, 全顎全歯面の歯周ポケットの進行状態を他のどんな方法よりも正確に速く把握出来る。臨床的に大変有効な診査, 評価方法である。さらに患者の動機づけとリコールシステムにも, 又, 他の臨床データーとともに詳細な分析にも応用出来る。

We present a case of a 15-month-old infant with intracranial cavernous angioma in the right frontal lobe in which the cerebral angiogram revealed transmedullary collecting veins characteristic of venous angioma around the lesion. This vascular malformation was histologically confirmed to be a cavernous angioma.

A rare case of epidermoid cyst traversing the brain stem is presented. Computed tomography revealed the mass within the fourth ventricle; magnetic resonance imaging showed the dumbbell-shaped mass extending from the prepontine cistern to the fourth ventricle. Despite the high mortality and morbidity of brain stem epidermoid cysts in the literature, the tumor was successfully removed. The advantages of magnetic resonance imaging over computed tomography are described.

Mechanical properties of human intracranial arteries were studied with regard to their aging changes as well as cerebral vasospasm. There exists a considerable difference in the development of sclerosis between the intracranial and the extracranial arteries. Intracranial arteries are already stiff at birth and become stiffer with age. Their increase in stiffness is attributable to the marked thickening of their walls, which compensates for the decrease of their elastic modulus with age. The pressure-diameter curve of the intracranial vertebral arteries subjected to subarachnoid hemorrhage is biphasic and has a sharp flexion at the pressure of 180 mmHg when their smooth muscle is activated. Pressure elevation yields little change of diameter in the strongly constricted vessel up to the pressure level at the flexion point, above which the constriction is released abruptly. The existence of flexion point at a high pressure level is an important mechanical feature in considering the development of cerebral ischemia produced by the vasospasm.

Local cerebral blood flow (lCBF) and electroencephalogram were monitored in six monkeys after a transfusion using a perfluorochemical suspension (Fluosol-DA, 20%) that has been manufactured as a blood substitute and is known to be synthetic, biologically inert, and nontoxic and to have a high capacity for carrying oxygen. The animals were mechanically ventilated, and blood gases were maintained at physiological levels. Fluosol-DA, 20% was administered either by an exchange transfusion of 20 ml/kg or by an infusion of 8 ml/kg followed by an exchange transfusion of 12 ml/kg. lCBF was measured using the hydrogen clearance technique. An equation was proposed to estimate the tissue-blood partition coefficient of hydrogen; this coefficient is considered to be dependent upon the amount of perfluorochemicals in the blood and was used to calculate lCBF. Systemic blood pressure, pulse rate, central venous pressure, electroencephalogram, and gas analysis of the blood from the femoral artery, the femoral vein, and the superior sagittal sinus showed little change throughout the experiment. lCBF was increased by 12% (p less than 0.005) after the infusion of Fluosol-DA, 20% of 8 ml/kg and by 31% (p less than 0.02) after the exchange transfusion. Hyperventilation reduced lCBF significantly (p less than 0.005), which implies that the reactivity of the cerebral blood vessels to hypocarbia was not impaired by the administration of FLuosol-DA, 20%. Both the results of this study and the physical properties of Fluosol-DA, 20% suggest that this blood substitute can safely be used for normal human brains and that it might also be effective for ischemic brains.

A rare case of a suprasellar germinoma occurring 2 years after total removal of a pineal benign teratoma is presented. The suprasellar germinoma was not considered a recurrence or dissemination from the pineal tumor, but to have been transformed from germ cells present in the suprasellar region. Although it is controversial whether radiation treatment should be given to a patient with a totally removed benign teratoma, careful follow-up computed tomography scans are indispensable for detecting a possible occurrence of other germ cell tumors.

In order to find a relationship between ductal hyperplasia and carcinoma of the pancreas, histological and histochemical examinations were made on pancreatic specimens of 1,174 autopsy patients with special attention to the age incidence of the former. Ductal hyperplasia was divided into 3 types; nonpapillary, papillary, and atypical hyperplasia. All three types of hyperplasia and ductal carcinoma showed a similar tinctorial property in mucous histochemistry. In general, atypical hyperplasia was seen in the pancreas having papillary hyperplasia which was found in the pancreas associated with nonpapillary hyperplasia. All three types of hyperplasia were apparently more frequent in cancerous pancreases than in non-cancerous ones. They were also more common in the head of the pancreas than in the body and tail. Age incidence also suggests a sequential change from nonpapillary hyperplasia through papillary and atypical ones to carcinoma.

Craniopharyngioma typically appears on a computed tomography scan as a suprasellar mass with calcification, cyst, and contrast-medium enhancement. A huge cystic craniopharyngioma with atypical computed tomographic findings of an isodense, apparently solid temporal mass is presented. Computed tomographic characteristics of our 32 cases with craniopharyngiomas are discussed. The existence of an atypical craniopharyngioma should be taken into account in making an accurate preoperative diagnosis.

The computed tomographic (CT) and pathologic findings in three cases of intra- and suprasellar epithelial cysts (symptomatic Rathke cleft cysts) are described. Literature review revealed that the characteristic CT finding is an intrasellar and/or suprasellar low-density mass that may or may not be enhanced. The enhancement is ringlike or capsular in nature. Whether the cyst wall is enhanced or not seems to be dependent on the histologic features. It is suggested that the enhancement may be caused by an inflammatory process, either septic or aseptic, or squamous metaplasia in the wall, which is possibly induced by degeneration or infection of the cyst contents. Without these additional pathologic processes, the Rathke cleft cyst, a simple retention cyst, may exhibit no contrast enhancement.

Acid proteinase of granulomatous tissues in rats with carrageenin-induced inflammation released two types of kinin from T-kininogen. The kinin was identified as Ile-Ser-bradykinin (T-kinin) and a novel kinin, Met-Ile-Ser-bradykinin (Met-T-kinin), from determination of its amino acid composition and its immunoreactivity toward anti-bradykinin antiserum. The release of T-kinin and Met-T-kinin from T-kininogen were found to occur by consecutive cleavage by cathepsin D and 72 kDa protease.

Fluosol-DA, 20% is a newly developed synthetic perfluorochemical emulsion experimentally known to be biologically inert, non-toxic and to have a high oxygen carrying capacity. On this basis, the effect of its administration was evaluated in cases of cerebral ischemia. A total of 51 administrations was performed in 24 patients suffering from symptomatic cerebral vasospasm due to ruptured aneurysms. Their neurological conditions were evaluated before and after intravenous infusion at a dose of 10 ml/kg in 60 minutes. Regional cerebral blood flow and power spectrum displayed EEG were recorded in 2 and 6 patients, respectively. Fifteen cases (62%) out of twenty four (28/51 times of administration) showed improvement of disturbed consciousness and/or motor weakness which continued for about 24 hours after the administration. The solution was not effective in 9 cases (38%). No aggravation was observed. Cases with anterior communicating artery aneurysms had a better improvement ratio (10/11 cases, 18/24 times) than those with aneurysms located in other regions (5/13 cases, 10/27 times). The solution more effectively improved motor weakness (14/27 times) than disturbed consciousness (18/49 times). Mild consciousness disturbance was found to improve better (16/39 times) than severe disturbance. Marked increase of regional cerebral blood flow (Case 7) or the appearance of α wave on EEG (Case 24) were observed in accordance with the improvement of the conditions. From these clinical data, Fluosol-DA, 20% is considered to be an effective treatment for the improvement of cerebral ischemia due to vasospasm.

Microstructural components were analyzed quantitatively by means of a microphotometric technique applied to three kinds of major cerebral arteries and two kinds of extracranial arteries of comparable size obtained from human autopsy subjects. No statistically significant difference was found in the fractions of three structural components, elastin (Fe), collagen (Fc), and smooth muscle (Fm), in the total of fractions of these three components and in the ratio of collagen to elastin content (Fc/Fe) either between cerebral arteries or between extracranial arteries. The Fe-values were significantly less in cerebral arteries than in extracranial arteries. The Fc/Fe ratios in cerebral arteries were about triple those in extracranial arteries. Although there was no statistically significant difference in the Fe- and Fm-values between two age groups, under 49 and over 50 years old, the Fc-value and the Fc/Fe ratio were higher in the older age group. This change of microstructural composition with age was...

A number of reports have suggested that giant aneurysms of the internal carotid artery can be treated by extracranial-intracranial (EC-IC) bypass and subsequent ligation of the internal carotid artery (IC) with little morbidity [5, 6, 8–11]. Some literature, however, stresses the risk of ischemic complications related to carotid ligation [2, 9]. The purpose of this study is to confirm the effect of this approach and to explore the cause of ischemic complications encountered during or after carotid occlusion by sequential computerized tomography (CT) and magnetic resonance imaging (MRI).

Membrane cofactor protein (MCP) cDNA was transfected into Chinese hamster ovarian tumor (CHO) cells and the functional properties of the expressed protein were studied. Cells adherent to flasks were essential for continuous expression of MCP on CHO cells. If the cells were maintained in noncoated flasks, MCP expression was markedly reduced but upon being transferred to coated flasks reexpressed the protein. MCP expressed on CHO cells had the expected m.w., approximately 50 kDa, and possessed factor I-cofactor activity. By a propidium iodide incorporation assay and by 51Cr release assay, antibody-sensitized CHO cells expressing MCP were protected from C-mediated cytotoxicity. The inhibition of lytic activity correlated with a decrease in C3 deposition. This host cell protective activity was exerted efficiently for the alternative pathway. The classical pathway was not blocked by MCP unless the cells were presensitized with low concentrations of antibody. These results imply that MCP primarily protects host cells from alternative pathway-mediated C3 targeting. In a pathologic state such as autoimmune diseases, the binding of an autoantibody to a target may overcome this protective effect of MCP via the classical pathway.

Treatment of human C4 with chemical denaturants and heat produces rapid, autolytic peptide bond cleavage of the alpha-chain. These alpha-chain fragments are linked to the parent C4 molecule through disulfide bonds. On more prolonged heating, however, there is liberation of several peptides, including the beta-chain, the gamma-chain, and a C-terminal alpha-chain fragment. This reaction is inhibited by iodoacetamide. By using a fluorescent thiol reagent and 14C-iodoacetamide, the thiol group present on each peptide was analyzed. The results suggest that the thiol residue exposed by cleavage of the thioester bond induces thiol-disulfide interchange reactions to liberate the peptides. Based on the identification of fragments liberated, the kinetics of their appearance, their sulfhydryl content, and the reported primary structure of human C4, a model of the interchain disulfide bonds is proposed in which the amino terminal portion of the alpha-chain is disulfide-linked to both the beta- and gamma-chains, whereas the carboxyl terminal portion of the alpha-chain is disulfide-linked to only the gamma-chain.

Recent studies have concluded that after complement activation the final physiologic degradation products of C3 are C3c and the fragment of relative molecular mass (Mr) 42,000 which contains the C3d and C3g domains and was therefore named C3d,g. Using fluorescent labelled C3b as a substrate, we have determined the putative C3d,g ('C3d,g') producing activity of both normal and hereditary angioneurotic oedema (HANE) plasmas. In normal plasmas, the rate of production of C3d,g was 1.0 +/- 0.2 X 10(-10) mol/ml/h and this activity was blocked by antibodies to I. In contrast, HANE, plasmas (deficient in C1INH) showed more than twice as much 'C3d,g' production as normal plasmas and both antibodies to I and kallikrein were required to inhibit this activity. Because of this result, a more sensitive gel system was employed to detect the Mr 42,000 peptide and two 'C3d,g' fragments of approximately equal intensity with Mr of 42,000 and 43,000 were defined. Incubation of purified kallikrein with labelled iC3b produced a C3d,g-like fragment, C3d-k, that aligned with the band of 43,000 Mr generated in HANE plasma. These results indicate that HANE plasma, in contrast to normal plasma, generates the bioactive C3d-k fragment. C1INH blocks the activities of kallikrein and C1s, and C3d-k generation in HANE plasma is probably secondary to the proteolytic activity of kallikrein.