An increased dose of insulin detemir improves glycaemic control and reduces body weight of Japanese patients with diabetes.

AIMS: The aim of study was to evaluate the safety and efficacy of insulin detemir as a basal insulin switching from neutral protamine Hagedorn insulin (NPH) and insulin glargine in patients with diabetes on an intensive insulin therapy regimen. METHODS: This 6-month multicentre, prospective, treat-to-target [glycosylated haemoglobin (HbA(1c) ) less than 6.5%] trial included 92 people with diabetes (61 type 1, 29 type 2 and two unknown diabetes types). Detemir was administered first with fixed dose and injection times and then adapted to optimal dose after 3 months. RESULTS: Mean HbA(1c) (%) of all the subjects at months 4 to 6 of the study was improved compared with month 0 (7.34 ± 0.87, 7.28 ± 0.88, 7.25 ± 0.93 vs. 7.55 ± 1.18; p < 0.05 paired t-test). However, significant improvement was seen only among the patients who had previously used NPH as a basal insulin. Twice-daily injection of basal insulin increased among people in the type 1 previously injected insulin glargine. Total insulin dose increased in the type 1 glargine group. The mean body weight change in the highest quartile body mass index (BMI) group was from 70.7 to 69.3 kg over the 6 months. Quality of life (QoL) relating to the patients' glycaemic control tended to improve without a change in frequency of hypoglycaemia. CONCLUSIONS: The results suggest that insulin detemir has a greater effect on glycaemic control in subjects with poor glycaemic control using NPH; can reduce or maintain body weight in obese patients; and obtains perceptive stability for patients with unstable glycaemic control.

Is driving a car a risk for Legionnaires' disease?

Legionnaires' disease (LD) is a major cause of severe community-acquired pneumonia but the source and mode of transmission are not always apparent, especially in sporadic cases. We hypothesized that LD can be acquired from the air-conditioning systems of motor cars. Swabs were taken from the evaporator compartments of the air-conditioning system of scrapped cars. Healthy subjects who were mainly employees of regional transportation companies were tested for antibody to Legionella pneumophila serogroups 1-6; they also completed a questionnaire. Legionella species were detected in 11/22 scrapped cars by the loop-mediated isothermal amplification method. The prevalence of microplate agglutination titres > or =1:32 was significantly higher in subjects who sometimes used car air-conditioning systems. Although we did not prove a direct link between Legionella spp. in the car evaporator and LD, our findings point to a potential risk of car air-conditioning systems in LD, which needs further investigation.

Longitudinal Findings of MRI and PET in West Syndrome with Subtle Focal Cortical Dysplasia.

BACKGROUND AND PURPOSE: Despite the development of neuroimaging, identification of focal cortical dysplasia remains challenging. The purpose of this study was to show the longitudinal changes of MR imaging and FDG-PET in patients with West syndrome and subtle focal cortical dysplasia. MATERIALS AND METHODS: Among 52 consecutive patients with West syndrome, 4 were diagnosed with subtle focal cortical dysplasia on 3T MR imaging. MR imaging and PET findings were evaluated longitudinally at onset and at 12 and 24 months of age. RESULTS: At the onset of West syndrome, MR imaging demonstrated focal signal abnormalities of the subcortical white matter in 2 patients. In the other 2 patients, focal subcortical high-intensity signals became visible on follow-up T2WI as myelination progressed. PET at onset showed focal cortical hypometabolism in 3 patients, with 1 of these patients also having focal hypermetabolism and 1 having normal findings. On PET at 24 months, hypometabolism persisted in 2 patients and disappeared in 1, and hypermetabolism disappeared in 1. In 1 patient with normal MR imaging and PET findings at onset, focal hyperintensity and hypometabolism first appeared at 24 months of age. The findings on MR imaging and PET in these patients evolved differently with brain maturation and the clinical course. CONCLUSIONS: Subtle focal cortical dysplasia can be undetectable on MR imaging at the onset of West syndrome and is not always accompanied by hypometabolism or hypermetabolism on PET. Longitudinal MR imaging and PET studies may be useful for detecting such lesions. Even in West syndrome with a congenital structural abnormality, PET findings evolve differently with brain maturation and the clinical condition.

Synthesis and structural characterization of the first neptunium based metal-organic frameworks incorporating {Np6O8} hexanuclear clusters.

Successful synthesis of the first transuranium metal-organic frameworks (TRU-MOFs) involving tetravalent Np4+ is reported. These compounds were obtained from the controlled hydrolysis of Np4+ in the presence of dicarboxylate ligands. The final structures contain the [Np6O4(OH)4(H2O)6]12+ unit, which were never crystallized before with tetravalent neptunium, associated with ditopic ligands.

Predominant area of brain lesions in neonates with herpes simplex encephalitis.

OBJECTIVE: Nonspecific manifestations and a varied distribution of brain lesions can delay the diagnosis of herpes simplex encephalitis (HSE) in neonates. The aim of this study was to report predominant brain lesions in neonatal HSE, and then to investigate the association between pattern of predominant brain lesions, clinical variables and neurodevelopmental outcome. STUDY DESIGN: A multicenter retrospective study was performed in neonates diagnosed with HSE between 2009 and 2014. Magnetic resonance (MR) images, including diffusion-weighted images, were obtained in the acute and chronic phase. RESULTS: Three predominant areas of brain injury could be defined based on characteristic MRI findings in 10 of the 13 infants (77%). The inferior frontal/temporal pole area was involved in five (38%) patients. The watershed distribution was present in six (46%) patients. Four (31%) infants involved the corticospinal tract area. No significant association was found between any predominant distribution of brain lesion pattern and sex, country, viral type or viral load. However, the corticospinal tract involvement was significantly associated with motor impairment (P=0.045). CONCLUSION: Three predominant areas of brain lesion could be recognized in neonatal HSE. Recognition of those areas can improve prediction of neurodevelopmental outcome.

The specific sorption of Np(V) on the corundum (α-Al2O3) surface in the presence of trivalent lanthanides Eu(III) and Gd(III): A batch sorption and XAS study.

The sorption of pentavalent neptunium, Np(V), on corundum (α-Al2O3) was investigated in the absence and presence of trivalent europium or gadolinium as a competing element under CO2-free conditions. The objective of this study was to investigate how a trivalent metal ion with a higher charge than that of the neptunyl(V) ion would affect the sorption of Np(V) when allowed to adsorb on the mineral surface before the addition of Np(V). Batch sorption experiments conducted as a function of pH (pH-edges) and as a function of Np(V) concentration (isotherms) in the absence and presence of 1×10(-5)M Eu(III) showed no sign of Eu being able to block Np sorption sites. Surface complexation modelling using the diffuse double layer model was applied to the batch data to obtain surface complexation constants for the formed Np(V) complexes on corundum. To account for potential changes occurring in the coordination environment of the neptunium ion in the presence of a trivalent lanthanide, X-ray absorption spectroscopy (XAS) measurements were carried out on the samples containing only Np(V) and Np(V)+Gd(III). The results reveal the presence of a bidentate Np(V) edge-sharing complex on the corundum surface in the absence of Gd(III), while the coordination environment of Np(V) on the corundum surface could be changed when Gd(III) is added to the sample before the sorption of Np(V).

Accumulation of plutonium in mammalian wildlife tissues following dispersal by accidental-release tests.

We examined the distribution of plutonium (Pu) in the tissues of mammalian wildlife inhabiting the relatively undisturbed, semi-arid former Taranaki weapons test site, Maralinga, Australia. The accumulation of absorbed Pu was highest in the skeleton (83% ± 6%), followed by muscle (10% ± 9%), liver (6% ± 6%), kidneys (0.6% ± 0.4%), and blood (0.2%). Pu activity concentrations in lung tissues were elevated relative to the body average. Foetal transfer was higher in the wildlife data than in previous laboratory studies. The amount of Pu in the gastrointestinal tract was highly elevated relative to that absorbed within the body, potentially increasing transfer of Pu to wildlife and human consumers that may ingest gastrointestinal tract organs. The Pu distribution in the Maralinga mammalian wildlife generally aligns with previous studies related to environmental exposure (e.g. Pu in humans from worldwide fallout), but contrasts with the partitioning models that have traditionally been used for human worker-protection purposes (approximately equal deposition in bone and liver) which appear to under-predict the skeletal accumulation in environmental exposure conditions.

Enzymatic properties of endo-beta-N-acetylglucosaminidases from developing tomato fruits and soybean seeds: substrate specificity of plant origin endoglycosidase.

Substrate specificity and some other enzymatic properties of partial purified endo-beta-N-acetylglucosaminidases (endo-beta-GlcNAc-ase) from developing soybean seeds (Glycine max, Endo-GM) and developing tomato fruits (Lycopersicum esculentum, Endo-LE) were studied. The substrate specificity of these two endoglycosidases was explored and compared with regard to various pyridylaminated N-glycans derived from some naturally occurring glycoproteins. For Endo-GM and Endo-LE, several high mannose-type sugar chains bearing alpha 1-2 mannosyl residue(s), Man9-6GlcNAc2-PA (PA is pyridylamino) (80-100% relative hydrolysis), were most favored substrates followed by Man5GlcNAc2-PA (32% for Endo-LE, 43% for Endo-GM), a typical hybrid-type structure (GlcNAc1Man5GlcNAc2-PA; 34% for Endo-LE, 37% for Endo-GM), and then the common core pentasaccharide of N-glycan (Man3GlcNAc2-PA; 9% for Endo-GM and 16% for Endo-LE). On the contrary, both Endo-GM and Endo-LE could barely hydrolyze the xylose-containing N-glycans (Man3Xyl1GlcNAc2-PA, Man3Fuc1Xyl1GlcNAc2-PA) found ubiquitously in plant cells. The molecular mass of these two endoglycosidases was approximately 62 kDa by gel filtration and both Endo-GM and Endo-LE showed maximal activities for Man6GlcNAc2-PA in a weak acidic region (pH 6.0-6.5).

A new method for assessment of collateral development after acute myocardial infarction.

OBJECTIVES: The purpose of this study was to test the hypothesis that the diameter of the recipient coronary artery of the well developed collateral circulation in patients with acute myocardial infarction increases because of the augmented intravascular pressure caused by subsequent collateral development. BACKGROUND: It is well known that collateral circulation develops after acute myocardial infarction. However, some patients have a well developed collateral circulation at the onset of infarction, which may limit the angiographic evaluation of further development of collateral circulation. METHODS: We measured the diameter of the donor and recipient arteries of the collateral circulation by means of a computer-assisted analysis system in seven patients with acute myocardial infarction who had a totally occluded infarct-related coronary artery during the acute and chronic stages of infarction. All coronary angiograms were obtained after the administration of sublingual nitroglycerin. The measurement was repeated immediately after (within 6 h) and late after (42 +/- 11 days) the onset of acute myocardial infarction. RESULTS: The diameter of the donor artery remained unchanged (1.32 +/- 0.98 vs. 1.42 +/- 1.12 mm). In contrast, the diameter of the recipient artery increased from 1.25 +/- 0.63 to 1.55 +/- 0.61 mm (p < 0.01). These changes in coronary artery diameter were associated with an improvement in regional myocardial wall motion at rest in infarct areas (6.7 +/- 7.0% vs. 13.6 +/- 10.7%, p < 0.05). CONCLUSIONS: These findings indicate that serial measurement of coronary artery diameter is useful for the evaluation of collateral development after acute myocardial infarction.

NMR structure of the Streptomyces metalloproteinase inhibitor, SMPI, isolated from Streptomyces nigrescens TK-23: another example of an ancestral beta gamma-crystallin precursor structure.

The Streptomyces metalloproteinase inhibitor, SMPI, isolated from Streptomyces nigrescens TK-23, is a proteinaceous metalloproteinase inhibitor, and consists of 102 amino acid residues with two disulfide bridges. SMPI specifically inhibits metalloproteinases such as thermolysin. In the present work, the solution structure of SMPI was determined on the basis of 1536 nuclear Overhauser enhancement derived distance restraints and 52 dihedral angle restraints obtained from three-bond spin coupling constants. The final ensemble of 20 NMR structures overlaid onto their mean coordinate with backbone (N, Calpha, C') r.m.s.d. values of 0. 45(+/-0.11) A and 0.57(+/-0.18) A for residues 6 to 99 and the entire 102 residues, respectively. SMPI is essentially composed of two beta-sheets, each consisting of four antiparallel beta-strands. The structure can be considered as two Greek key motifs with 2-fold internal symmetry, a Greek key beta-barrel. One unique structural feature found in SMPI is in its extension between the first and second strands of the second Greek key motif. Interestingly, this extended segment is known to be involved in the inhibitory activity of SMPI. In the absence of sequence similarity, the SMPI structure shows clear similarity to both domains of the eye lens crystallins, both domains of the calcium sensor protein-S, as well as the single-domain yeast killer toxin. The yeast killer toxin structure was thought to be a precursor of the two-domain beta gamma-crystallin proteins, because of its structural similarity to each domain of the beta gamma-crystallins. SMPI thus provides another example of a single-domain protein structure that corresponds to the ancestral fold from which the two-domain proteins in the beta gamma-crystallin superfamily are believed to have evolved.

Elucidation of the mode of interaction of thermolysin with a proteinaceous metalloproteinase inhibitor, SMPI, based on a model complex structure and a structural dynamics analysis.

SMPI is a proteinaceous microbial metalloproteinase inhibitor that was isolated from Streptomyces nigrescens TK-23 in 1979. SMPI is known to selectively inhibit the metalloproteinases in the gluzincin family, according to the Rawling and Barrett classification. There has been no report on the interaction of a metalloproteinase in the family of gluzincins with its specific proteinaceous inhibitor. We have solved the solution structure of SMPI by NMR. Here, we report the binding mode of SMPI to thermolysin, based on the model complex structure generated using our high-resolution NMR structure of SMPI and the crystal structure of thermolysin. The obtained complex model shows that the extruded loop of SMPI, with the scissile bond Cys64-Val65, is complementary in shape to the active cleft of thermolysin. In the complex, the Cys64 (P1) carbonyl oxygen atom can form a tetrahedral coordination to the active zinc in thermolysin, and simultaneously, the methyl groups of Val65 (P1') are closely located in the hydrophobic S1' pocket in thermolysin. From the electrostatic potential surface calculation, the active loop of SMPI and the active cleft in thermolysin have been shown to be complementary in the surface charge distribution, resulting in the stabilization of the complex. The apparently large active loop is less flexible, but maintains a conformation in the nano- to picosecond time-scale, as elucidated from the 15N spin relaxation analysis. This is a quite different structural feature of SMPI from the flexible binding loop generally found in the serine proteinase inhibitors, such as SSI and eglin c, and can be related to the narrow specificity of SMPI. The present study provides the first insight into the interaction between a proteinaceous inhibitor and a gluzincin metalloproteinase.

p21 expression as a predictor for favorable prognosis in squamous cell carcinoma of the lung.

Although p21 WAF1/Cip1 expression has been detected immunohistochemically in non-small cell lung cancer (NSCLC), the associations between p21 expression and clinical characteristics are unknown. To determine the association between p21 expression and clinical features, p21 expression was immunohistochemically analyzed in paraffin-embedded tumor samples from 137 patients with curatively resected NSCLC. p21 expression, indicating normal p21 function, was detected in 48 (35.0%) of the 137 patients with curatively resected NSCLC and was detected more frequently in patients with stage I or II disease (40.2%) than in those with stage IIIA disease (22.5%; P = 0.0483). There was no difference in the positive rate between squamous cell carcinoma [SCC; 15 of 48 (31.3%)] and adenocarcinoma [30 of 77 (39.0%)]. For SCC, patients with tumors expressing p21 survived longer than did those with tumors negative for p21 expression; however, the corresponding survival time was not significant for adenocarcinoma. On the other hand, p53 expression, detected in 58 (42.3%) of these patients, did not act as any predictor for prognosis in either SCC or adenocarcinoma. Our findings suggest that the presence of p21 expression is associated with favorable prognosis in SCC and may be useful in obtaining candidates for adjuvant therapies from among patients with SCC.

Importance of myocardial ischaemia for recruitment of coronary collateral circulation in dogs.

STUDY OBJECTIVE: The aim of the study was to investigate collateral coronary flow and regional myocardial function following different coronary occlusion protocols. DESIGN: Effects of brief left anterior descending artery (LAD) occlusions in dogs (using a pneumatic occluder around the proximal artery) on collateral circulation were evaluated using three different protocols, each producing the same period of pressure gradient across the collateral network: (1) 10 s occlusion X 30 at 1 min intervals; (2) 1 min occlusion X 5 at 1 min intervals; (3) 5 min occlusion X 1. Each protocol was followed by a 10 s occlusion after a further 1 min period. SUBJECTS: 14 mongrel dogs of either sex were used, weight 10-21 kg. MEASUREMENTS AND MAIN RESULTS: Left ventricular pressure, left circumflex coronary artery (LCCA) flow, and subendocardial segment shortening (% delta L) in the area perfused by the LAD were monitored. Collateral blood flow from LCCA to LAD territory was measured as a stepwise decrease in LCCA flow on release of LAD occlusion. During the first 10 s of occlusion, % delta L decreased from 23.6(SEM 2.2)% to 14.2(2.9)%. After protocol (1), % delta L decreased from 23.1(2.2)% to 14.8(3.0)%. By contrast, after protocol (2) and (3) % delta L decreased only slightly, from 22.7(2.6)% to 20.5(2.8)%, and from 22.4(2.4)% to 19.8(2.4)%, respectively. Although collateral blood flow remained unchanged after protocol (1), it increased from 1.6(0.4) ml.min-1 during the first LAD occlusion to 3.0(0.7) ml.min-1 (p less than 0.05) after protocol (2), and to 3.5(0.6) ml.min-1 (p less than 0.05) after protocol 3. Haemodynamic measurements prior to each 10 s LAD test occlusion remained unchanged throughout the experiment. CONCLUSIONS: The pressure gradient across the collateral network cannot dilate pre-existing collateral vessels by itself, but ischaemia related metabolites may play an important role in the recruitment of collateral circulation.

Primary smooth muscle tumor of the liver encasing hepatobiliary cystadenoma without mesenchymal stroma.

We describe a 59-year-old Japanese woman with a large mass of her liver encasing cystic components. Radiologic imaging showed the mass to be hypervascular, and surgical resection disclosed a white tumor. The solid portion was immunohistochemically characterized as a smooth muscle tumor. The cystic components were multilocular and lined with columnar epithelium, consistent with a hepatobiliary cystadenoma. The epithelium strongly stained for CA19-9. The subepithelial space was occupied by collagenous connective tissue interspersed with a small number of spindle-shaped cells. The cystic lesions lacked the mesenchymal stroma between the epithelium and connective tissue layer. There have been no previous reports of a hepatic smooth muscle tumor encasing a hepatobiliary cystadenoma. Because of the pathogenesis of the cystadenoma, it is possible to assume that the smooth muscle tumor also arose from the cells composing the biliary duct in association with the development of the cystadenoma.

Endothelin-specific antibodies decrease blood pressure and increase glomerular filtration rate and renal plasma flow in spontaneously hypertensive rats.

OBJECTIVE: Studies were undertaken to clarify the pathophysiologic significance of endogenous endothelin in the control of blood pressure and renal hemodynamics in spontaneously hypertensive rats (SHR). DESIGN: The technique of passive immunization was used to neutralize endogenous endothelin in order to estimate the contribution of endothelin to the in vivo control of blood pressure and renal hemodynamics. METHODS: Endothelin-specific antibodies were administered intravenously into anesthetized SHR and Wistar-Kyoto (WKY) rats, and the effects upon blood pressure and renal function (renal plasma flow and glomerular filtration rate) assessed. Using the same antibodies, baseline plasma levels of endothelin in both strains of rats were determined by radioimmunoassay. RESULTS: Infusion of endothelin-specific antibodies into SHR decreased mean arterial pressure by approximately 10% and renal vascular resistance and renal vascular resistance by approximately 35%. Glomerular filtration rate and renal plasma flow both increased by approximately 50% over control. In contrast, infusion of normal rabbit serum into SHR or of endothelin-specific antibodies into WKY rats did not result in any significant change in renal hemodynamics or arterial blood pressure. Baseline plasma levels of immunoreactive endothelin in SHR were significantly lower than those in WKY rats. CONCLUSION: These results suggest that endothelin plays an important role in the modulation of systemic blood pressure and renal function in SHR.

Blood coagulation in the hepatic sinusoids as a contributing factor in liver injury following orthotopic liver transplantation in the rat.

Blood coagulation equilibrium in the hepatic sinusoids may be deranged after orthotopic liver transplantation, since tissue factor activity increases in Kupffer cells and thrombomodulin expression disappears in sinusoidal endothelial cells in orthotopically transplanted rat liver. The presence of sinusoidal blood coagulopathy and its contribution to the development of early graft failure following orthotopic liver transplantation were investigated in rats. Orthotopic liver transplantation was performed using livers preserved in cold UW solution, according to the method of Kamada, in rats. Abnormalities in the hepatic sinusoids were evaluated electron-microscopically. Anticoagulation therapy was done using antithrombin III concentrate infused immediately and 12 hr after operation. Fibrin deposition and endothelial cell destruction in the hepatic sinusoids were observed in transplanted rats 5 hr after operation. In these rats, plasma antithrombin III activity was decreased to less than 40%o of normal levels, and massive hepatic necrosis developed with increased plasma thrombin-antithrombin III complex concentration 24 hr after operation. Anticoagulation therapy significantly attenuated the extent of hepatic necrosis, with normalization of plasma antithrombin III activity and further increase in plasma thrombin-antithrombin III complex concentration. A hypercoagulative state exists after orthotopic liver transplantation in rats. Fibrin deposition in the hepatic sinusoids associated with this state may contribute to the development of early graft injury.

Importance of coronary collateral circulation for kinetics of serum creatine kinase in acute myocardial infarction.

The effect of coronary collateral perfusion on the kinetics of creatine kinase (CK) was examined in 32 patients undergoing intracoronary thrombolysis within 6 hours after the onset of a first acute myocardial infarction (AMI). Blood sampling for CK was performed every 2 to 4 hours for a period of 72 hours after AMI. The cumulative CK release was determined using the integrated appearance function curve with the individual disappearance rate. In 19 patients in whom thrombolysis was successful (group A), time to peak CK level was 11 +/- 1 (standard error of the mean) hours after AMI and cumulative CK release was 2,599 +/- 424 U/liter. In 6 patients who had a significant collateral circulation to the infarct-related coronary artery and unsuccessful reperfusion (group B), the time to peak CK was 16 +/- 1 hours (p less than 0.05 compared with group A) and cumulative CK release was 1,897 +/- 478 U/liter (difference not significant compared with group A). In the remaining 7 patients, with neither recanalization nor significant collateral perfusion group C, time to peak CK was 21 +/- 1 hours and significantly (p less than 0.05) longer than groups A and B. Cumulative CK release (2,707 +/- 776 U/liter) was not significantly different from groups A and B. Thus, collateral perfusion is an important determinant of the CK time-activity curve during AMI. Early peaking of CK levels does not reliably identify spontaneous or drug-induced recanalization of the infarct-related coronary artery.

Functional characteristics of nonischemic region during pacing-induced myocardial ischemia in angina pectoris.

To investigate the details of the hyperfunction of nonischemic area during acute ischemia, the regional myocardial function at rest and immediately after rapid cardiac pacing was compared using cineventriculography in 12 patients with stable effort angina. Three left ventricular boundaries at the time of end-diastole, aortic valve opening and end-systole were superimposed, and 128 radial grids were drawn from the center of gravity of end-diastolic frame to the endocardial margin. The changes in the length of each radial grid provided quantitative description of segmental systolic function. In the ischemic area, the percent of total segment shortening decreased from 36 +/- 6% (mean +/- standard error of the mean) to 24 +/- 8% (p less than 0.05) in patients with a significant narrowing of left anterior descending coronary artery (LAD), and from 42 +/- 6% to 20 +/- 4% (p less than 0.05) in those with right coronary artery (RCA) involvement. In the nonischemic area, the percent of total segment shortening increased from 33 +/- 7% to 44 +/- 7% (p less than 0.05) in LAD disease, while it was unchanged in RCA involvement (40 +/- 5% vs 41 +/- 7%). The percentage of isovolumic segment shortening increased from 1 +/- 4% to 7 +/- 3% (p less than 0.05) and from 1 +/- 1% to 5 +/- 2% (p less than 0.05) in LAD and RCA involvement, respectively. Meanwhile, ejection phase shortening did not change significantly (33 +/- 6% vs 40 +/- 7% in LAD involvement, and 39 +/- 6% vs 38 +/- 7% in RCA involvement).(ABSTRACT TRUNCATED AT 250 WORDS)