Insulin degludec overdose may lead to long-lasting hypoglycaemia through its markedly prolonged half-life.

BACKGROUND: Overdose of insulin often causes long-lasting severe hypoglycaemia. Insulin degludec has the longest duration of action among the available insulin products; thus, an overdose of insulin degludec can lead to long-lasting hypoglycaemia. In the present paper, we report the case of a woman with long-lasting hypoglycaemia attributable to insulin degludec overdose and markedly prolonged insulin degludec half-life. CASE REPORT: A 64-year-old woman with Type 2 diabetes receiving insulin therapy was taken to an emergency department because of disturbed consciousness 21 h after self-injection of 300 units of insulin degludec (4.34 units/kg). Her plasma glucose level was 2.3 mmol/l. She received repeated intravenous boluses of dextrose for 43 h with continuous intravenous dextrose infusion, but no improvement in long-lasting hypoglycaemia or consciousness was observed. Considering the possibility of adrenal insufficiency, intravenous dexamethasone was administered, and her plasma glucose levels subsequently remained above 5.5 mmol/l without intravenous dextrose boluses. She gradually regained consciousness. A total of 34 h after the overdose, her plasma immunoreactive insulin levels were markedly increased and then gradually declined over ~400 h. The insulin degludec half-life was 40.76 h. CONCLUSION: Although the reported half-life of insulin degludec in the body is ~25 h when administered in standard doses (0.4-0.8 units/kg), no study has investigated its half-life after overdose. In the present case, the half-life of insulin degludec was ~1.6 times longer than that observed with standard doses, probably leading to long-lasting hypoglycaemia. Physicians should be aware of the possibility of unexpected long-lasting severe hypoglycaemia resulting from insulin degludec overdose.

Insulinoma may mask the existence of Type 1 diabetes.

BACKGROUND: Insulinoma is a tumour of insulin-producing cells of the pancreas and is known to be one of the causes of hypoglycaemia. Usually, appropriate removal of the insulinoma results in normalization of blood glucose levels. However, we found novel cases of insulinoma, in which hyperglycaemia developed soon after resection of the insulinoma. CASE REPORT: We encountered two patients with repeated hypoglycaemia caused by insulinoma. Following removal of the insulinoma, unanticipated hyperglycaemia was observed in both patients. Thereafter, their blood tests revealed low levels of serum C-peptide and high titres of anti-glutamic acid decarboxylase antibody, indicating concomitant Type 1 diabetes. Indeed, histological examination of the resected specimen revealed that one patient showed insulitis in non-tumorous pancreatic tissue in which ß-cells had already disappeared. Moreover, inflammatory cells infiltrated the insulinoma, as if it were insulitis of Type 1 diabetes, suggesting the existence of anti-islet autoimmunity. CONCLUSION: These are first cases of insulinoma associated with underlying Type 1 diabetes. Physicians should be aware of the possibility that insulinoma may mask Type 1 diabetes, and measurement of anti-islet autoantibodies may be helpful to find underlying Type 1 diabetes, such as in these cases. It is pathologically interesting that the immune cell infiltration into insulinoma may be suggestive of anti-islet autoimmunity.

Increased granzyme B production from peripheral blood mononuclear cells in patients with acute coronary syndrome.

OBJECTIVES: To clarify the role of granzyme B in acute coronary syndrome. DESIGN AND SETTING: Granzyme B is a member of the serine esterase family released from cytotoxic lymphocytes and plays an important role in cellular apoptosis by activating intracellular caspases. Granzyme B expression was compared between patients with stable and unstable angina pectoris (UAP). PATIENTS: 173 patients with coronary artery disease (CAD) were enrolled. 84 patients were found to have stable angina pectoris (SAP) and 89 patients to have UAP. METHODS: Peripheral blood was drawn from the patients. Peripheral blood mononuclear cells (PBMCs) isolated by gradient centrifugation were cultured at a density of 2x106 cells/ml for 24 hours. The supernatants were collected 24 hours after incubation and the granzyme B level was measured by enzyme-linked immunosorbent assay. Polychromic flow cytometric analysis was performed to evaluate the expression of granzyme B in the cells. RESULTS: Granzyme B production from PBMCs of UAP patients was significantly higher than from those of patients with SAP (39.1 (SEM 6.6) versus 17.0 (SEM 1.8) pg/ml, p<0.05). Granzyme B production from PBMCs increased with the increasing TIMI risk score in UAP patients. The percentage of granzyme B-positive lymphocytes to CD3-positive lymphocytes in UAP patients was significantly higher than in SAP (32.1% (SEM 1.6%) versus 18.4% (SEM 0.9%), p<0.01). CONCLUSIONS: These results suggest that granzyme B might play an important role in triggering acute coronary events by inducing apoptosis and the degradation of atherosclerotic coronary plaques.

Phylogeography of a northeast Asian spruce, Picea jezoensis, inferred from genetic variation observed in organelle DNA markers.

Range-wide genetic variation of the widespread cold-temperate spruce Picea jezoensis was studied throughout northeast Asia using maternally inherited mitochondrial DNA and paternally inherited chloroplast DNA markers. This study assessed 33 natural populations including three varieties of the species in Japan, Russia, China, and South Korea. We depicted sharp suture zones in straits around Japan in the geographical distribution pattern of mitochondrial haplotypes (GST=0.901; NST=0.934). In contrast, we detected possible extensive pollen flow without seed flow across the straits around Japan during the past population history in the distribution pattern of chloroplast haplotypes (GST=0.233; NST=0.333). The analysis of isolation by distance of the species implied that by acting as a barrier for the movement of seeds and pollen, the sharp suture zones contributed considerably to the level of genetic differentiation between populations. Constructed networks of mitochondrial haplotypes allowed inference of the phylogeographical history of the species. We deduced that the disjunction with Kamchatka populations reflects range expansion and contraction to the north of the current distribution. Within Japan, we detected phylogeographically different types of P. jezoensis between Hokkaido and Honshu islands; P. jezoensis in Honshu Island may have colonized this region from the Asian continent via the Korean peninsula and the species in Hokkaido Island is likely to have spread from the Asian continent via Sakhalin through land bridges. Japanese endemism of mitochondrial haplotypes in Hokkaido and Honshu islands might have been promoted by separation of these islands from each other and from the Asian continent by the straits during the late Quaternary.

Increased urinary 15-F2t-isoprostane concentrations in patients with non-ischaemic congestive heart failure: a marker of oxidative stress.

OBJECTIVE: To investigate a novel marker of oxidative stress in patients with congestive heart failure (CHF). PATIENTS: 15 patients with mild CHF, 15 patients with severe CHF with acute exacerbation, and 15 control subjects. MAIN OUTCOME MEASURES: Measurement of urinary 15-F2t-isoprostane, plasma brain natriuretic peptide (BNP), serum interleukin 6 (IL-6), and serum thrombomodulin concentrations. In patients with severe CHF, samples were taken at admission and 4, 7, and 14 days after admission. RESULTS: Urinary 15-F2t-isoprostane, plasma BNP, and serum IL-6 concentrations in patients with severe CHF were significantly higher than those in control subjects or in patients with mild CHF. However, concentrations of serum thrombomodulin, a marker of endothelial damage, were not different between patients with CHF and control subjects. In addition, urinary 15-F2t-isoprostane, plasma BNP, and serum IL-6 concentrations in patients with severe CHF gradually decreased in proportion to the severity of CHF during hospitalisation. Interestingly, urinary 15-F2t-isoprostane concentrations significantly correlated with plasma BNP concentrations and serum IL-6 concentrations, but not with serum thrombomodulin concentrations. CONCLUSIONS: Urinary 15-F2t-isoprostane concentrations increased in proportion to the severity of CHF in patients. This may be caused by increased 15-F2t-isoprostane production. These findings suggest that urinary 15-F2t-isoprostane may be a marker of morbidity as well as oxidative stress in patients with CHF.

Histological analysis of human tooth development in NOD/scid mice.

An increasing number of elderly people suffer from the loss of teeth due to periodontitis or dental caries. Currently accepted functional prosthetic rehabilitation includes removable or fixed prostheses, with or without osseointegrated dental implants. All of them, however, are foreign bodies for the organism. In this regard, the ideal materials are natural teeth, which do not stimulate inflammatory responses. Tissue engineering has made great progress in regenerating a variety of cell types, such as bone cells. Regenerated tooth would be of great use and importance as a material for novel dental implants. However, clear mechanisms of tooth formation have not yet been elucidated. We describe here an experimental model where normal human tooth morphogenesis and dentition occur in NOD/scid mice subcutaneous tissues. Our system would contribute not only to developing, but also understanding the process of human tooth development.

A new idea for a protective balloon system during carotid stenting.

Percutaneous transluminal angioplasty with stenting for high-grade carotid stenosis has been recently come into use. However, distal embolic events remain a problem with this procedure compared to results with established carotid endarterectomy. To counteract such problems, various blocking balloon system such as a simple distal blocking balloon system or a thrombi catching system have been used in some instances. This time, a double-balloon system was used as a proximal blocking system during predilation, and an existing distal blocking system was used during practical carotid stenting. These systems were applied to six cases. In addition, we used a modified conventional blood transfusion system for filtration and retrieval of the aspirated blood. Compared with the simple distal blocking balloon system, occurrence of distal emboli could be reduced with our new combined method although the number of cases is too small to reach any definite conclusions.

Measurement of the maxilla and zygoma as an aid in installing zygomatic implants.

PURPOSE: This study used maxillary and zygomatic measurements to obtain information for installing zygomatic implants. PATIENTS AND METHODS: Angular and linear distances between the maxilla and the zygoma were measured in 12 cadavers (n = 22 sides) classified into short and tall groups by height (140 to 159 cm and 160 to 180 cm, respectively). RESULTS: Based on mean and standard deviation values, the installation angle of zygomatic implants was between 43.8 degrees and 50.6 degrees. The distance between the crest of the maxillary alveolar process near the palate and the jugale (Ju) point of the zygoma was between 44.3 and 54.3 mm. The minimum distance between the most lateral corner of the maxillary sinus and the Ju point was 6.41 mm, and the minimum anteroposterior length of the zygoma was 5.68 mm in the shorter group. CONCLUSIONS: When the installation angle of zygomatic implants is 43.8 degrees or less, perforation of the maxilla and the zygoma or the infratemporal fossa must be avoided. When the angle is 50.6 degrees or more, perforation of the orbital floor must be avoided. Special attention is needed to ensure osseointegration in shorter patients, because the distance between the most lateral corner of the antrum supporting the zygomatic implant and the Ju point is 10 mm or less. The apex of the implant is 3.75 mm in diameter, and the thickness of the zygoma must be 5.75 mm or more. The threads of the implant must not be exposed from the zygoma in shorter patients.

Asymmetric epoxidation with a photoactivated [Ru(salen)] complex.

(Nitrosyl)(salen)ruthenium(II) complex 1 was found to serve as an efficient catalyst for the epoxidation of conjugated olefins under photoirradiation, with 2,6-dichloropyridine N-oxide (2) or tetramethylpyrazine N,N'-dioxide as a stoichiometric oxidant. High enantioselectivity was achieved irrespective of the substitution pattern of olefins. The choice of solvent depends on stability of the resulting epoxides: high enantioselectivity is generally observed in the reaction with ethereal solvents, but use of benzene is recommended when the resulting epoxides are acid-sensitive.

Neurogenic pulmonary edema and large negative T waves associated with subarachnoid hemorrhage.

We describe a 72-year-old woman with hypertension who developed acute neurogenic pulmonary edema and giant negative T waves on electrocardiography (ECG) due to subarachnoid hemorrhage. The patient was alert and complained of precordial chest discomfort, dyspnea and shoulder stiffness. Echocardiography demonstrated normal left ventricle contraction with hypertrophy. Computed tomography (CT) and subsequent cerebral angiography revealed subarachnoid hemorrhage and saccular aneurysm at the anterior communicating artery. It is important to consider the possibility of subarachnoid hemorrhage when a patient shows pulmonary edema and ECG abnormalities even without typical clinical signs of subarachnoid hemorrhage.

Substrate affects the initial attachment and subsequent behavior of human osteoblastic cells (Saos-2).

Interaction between implant materials and bone cells contributes to the clinical success of dental implants. The object of this study was to investigate the initial attachment and subsequent behavior of human osteoblastic cells (Saos-2) to pure titanium (Ti), hydroxyapatite (HA), and glass. We, therefore, performed a time-course study for examining the area, attachment rate, distribution of focal adhesion kinase (FAK) vinculin, and actin, and the motility of Saos-2 cells on the materials. On Ti, cell area increased gradually, whereas on HA, cells spread quickly, but quitted spreading at 12 h after cell seeding. The number of cells on HA was greater than on the other materials. On Ti, the numbers of FAK- and vinculin-positive focal adhesions increased continuously. On HA, although the number of FAK-positive focal adhesions also increased continuously, the number of vinculin-positive focal adhesions decreased. Furthermore, actin staining showed that the cells on HA poorly formed stress fibers with weak polarity, whereas the cell on Ti possessed well-defined polarized stress fibers. On HA, cells started extension earlier than on Ti, motility was inactive, and the cells settled on the materials. These results suggest that the earlier settling of osteoblasts on HA might result in earlier osteogenesis on HA than other materials.

Isolated tricuspid valve endocarditis due to Candida parapsilosis associated with long-term central venous catheter implantation.

A 72-year-old man was treated for fungal tricuspid valve endocarditis (TVE) with significant tricuspid valvular regurgitation and severe congestive heart failure caused by Candida parapsilosis. The patient had received hyperalimentation and antibiotic therapy for three months through a central venous catheter after the surgical treatment of ileus. The patient was treated medically with amphotericin B and fluconazole because of high surgical risk due to severe pulmonary emphysema, and he responded well. Although TVE caused by C. parapsilosis is rare, we should consider this possibility in patients receiving long-term hyperalimentation and antibiotic therapy using a central venous catheter.

Predictability of internal carotid artery (ICA) dissectability in cases showing ICA involvement in parasellar meningioma.

The present study identified predictors for surgical internal carotid artery (ICA) dissection in cases showing ICA involvement in parasellar meningiomas. Twelve cases encountered over the past 4 years were reviewed. Based on MRI findings, patients were divided into two groups; six patients demonstrated complete ICA involvement (encasement) and the other six showed partial ICA involvement (engulfment). The ICA was dissected in all cases in the engulfment group and in four of six cases in the encasement group. The ICA can be dissected even if it is involved at the centre of the tumour if the tumour is soft and can be aspirated. Preservation of the perforating arteries is more important and more difficult. Angiographic finding showing encasement of a long segment of the ICA is unfavourable because of the high possibility that the perforating arteries are involved. Local stenosis of ICA is another unfavourable finding for surgical dissection because tumour invasion of the arterial wall would be suspected. Thus, ICA encasement by the tumour is the less favourable finding for surgery but it is not a decisive predictor. More important findings for ICA dissection in cases showing ICA encasement are involvement of a long segment of the ICA and local ICA stenosis on angiogram.

Different patterns of silent cerebral infarct in patients with coronary artery disease or hypertension.

The aim of the present study was to clarify the differences in the progression and the characteristics of silent cerebral infarcts (SCI) between patients with coronary artery disease (CAD) and hypertensive patients. Silent cerebral infarcts, a powerful prognostic indicator for stroke, are frequently found in patients with CAD and in hypertensives. However, the differences in the characteristics of SCI and related risk factors between CAD and hypertensive patients have not been thoroughly investigated. We evaluated the number of SCI and their distribution using brain magnetic resonance imaging (T1- and T2-weighted images) in 107 patients with CAD (validated by coronary angiography) and 101 hypertensive patients without history of clinical stroke. The prevalence of multiple SCI (three or more infarcts per person) in patients with CAD and with hypertension was significantly higher than in hypertensives without CAD (46% v 21%; P = .001), whereas that of patients with CAD without hypertension was intermediate (31%). The patients with multi- (two- or three-vessel) vessel diseases (VD) had a significantly higher prevalence of multiple SCI than the hypertensives and the no-stenosis or 1-VD group (68.1% in the 3-VD group, 52.0% in the 2-VD group, 26.8% in the 1-VD group, and 21.0% in the no-stenosis group). Multiple logistic regression analysis revealed that in the CAD group, the number of involved coronary arteries was an independent determinant of SCI (P < .005), whereas in the hypertensive group, age was an independent determinant of SCI (P < .005). When we investigated the distribution of SCI, in the CAD group, SCI in the deep perforator territory (the basal ganglia and the thalamus) were independently associated with the number of involved coronary arteries (P < .005), whereas SCI in the white matter were independently associated with age only (P < .005). In conclusion, SCI were more advanced in the patients with multivessel CAD than in the hypertensive patients, and were more common in patients with CAD and hypertension than in those without hypertension. Coronary atherosclerosis was independently and specifically associated with SCI located in the deep perferator territory but not of SCI located in the white matter. The CAD-atherosclerosis and hypertension may be independently involved in the pathologic process of SCI.

Tissue factor expression in coronary circulation as a prognostic factor for late restenosis after coronary angioplasty.

We investigated changes in blood coagulation in the coronary circulation after percutaneous transluminal coronary angioplasty (PTCA) and its clinical significance. We examined 43 patients with ischemic heart disease who underwent elective PTCA of isolated stenotic lesions in the left coronary artery. Ten patients underwent PTCA alone, 15 received percutaneous transluminal rotational atherectomy (PTRA) and 18 stent implantation. Blood samples were drawn from the coronary sinus before and immediately after PTCA, as well as 4 and 24 h later. Plasma levels of tissue factor (TF), thrombin-antithrombin III complex (TAT) and prothrombin fragment 1+2 (F 1+2) were measured by enzyme-linked immunosorbent assay. Follow-up coronary angiography was performed 6 months after PTCA. Minimal luminal diameter was assessed by quantitative coronary angiography to evaluate late loss index. TF, TAT and F 1+2 levels in the coronary sinus blood showed significant increases 24 h after PTCA. A significant positive correlation was found between changes in TF levels 24 h after PTCA and late loss index 6 months after the procedure. TF levels in the coronary sinus blood were significantly higher in patients with late restenosis than in those without restenosis. These results suggest that TF expression in the coronary circulation after PTCA is a prognostic factor for late restenosis.

Chemokine expression in coronary circulation after coronary angioplasty as a prognostic factor for restenosis.

Recent studies have clarified the significance of chemokines in cardiovascular diseases, such as development of atherosclerosis, atheromatous plaque rupture and restenosis after coronary angioplasty. We investigated changes in chemokine expression in the coronary circulation induced by percutaneous transluminal coronary angioplasty (PTCA) and their clinical significance. We examined 40 patients with angina pectoris who underwent elective PTCA for isolated stenotic lesions of the left coronary artery. Eight patients received PTCA only, 14 percutaneous transluminal rotational atherectomy and 18 stent implantation. Venous blood samples were obtained from the coronary sinus before, and immediately after as well as 4 and 24 h after PTCA. Plasma levels of interleukin (IL)-8, macrophage-colony stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP)-1 were measured by enzyme-linked immunosorbent assay. Plasma levels of M-CSF in the coronary sinus blood showed significant increases 4 and 24 h after PTCA. On the other hand, plasma MCP-1 levels did not change significantly during a 24-h observation period after PTCA. Immunoreactive IL-8 was not detected in any patients before or after PTCA. A significant positive correlation was found between plasma M-CSF levels 24 h after PTCA and late loss index 6 months after the procedure. Plasma levels of M-CSF 24 h after PTCA were significantly higher in patients with than in those without late restenosis. PTCA induced increases in plasma levels of M-CSF in the coronary circulation. Increased M-CSF expression may be involved in neointima formation at injured vessels through activation of mononuclear phagocytes.

Studies on the psychosomatic functioning of ill-health according to Eastern and Western medicine 5. Psychosomatic characteristics of anxiety and anxiety-affinitive constitution.

In successive studies of the psychosomatic functioning of ill-health according to Oriental and Western medicine in medical students, we established the existence of the psychosomatic characteristics we have provisionally termed the anxiety-affinitve constitution at the core of ill-health. Therefore, we conducted this research because our previous investigation showed this constitution included a high complexity of respiratory movement and eye movement with a significant correlation to the State Trait Anxiety Inventory (STAI). We examined the correlation between the STAI and somatic function of 88 medical students to identify the psychosomatic characteristics of anxiety and the anxiety-affinitive constitution. These tests included STAI, fractal (EEG, EOG, plethysmogram, respiratory curves, and EMG) and non-fractal (accelerated plethysmogram) dimension analyses, and malocclusion (based on Angle's classification). In particular, EOG, plethysmogram, and respiratory curves are known to have close association with trait anxiety. We were able to discover the correlation between (1) trait anxiety and thoracic and abdominal respiratory movements, and malocclusion (Class III), and (2) the correlation of state anxiety with thoracic respiratory movement, horizontal eye movement, a plethysmogram and an EEG-Pz (in males only). In subsequent study the relation between thoracic dominance and state-trait anxiety and between abdominal dominance and state-trait anxiety should be assessed to develop this research regarding the psychosomatic characteristics of anxiety and the anxiety-affinitive constitution. Further, it is essential to create an anxiety-affinitve constitution index based on multi-regression analysis.

Histologic study of the bone adjacent to titanium bone screws used for mandibular fracture treatment.

PURPOSE: Titanium miniplates have been widely used in mandibular fracture fixation because of their strength and excellent biocompatibility. However, the condition of the bone adjacent to titanium bone screws has not been clarified. This study histologically examined the bone-screw interface in patients treated for mandibular fractures. PATIENTS AND MATERIALS: Specimens were obtained from 14 patients, and the undecalcified sections were stained by the toluidine blue and Levai Laczko methods and examined with light microscopy. The mean ratio of direct contact between the bone and the titanium bone screw surface was also analyzed using a computer-aided image analyzer. RESULTS: The formation of new bone was observed around the titanium bone screws in all cases. In areas of cortical bone, partial interposition of soft tissues was rarely observed. However, in areas of cancellous bone, partial interposition of soft tissues was seen, and bone resorption between the bone and soft tissues was noted. The mean ratio of direct contact between all of the adjacent bone and the surface of the titanium bone screws was 64.4%. The mean ratio of direct contact between cortical bone and the titanium bone screws was 82.4%. Black particles were observed in the bone and soft tissues around the titanium bone screws, and multinuclear giant cells resembling macrophages were observed near these particles. CONCLUSION: Titanium bone screws used for mandibular fracture fixation develop almost complete contact with new bone. Some metalosis is present.

Homing receptor expression on cord blood T lymphocytes and the development of atopic eczema in infants.

Expression of the gut-homing receptor integrin alphaEbeta7, but not cutaneous lymphocyte-associated antigen (CLA), on milk allergen-stimulated cord blood T lymphocytes precedes the development of milk-induced eczema in early infancy. The data indicate the involvement of integrin alphaEbeta7 in the development of infantile allergic eczema and provide a clue to the avoidance of specific allergens and novel therapy targeting homing receptors in food allergy.

Demonstration of Akabane virus antigen using immunohistochemistry in naturally infected newborn calves.

Eight newborn calves showing ataxia were necropsied and examined histologically. Six of seven cerebrospinal fluid samples collected from these animals had neutralizing antibody for Akabane virus (AKV). All examined calves had nonsuppurative encephalomyelitis, localized mainly in the midbrain and spinal cord. Corresponding to the encephalitic lesion, AKV antigen was demonstrated in neuroglial cells in the brain stem and neuronal cells in the ventral horn of the spinal cord. This is the first study to demonstrate AKV antigen by immunohistochemistry in naturally infected newborn calves.