Comparison of insulin degludec with insulin detemir in type 1 diabetes: a 1-year treat-to-target trial.

The long-term safety and tolerability of insulin degludec (IDeg) was compared with that of insulin detemir (IDet), as basal treatment in participants with type 1 diabetes mellitus (T1DM). In the present multinational, 26-week core + 26-week extension, controlled, open-label, parallel-group trial, adults with T1DM were randomized to IDeg or IDet as basal insulin treatment combined with meal-time bolus insulin aspart. IDeg was administered once daily, whilst IDet was administered once or twice daily depending on patients' glycaemic control. After 1 year, IDeg provided a 33% lower rate of nocturnal hypoglycaemia compared with IDet: estimated rate ratio (IDeg : IDet) 0.67 [95% confidence interval (CI) 0.51; 0.88]; p < 0.05. IDeg improved glycated haemoglobin after 1 year of treatment, similarly to IDet, but IDeg also provided a significantly greater reduction in fasting plasma glucose compared with IDet: estimated difference (IDeg - IDet) -1.11 (95% CI -1.83; -0.40) mmol/l; p < 0.05. The present study confirmed the long-term safety and tolerability profile of IDeg in patients with T1DM. IDeg provided a lower risk of nocturnal confirmed hypoglycaemia than IDet.

A comparison of IDeg + IAsp versus IDet + IAsp in subjects with type 1 diabetes: subgroup analysis of Japanese subjects.

OBJECTIVE: Efficacy and safety were compared between insulin degludec (IDeg) once daily (OD) in combination with mealtime insulin aspart (IAsp) and insulin detemir (IDet) OD or twice daily (BID) in combination with mealtime IAsp in Japanese subjects with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This was a post hoc analysis of a multinational, controlled, open-label, parallel-group, treat-to-target trial that randomised adults [aged ≥18 years (≥20 years for Japan)] with T1DM for ≥12 months to basal IDeg OD (n = 124) or IDet (n = 62), both with mealtime bolus IAsp. The IDet dosing was adjusted to BID if required at ≥8 weeks. RESULTS: The estimated mean change in HbA1c from baseline to week 26 (the primary outcome measure) was -1.03 % in the IDeg + IAsp group and -0.94 % in the IDet + IAsp group (mean estimated treatment difference [ETD] -0.09; 95 % confidence interval [CI] -0.29, 0.10). Significantly greater reductions in fasting plasma glucose were observed in the IDeg + IAsp group (mean ETD -39.36 mg/dL; 95 % CI -56.04, -22.68). Both groups had similar rates of confirmed hypoglycaemia (59.9 and 59.2 per patient-year of exposure [PYE] with IDeg + IAsp and IDet + IAsp, respectively). Rates of nocturnal confirmed hypoglycaemia were significantly lower with IDeg + IAsp than with IDet + IAsp (5.2 vs 9.5 episodes per PYE; estimated ratio 0.48; 95 % CI 0.31, 0.75). Adverse event profiles were similar. CONCLUSION: The findings were consistent with those of the global trial population. IDeg + IAsp may represent an improvement on current standard treatments for Japanese patients with T1DM.

Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: a 26-week randomized, open-label, treat-to-target non-inferiority trial.

AIMS: The efficacy and safety of insulin degludec (IDeg) was compared with insulin detemir (IDet), both administered once daily (OD) as basal treatment in participants with type 1 diabetes mellitus (T1DM). The primary outcome was non-inferiority of IDeg to IDet in glycated haemoglobin (HbA1c) reduction after 26 weeks. METHODS: This multinational, 26-week, controlled, open-label, parallel-group trial randomized adults with T1DM to IDeg or IDet as OD basal insulin treatment combined with mealtime bolus insulin aspart (IAsp). Participants with T1DM treated with any basal-bolus insulin regimen for ≥ 12 months prior to the trial, a mean HbA1c ≤ 10.0% (85.8 mmol/mol) and body mass index (BMI) ≤ 35.0 kg/m(2) at screening participated in the trial (IDeg: N = 302; IDet: N = 153). RESULTS: After 26 weeks, HbA1c decreased 0.73% (8.0 mmol/mol) (IDeg) and 0.65% (7.1 mmol/mol) (IDet) [estimated treatment difference (ETD) IDeg-IDet: -0.09% (-0.23; 0.05)95% CI (-10.0 mmol/mol [-2.6; 0.6]95% CI ); confirming non-inferiority]. Mean fasting plasma glucose improved in both groups, and was lower with IDeg than IDet [ETD IDeg-IDet: -1.66 mmol/l (-2.37; -0.95)95% CI , p < 0.0001]. The rate of confirmed hypoglycaemia was similar with IDeg and IDet [45.83 vs. 45.69 episodes per patient-year of exposure (PYE); estimated rate ratio (RR) IDeg/IDet: 0.98 (0.80; 1.20)95% CI , p = 0.86]. The rate of nocturnal confirmed hypoglycaemia was lower with IDeg than IDet [4.14 vs. 5.93 episodes per PYE; RR IDeg/IDet: 0.66 (0.49; 0.88)95% CI , p = 0.0049]. Adverse event profiles were similar between groups. CONCLUSION: IDeg administered OD in basal-bolus therapy effectively improved long-term glycaemic control in participants with T1DM with a lower risk of nocturnal confirmed hypoglycaemia than IDet.

Leisure-time physical activity is a significant predictor of stroke and total mortality in Japanese patients with type 2 diabetes: analysis from the Japan Diabetes Complications Study (JDCS).

AIMS/HYPOTHESIS: Our aim was to clarify the association between leisure-time physical activity (LTPA) and cardiovascular events and total mortality in a nationwide cohort of Japanese diabetic patients. METHODS: Eligible patients (1,702) with type 2 diabetes (mean age, 58.5 years; 47% women) from 59 institutes were followed for a median of 8.05 years. A comprehensive lifestyle survey including LTPA and occupation was performed using standardised questionnaires. Outcome was occurrence of coronary heart disease (CHD), stroke and total mortality. The adjusted HR and 95% CI were calculated by Cox regression analysis. RESULTS: A significant reduction in HR in patients in the top (≥ 15.4 metabolic equivalents [MET] h/week) vs the bottom tertile (≤ 3.7 MET h/week) of LTPA, adjusted by age, sex and diabetes duration, was observed in stroke (HR 0.55, 95% CI 0.32, 0.94) and total mortality (HR 0.49, 95% CI 0.26, 0.91) but not in CHD (HR 0.77, 95% CI 0.48, 1.25). The HR for stroke became borderline significant or nonsignificant after adjustment for lifestyle or clinical variables including diet or serum lipids. The significantly reduced total mortality by LTPA was independent of these variables and seemed not to be, at least mainly, attributed to reduced cardiovascular disease. CONCLUSIONS/INTERPRETATION: In Japanese persons with type 2 diabetes, LTPA of 15.4 MET h/week or more was associated with a significantly lower risk of stroke partly through ameliorating combinations of cardiovascular risk factors. It was also associated with significantly reduced total mortality but independently of cardiovascular risk factors or events. These findings, implying differences from Western diabetic populations, should be considered in the clinical management of East Asians with diabetes.

Estradiol and raloxifene induce the proliferation of osteoblasts through G-protein-coupled receptor GPR30.

BACKGROUND: Although G-protein-coupled receptor, GPR30, has been considered as a G-protein-coupled estrogen receptor, conflicting results have been reported and the function of GPR30 in bone remains unresolved. The aim of this study was to clarify the functional role of GPR30 in osteoblasts using its derived cell line. METHODS AND RESULTS: Immunohistochemical study revealed that GPR30 is expressed in human osteoblasts. Human fetal osteoblast cell lines, hFOB cells, which express GPR30 but lack estrogen receptor, were used for the in vitro experiments. Estradiol or raloxifene induced the proliferation of hFOB cells, which was accompanied by the activation of mitogen-activated protein (MAP) kinase. Those proliferative effects were completely abrogated by the transfection of GPR30 small interfering RNA, while the transfection alone did not affect the cell viability. CONCLUSION: GPR30 is required for the proliferation of hFOB cells induced by estradiol or raloxifene. This proliferative effect was at least partly mediated via MAP kinase activation. These findings revealed a novel function of GPR30 in osteoblasts and might lead to a better understanding of how estrogen and selective estrogen receptor modulators show their osteoprotective effects.

Evaluation of injection force of three insulin delivery pens.

OBJECTIVE: Reduced injection force is among the modifications to the Next Generation FlexPen (NGFP). This force was compared with two other prefilled pens: SoloStar (SS) and KwikPen (KP). RESEARCH DESIGN/METHODS: The injection force of the pens was measured, with either a BD Micro-Fine 31G thin-wall needle, or a NovoFine 32G Tip extra thin wall needle attached. Pens of each type were tested with both needles, during injection of 20 U insulin, at speeds 3.3, 5 and 8.3 mm/s. RESULTS: NGFP had a significantly (p < 0.05) lower mean injection force than SS or KP, at all injection speeds, with both needles. Injection forces (mean +/- s.d.) with NGFP and the BD Micro-Fine() 31G thin-wall needle were: 8.1 +/- 0.7, 10.7 +/- 1.4 and 15.6 +/- 0.9 N at the three speeds, respectively. For SS, the corresponding values were: 9.2 +/- 0.5, 13.3 +/- 0.8 and 20.7 +/- 2.4 N. For KP they were: 12.5 +/- 1.6, 16.9 +/- 1.2 and 24.5 +/- 2.6 N. Attached to the NovoFine 32G Tip extra thin wall needle, the NGFP injection forces were: 5.7 +/- 0.4, 8.2 +/- 0.7 and 12.7 +/- 0.5 N; with SS were: 6.7 +/- 0.3, 10.4 +/- 2.1 and 16.3 +/- 1.1 N; and with KP were: 9.1 +/- 1.3, 13.1 +/- 0.8 and 21.6 +/- 2.0 N. The injection force with NGFP was 12 - 25% lower compared with SS and 35 - 41% lower compared with KP. CONCLUSIONS: This study shows that NGFP has a significantly lower injection force than SS or KP.

[Concurrent chemoradiation therapy with nedaplatin for high-risk cervical cancer--clinical investigation of adverse events].

A clinical investigation of adverse events was conducted to confirm the safety of concurrent chemotherapy using nedaplatin (cisplatin derivative) and radiotherapy in the high-risk carcinoma of the uterine cervix. Seven patients who were treated with radical radiotherapy and 5 patients who were treated with adjunctive radiotherapy after radical hysterectomy and pelvic lymphadenectomy were eligible for the study. Nedaplatin was given intravenously at 70 mg/m2 on day 1 and day 29, and a total of 24 courses of nedaplatin administration were observed. None of the planned radiotherapy was postponed or discontinued due to side effects. Major adverse effects observed were gastrointestinal effects such as anorexia (66.7%), nausea and vomiting (33.3%) and diarrhea (66.7%). Grade 3 (in the 2nd course) and Grade 4 (in the 1st course) diarrhea was observed in one patient, which was easily relieved by antidiarrheal. Hematologic side effects were also major, including leukopenia (62.5%), neutropenia (75.0%), anemia (75.0%), and thrombocytopenia (33.3%). Hematologic effects were generally moderate; no Grade 4 (severe) effects were observed. Although these hematologic effects were lasting longer compared with radiation therapy alone, there were no significant differences in the seriousness of these side effects. Concurrent chemoradiation therapy with nedaplatin 70 mg/m2 every 4 weeks was safe and adverse effects were self-limited or resolved with medical management. Dose escalation in the phase III clinical study may be considered.

Occurrence of coring in insulin vials and possibility of rubber piece contamination by self-injection.

Coring is reported to occur because rubber pieces are shaved off from a rubber stopper when a needle is inserted into the rubber stopper of transfusion liquid formulation. We verified whether coring really occurs in insulin vials of self-injecting patients. We collected insulin cartridges from 30 hospitalized patients and used the primary injection (trial injection), the secondary injection and the cartridge remaining preparation as samples. We observed the rubber pieces using a microscope and measured the shape, number of pieces. The occurrence rate of coring was 73% for the primary injection, 47% for the secondary injection and 97% for the cartridge remaining preparation. The rubber pieces in the primary injection and the secondary injection which went through the needle are mostly in aggregate shape and the rubber pieces in the cartridge remaining preparation which did not go through the needle are mostly in needle-like shape. A number of small rubber pieces are found in both the primary injection and the secondary injection, indicating a high possibility that rubber pieces may be injected under subcutaneous tissue. The coring is considered to occur because needles are repeatedly inserted and rotated at the same spot. It is required to improve the structure to mount a needle to the pen-type injector in future. Coring is a very serious problem from the medical and pharmaceutical points of view. Further study should be made on the implication to latex allergy and lipodystrophy.

Traumatic paraplegia in snowboarders.

STUDY DESIGN: Patients with traumatic paraplegia resulting from snowboarding accidents were reviewed. OBJECTIVE: To understand the clinical features and mechanisms of paraplegic snowboarding injuries. SUMMARY OF BACKGROUND DATA: The recent explosion in the popularity of snowboarding has resulted in dramatically increased numbers of snowboarding injuries. However, little information is available as to the types and mechanisms of snowboard-related spinal injuries and their neurologic involvement. METHODS: The subjects of this study were six male patients, with an average age of 23.7 years, referred to the authors' institution for neurologic deficits associated with spinal injuries between January 1996 and March 1999. The clinical features of these patients were reviewed with respect to the mechanism of the injury, fracture pattern, neurologic status, treatment, and clinical outcome. The mean follow-up period was 23.7 months. RESULTS: The six snowboarders with traumatic paraplegia constituted a very homogenous group with the following features: They were all young men between the ages of 23 and 25 years. All the injuries had occurred at the vertebral junctions. The primary mechanism of the fractures was a backward fall from an intentional jump. The fracture patterns were of the flexion-distraction type. These homologous features suggest that this snowboarding group is at high risk for severe spinal injury. CONCLUSION: The high risk of traumatic paraplegia for a group within the snowboarding population requires the development and provision of injury prevention strategies specific to this group.

Preparation of mononuclear tungsten tris(sulfido) and molybdenum sulfido-tetrasulfido complexes with hydridotris(pyrazolyl)borate coligand and conversion of the former into sulfido-bridged bimetallic complex having Pt(mu-S)2WS core.

Treatment of [Et4N][(Me2Tp)W(CO)3] (Me2Tp = HB(3,5-dimethylpyrazol-1-yl)3) with S8 in DMF at room temperature afforded a tris(sulfido) complex [Et4N][(Me2Tp)WS3] (1a), while that of [Et4N][TpW(CO)3] (Tp = HB(pyrazol-1-yl)3) in MeCN resulted in the formation of [Et4N][TpWS3] (1b) along with [Et4N]2[[WO(S2)2]2(mu-S)] (6) as a byproduct. Under similar conditions, [Et4N][(Me2Tp)Mo(CO)3] gave a mixture of a sulfido-tetrasulfido complex [Et4N][(Me2Tp)MoS(S4)] (2a) and its monooxo analogue [Et4N][(Me2Tp)MoO(S4)], although a sulfido-tetrasulfido complex [Et4N][TpMoS(S4)] (2b) was exclusively obtained from [Et4N][TpMo(CO)3]. The reaction of 1a with [PtCl2(cod)] (cod = 1,5-cyclooctadiene) in MeCN at room temperature led to the formation of a sulfido-bridged mixed-metal complex [Et4N][(Me2Tp)WS(mu-S)2PtCl2] (10). The structures of new complexes have been determined in detail by the X-ray analyses for 1a.MeCN, 1b, 2a, 2b, 6, and 10.

Two WD repeat-containing TATA-binding protein-associated factors in fission yeast that suppress defects in the anaphase-promoting complex.

The general transcription factor IID consists of the TATA-binding protein (TBP) and multiple TBP-associated factors (TAFs). Here we report the isolation of two related TAF genes from the fission yeast Schizosaccharomyces pombe as multicopy suppressors of a temperature-sensitive mutation in the ubiquitin-conjugating enzyme gene ubcP4(+). The ubcP4(ts) mutation causes cell cycle arrest in mitosis, probably due to defects in ubiquitination mediated by the anaphase-promoting complex/cyclosome. One multicopy suppressor is the previously reported gene taf72(+), whereas the other is a previously unidentified gene named taf73(+). We show that the taf73(+) gene, like taf72(+), is essential for cell viability. The taf72(+) and taf73(+) genes encode proteins homologous to WD repeat-containing TAFs such as human TAF100, Drosophila TAF80/85, and Saccharomyces cerevisiae TAF90. We demonstrate that TAF72 and TAF73 proteins are present in the same complex with TBP and other TAFs and that TAF72, but not TAF73, is associated with the putative histone acetylase Gcn5. We also show that overexpression of TAF72 or TAF73 suppresses the cell cycle arrest in mitosis caused by a mutation in the anaphase-promoting complex/cyclosome subunit gene cut9(+). These results suggest that TAF72 and TAF73 may regulate the expression of genes involved in ubiquitin-dependent proteolysis during mitosis. Our study thus provides evidence for a possible role of WD repeat-containing TAFs in the expression of genes involved in progression through the M phase of the cell cycle.

Transformation of organic molecules on the low-valent [M(Ph(2)PCH(2)CH(2)PPh(2))(2)] moiety derived from trans-[M(N(2))(2)(Ph(2)PCH(2)CH(2)PPh(2))(2)] or related complexes (M = Mo, W).

A zero-valent [M(Ph(2)PCH(2)CH(2)PPh(2))(2)] moiety (M = Mo, W) generated in situ by dissociation of the N(2) ligands in trans-[M(N(2))(2)(Ph(2)PCH(2)CH(2)PPh(2))(2)] can activate pi-accepting organic molecules including isocyanides and nitriles, which undergo the electrophilic attack caused by a strong pi-donation from a zero-valent metal center. Cleavage of a variety of C-X bonds (X = H, C, N, O, P, halogen) also occurs at their electron-rich sites through oxidative addition to form reactive intermediates, which subsequently degradate to yield smaller molecules either bound to or dissociated from the metal center. The mechanism is substantiated unambiguously by isolation of numerous intermediate stages.

Crystal structure and magnetic properties of an octacyanometalate-based three-dimensional tungstate(V)-manganese(II) bimetallic assembly.

A single crystal of the title compound [MnII6(H2O)9[W(V)(CN)8]4 x 13H2O]n was synthesized in a hot aqueous solution containing octacyanotungstate, Na3[W(CN)8] x 3H2O, and Mn(ClO4)2 x 6H2O. The compound crystallized in the monoclinic system, space group P2(1)/c with cell constants a = 15.438(2) A, b = 14.691(2) A, c = 33.046(2) A, beta = 94.832(9) degrees, and Z = 4. The crystal consists of a W(V)-CN-MnII linked three-dimensional network [[MnII(H2O)]3[MnII(H2O)2]3[W(V)(CN)8]4]n and H2O molecules as crystal solvates. There are two kinds of W sites: one is close to a dodecahedron geometry with six bridging and two terminal CN ligands; the other is close to a bicapped trigonal prism with seven bridging and one terminal CN ligands. The field-cooled magnetization measurement showed that the compound exhibits a spontaneous magnetization below Tc = 54 K. Further magnetization measurements on the field dependence reveal it to be a ferrimagnet where all of the MnII ions are antiparallel to all the W(V) ions.

Induction of ubiquitin conjugating enzyme activity for degradation of topoisomerase II alpha during adenovirus E1A-induced apoptosis.

Topoisomerase (topo) II alpha is degraded via polyubiquitination during adenovirus E1A-induced apoptosis in MA1 cells, a derivative of the human epidermoid carcinoma cell line KB. Topo II alpha ubiquitination activity in MA1 cells increased nearly 10-fold after induction of E1A in response to dexamethasone. To identify a topo II alpha ubiquitination factor(s), the S100 fractions prepared from apoptosis-induced (42 h) and uninduced (0 h) MA1 cells were first fractionated by ubiquitin-Sepharose columns. The ubiquitination activity induced by E1A was predominantly eluted with 20 mM AMP. Further fractionation of the AMP eluates on Resource-Q columns and the thiolester formation of the proteins resolved by electrophoresis with biotinylated ubiquitin revealed that a species of E2 isozyme recovered in the QFT2 fraction increased markedly in MA1 cells after E1A expression. These results indicate that a ubiquitination factor(s) specific to topo II alpha is induced during E1A-induced apoptosis in MA1 cells.

A ubiquitin-conjugating enzyme in fission yeast that is essential for the onset of anaphase in mitosis.

A cDNA encoding a ubiquitin-conjugating enzyme designated UbcP4 in fission yeast was isolated. Disruption of its genomic gene revealed that it was essential for cell viability. In vivo depletion of the UbcP4 protein demonstrated that it was necessary for cell cycle progression at two phases, G2/M and metaphase/anaphase transitions. The G2 arrest of UbcP4-depleted cells was dependent upon chk1, which mediates checkpoint pathway. UbcP4-depleted cells arrested at metaphase had condensed chromosomes but were defective in separation. However, septum formation and cytokinesis were not restrained during the metaphase arrest. Overexpression of UbcP4 specifically rescued the growth defect of cut9ts cells at a restrictive temperature. cut9 encodes a component of the anaphase-promoting complex (APC) which is required for chromosome segregation at anaphase and moreover is defined as cyclin-specific ubiquitin ligase. Cdc13, a mitotic cyclin in fission yeast, was accumulated in the UbcP4-depleted cells. These results strongly suggested that UbcP4 is a ubiquitin-conjugating enzyme working in conjunction with APC and mediates the ubiquitin pathway for degradation of "sister chromatid holding protein(s)" at the onset of anaphase and possibly of mitotic cyclin at the exit of mitosis.