1-Naphthyl- and mesityltellurium(IV,II) derivatives of small bite chelating organic ligands: effect of steric bulk and intramolecular secondary bonding interaction on molecular geometry and supramolecular association

The synthesis and characterization of unsymmetric diorganotellurium compounds containing a sterically demanding I-naphthyl or
mesitylligand and a small bite chelating organic ligand capable of 1,4-Te···N(O) intramolecular interaction is described. The reaction
of ArTeCl₃ (Ar = I-C_lOH₇, Np; 2,4,6-Me<sub>3b>C₆H_2' Mes) with (SB)HgCI [SB = the Schiff base, 2-(4,4'-N0<sub>2b>C₆H_{4b>CH=NC6H3-Me)] or a methyl ketone (RCOCH3) afforded the corresponding dichlorides (SB)ArTeCI2 (Ar = Np, 1Aa; Mes, 1Ba) or (RCOCH2)ArTeCl2 (Ar = Np; R = Ph (2Aa), Me (3Aa), Np (4Aa); Ar = Mes, R = Ph (2Ba)). Reduction of 1Aa and 1Ba by Na2S205 readily gave the tellurides (SB)ArTe (Ar = Np (1A), Mes, (1B) but that of dichlorides derived from methylketones was complicated due to partial decomposition to tellurium powder and diarylditelluride (Ar2Te2), resulting in poor yields of the corresponding tellurides 2A, 2B and 3A. Oxidation of the isolated tellurides with S02b>Cl2, Br2 and I2 yielded the corresponding dihalides. All the synthesized compounds have been characterized with the help of IR, ¹H, ^l3C, and ¹²⁵Te NMR and in the case of 2Aa, and 2Ba by X-ray crystallography. Appearance of only one ¹²⁵Te signal indicated that the unsymmetric derivatives were stable to disproportionation to symmetric species. Intramolecular 1,4-Te&middot; . &middot;0 secondary bonding interactions (SBIs) are exhibited in the crystal structures of both the tellurium(IV) dichlorides, 2Aa, and 2Ba. Steric repulsion of the mesityl group in the latter dominates over lone pair-bond pair repulsion, resulting in significant widening of the equatorial C-Te-C angle. This appears to be responsible for the lack of Te&middot; . &middot;CI involved supramolecular associations in the crystal structure of 2Ba.}

Effect of vitamin D supplementation on vitamin D status and bone turnover markers in young adults

Objective: To assess the vitamin D status of healthy young people living in Northern Ireland and the effect of vitamin D supplementation on vitamin D status and bone turnover.

Design: Double-blinded randomised controlled intervention study.

Setting: University of Ulster, Coleraine, Northern Ireland.

Subjects: In total, 30 apparently healthy students (15 male and 15 female subjects), aged 18&ndash;27 years, were recruited from the university, with 27 completing the intervention.

Interventions: Subjects were randomly assigned, to receive either 15 mug (600 IU) vitamin D3 and 1500 mg calcium/day (vitamin D group), or 1500 mg calcium/day (control group) for 8 weeks between January and March. Vitamin D status, bone turnover markers, serum calcium and parathyroid hormone concentrations were measured at baseline and post intervention.

Results: At baseline, vitamin D status was low in both the vitamin D group (47.9 (s.d. 16.0)) and the control group (55.5 (s.d. 18.6) nmol/l 25(OH)D). Post intervention vitamin D status was significantly higher in the vitamin D-treated group (86.5 (s.d. 24.5)) compared to the control group (48.3 (s.d. 16.8) nmol/l) (P<0.0001). There was no significant effect of supplementation on bone turnover markers or PTH concentrations.

<b>Conclusions: This study suggests that young adults in Northern Ireland do not consume an adequate daily dietary intake of vitamin D to maintain plasma vitamin D concentrations in the wintertime. A daily supplement of 15 mug vitamin D3 significantly increased vitamin D status in these individuals to levels of sufficiency. Achievement of an optimum vitamin D status among young adults may have future positive health implications.

Studies of the human lymphocyte P2Z receptor and its activation of phospholipase D

Extracellular adenosine 5′-triphosphate (ATP) is an agonist for the P2Z receptor of human leukaemic lymphocytes and opens a Ca ²⁺-selective ion channel, which also conducts Ba²⁺, Sr²⁺ and the small fluorescent dye, ethidium⁺. A wide range of receptor agonists, many of which raise cytosolic [Ca²⁺] activate phospholipase D (PLD). In the present study, it was shown that both ATP and 3′-O-(4-benzoylbenzoyl)-ATP (BzATP) stimulated PLD activity in a concentration-dependent manner, and the inhibitory effects of suramin, oxidised ATP, extracellular Na⁺ and Mg²⁺ suggested that the effect of these agonists is mediated by P2Z receptors. The role of divalent cations in ATP-stimulated PLD activity was investigated. Several agonists (eg ATP, thapsigargin, ionomycin) stimulated a rise in cytosolic [Ca²⁺] in human lymphocytes, but only ATP and ionomycin stimulated PLD activity. When Ca²⁺ influx was prevented by EGTA, the majority of ATP-stimulated and all of ionomycin-stimulated PLD activity was inhibited. Preloading cells with the Ca²⁺ chelator, BAPTA, reduced cytosolic [Ca²⁺] and, paradoxically, ATP-stimulated PLD activity was potentiated. ATP-stimulated PLD activity was supported by both Ba²⁺ and Sr²⁺ when they were substituted for extracellular Ca²⁺. Furthermore, both ATP-stimulated PLD activity and ATP-stimulated ¹³³Ba²⁺ influx showed a linear dependence on extracellular [Ba²⁺]. Thus it was concluded that ATP stimulated PLD activity in direct proportion to the influx of divalent cations through the P2Z ion channel and this PLD activity was insensitive to changes in bulk cytosolic [Ca²⁺]. The calmodulin (Ca²⁺/CaM) inhibitor, trifluoperazine (TFP) inhibited ionomycin- and ATP-stimulated PLD activity and ATP-stimulated apoptosis, but had no effect on PLD activity already activated by ATP. However, TFP inhibited ATP-stimulated Ca²⁺, Ba²⁺ and ethidium⁺ fluxes, at concentrations below those which inhibit Ca²⁺/CaM, suggesting that TFP inhibits the P2Z receptor. Similarly, the isoquinolinesulphonamide, KN-62, a selective inhibitor of Ca²⁺/CaM-dependent protein kinase II (CaMKII), also prevented ATP-stimulated apoptosis, but had no effect on pre-activated PLD. In addition, KN-62, and an analogue, KN-04, which has no effect on CaMKII, potently inhibited ATP-stimulated Ba²⁺ influx (IC₅₀ 12.7 ± 1.5 and 17.3 ± 2.7 nM, respectively), ATP-stimulated ethidium⁺ uptake (IC₅₀ 13.1 ± 2.6 and 37.2 ± 8.9 nM, respectively), ATP-stimulated phospholipase D activity (50% inhibition 5.9 ± 1.2 and 9.7 ± 2.8 nM, respectively) and ATP-induced shedding of the surface adhesion molecule, L-selectin (IC₅₀ 31.5 ± 4.5 and 78.7 ± 10.8 nM, respectively). They did not inhibit phorbol ester- or ionomycin-stimulated PLD activity or phorbol ester-induced L-selectin shedding. Neither KN-62 nor KN-04 (both 500 nM) have any effect on UTP-stimulated Ca²⁺ transients in fura-2-loaded human neutrophils, a response which is mediated by the P2Y₂ receptor, neither did they inhibit ATP-stimulated contractile responses mediated by the P2X₁ receptor of guinea pig urinary bladder. Thus, KN-62 and KN-04 are almost equipotent as P2Z inhibitors with IC₅₀s in the nanomolar, indicating that their actions cannot be due to CaMKII inhibition, but rather that they are potent and direct inhibitors of the P2Z receptor. Extracellular ATP-induced shedding of L-selectin from lymphocytes into the medium is a Ca²⁺-independent response. L-selectin is either cleaved by a metalloproteinase or a PLD with specificity for glycosylphosphatidylinositol (GPI). The novel hydroxamic acid-based zinc chelator, Ro-31-9790 blocks ATP-induced L-selectin shedding, but was without effect on ATP-induced Ba²⁺ influx or ATP-stimulated PLD activity. Furthermore, another zinc chelator, 1,10-phenanthroline, an inhibitor of a GPI-PLD, potentiated rather than inhibited ATP-stimulated PLD activity, suggesting that ATP-induced L-selectin shedding and ATP-stimulated PLD activity are independent of each other. Although extracellular ATP is the natural ligand for the lymphocyte P2Z receptor, it is less potent than BzATP in stimulating Ba²⁺ influx. Concentration-response curves for BzATP- and ATP-stimulated ethidium⁺ influx gave EC₅₀s 15.4 ± 1.4 µM and 85.6 ± 8.8 µM, respectively. The maximal response to ATP was only 69.8 ± 1.9% of that for BzATP. Hill coefficients were 3.17 ± 0.24 and 2.09 ± 0.45 for BzATP and ATP respectively, suggesting greater positive cooperativity for BzATP than for ATP in opening the P2Z-operated ion channel. A rank order of agonist potency of BzATP > ATP = 2MeSATP > ATPγS was observed for agonist-stimulated ethidium⁺ influx, while maximal influxes followed a rank order of BzATP > ATP > 2MeSATP > ATPγS. When ATP (300 -1000 µM) was added simultaneously with 30 µM BzATP (EC₉₀), it reduced both ethidium⁺ and Ba²⁺ fluxes by 30 - 40% relative to values observed with BzATP alone. KN-62, previously shown to be a specific inhibitor of the lymphocyte P2Z receptor, was a less potent antagonist of BzATP-induced fluxes than ATP, when maximal concentrations of both agonists (50 and 500 µM respectively) were used. However, when BzATP (18 µM) was used at a concentration equiactive with a maximally effective ATP concentration, KN-62 showed the same inhibitory potency for both agonists. The ecto-ATPase antagonist, ARL-67156, inhibited both ATP- and BzATP-stimulated Ba²⁺ influx, suggesting that the lower efficacy of ATP compared with BzATP was not due to preferential hydrolysis of ATP. Thus, the natural ligand, ATP, is a partial agonist for the P2Z receptor while BzATP is a full agonist. Moreover the competitive studies show that only a single class of P2-receptor (P2Z class) is expressed on human leukaemic lymphocytes. Both ATP- and BzATP-stimulated PLD activity were significantly inhibited (P < 0.05) when cells were suspended in iso-osmotic choline Cl medium. Choline⁺ was found to be a permeant for the P2Z ion channel, since ATP induced a large uptake of [¹⁴C]choline⁺ (60 to 150 µmol/ml intracellular water) during a 5 min incubation, which remained in the cells for several hours, and ATP was used to load cells with these levels of choline⁺. Intracellular choline⁺ inhibited ATP-, BzATP-, PMA- and ionomycin-stimulated PLD activity. Brief exposure of lymphocytes to ATP increased the subsequent basal rate of ethidium⁺ uptake, and this was prevented by intracellular choline⁺. It is proposed that P2Z-mediated Ca²⁺ influx in lymphocytes activates PLD leading to significantly changes of the phospholipid composition of the plasma membrane, which subsequently produces a permeability lesion, which in turn contributes to cell death.

Assembly of 3-D network structures containing oxydiacetate and CeIII or CeIV

Reaction of CeCl₃&middot;7H₂O with Na₂(oda) (oda = O(CH_{2b>CO2)2²&mdash; oxydiacetate) in a 2:3 ratio gives the neutral cerium(III) complex [Ce2(oda)3(H2O)3]&middot;9H2O (1). Treatment of a 1:3 mixture of CeCl3&middot;7H2O and H2oda in water with 4 molar equivalents of NaOH also gives 1 but, with a larger excess of NaOH, the tri-sodium salt Na3[Ce(oda)3]&middot;9H2O (2) is isolated. Formation of a tri-ammonium analogue of 2 can be achieved by neutralisation of an aqueous solution of CeCl3&middot;7H2O and H2(oda) in a 1:3 ratio by NH4OH, giving (NH4)3[Ce(oda)3]&middot;7H2O (3). Use of the cerium(IV) reagent (NH4)2[Ce(NO3)6] with Na2(oda) results in reduction to cerium(III) under ambient conditions and isolation of 1. However, in the absence of light this reaction yields crystals of the novel cerium(IV) heterobimetallic [Ce(oda)3Na4(NO3)2] (4). Each of these complexes exhibit a 3-D network structure having a common nine-coordinate [Ce(oda)3]ⁿ&mdash; (n = 2 or 3) subunit, irrespective of the oxidation state of cerium. In 1, six [Ce(oda)3]³&mdash; anions are connected, through bridging bidentate carboxylates, to a second Ce³⁺ site further coordinated by three water molecules. In contrast, the ammonium salt 2, displays isolated [Ce(oda)3]³&mdash; anions, devoid of further carboxylate bonding, but enmeshed within a network of hydrogen-bonded NH4⁺ cations and water molecules. The remarkable structure of 4 consists of infinite 2-D sheets of [Na2(NO3)]+ pillared by [Ce(oda)3]^2&mdash; units, the connectivity arising by multidentate nitrate and carboxylate bridging.}

Overreporting of vitamin D deficiency by the Roche Elecsys vitamin D3 (25-OH) method

Background</b>: Vitamin D deficiency is common. Recently Roche Diagnostics removed their Elecsys Vitamin D3 (25OH) electrochemiluminescence immunoassay (ECLIA) from use, citing deteriorating traceability to the reference method (liquid chromatography tandem mass spectrometry; LCMSMS). We investigated the performance of the Roche assay (2 assay formulations) against an LCMSMS method and the widely used DiaSorin radioimmunoassay (RIA) method.

Methods: Two sets of samples from separate populations were assayed for vitamin D. The first set was assayed using three different methods: RIA (DiaSorin) in 2004, polyclonal ECLIA (Roche) in early 2009 and LCMSMS in early 2010. The second set was assayed using polyclonal and monoclonal ECLIA (Roche) and LCMSMS in mid-2010.

Results: The correlation of the polyclonal ECLIA with the RIA was poor (ECLIA = 0.45 x RIA + 19, r² = 0.59, n = 773). LCMSMS results correlated with RIA (RIA = 0.86 x LCMSMS + 4, r² = 0.69, n = 49) better than with polyclonal ECLIA (polyclonal ECLIA = 0.55 x LCMSMS + 6, r² = 0.62, n = 55) despite a storage interval of 6 years.

In recently collected samples monoclonal and polyclonal immunoassays gave similar results (monoclonal ECLIA = 0.93 polyclonal ECLIA -3, r² = 0.60, n = 153). The correlation between monoclonal Roche ECLIA and LCMSMS in these samples was very poor (monoclonal ECLIA = 0.31 x LCMSMS + 23, r² = 0.27).

<b>Conclusions: At the time of its removal from the market, the Roche Elecsys Vitamin D3 (25OH) assay showed unacceptable performance, underestimating vitamin D levels. It seems that this bias preceded the introduction of the monoclonal assay. The worldwide distribution of the assay and the duration of this bias likely led to a significant number of patients starting supplementation unnecessarily.

The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude

Background</b> Inadequate sun exposure and dietary vitamin D intake can result in vitamin D insufficiency. However, limited data are available on actual vitamin D status and predictors in healthy individuals in different regions and by season.

Methods We compared vitamin D status [25-hydroxyvitamin D; 25(OH)D] in people < 60 years of age using data from cross-sectional studies of three regions across Australia: southeast Queensland (27&deg;S; 167 females and 211 males), Geelong region (38&deg;S; 561 females), and Tasmania (43&deg;S; 432 females and 298 males).

Results The prevalence of vitamin D insufficiency (≤ 50 nmol/L) in women in winter/spring was 40.5% in southeast Queensland, 37.4% in the Geelong region, and 67.3% in Tasmania. Season, simulated maximum daily duration of vitamin D synthesis, and vitamin D effective daily dose each explained around 14% of the variation in 25(OH)D. Although latitude explained only 3.9% of the variation, a decrease in average 25(OH)D of 1.0 (95% confidence interval, 0.7&ndash;1.3) nmol/L for every degree increase in latitude may be clinically relevant. In some months, we found a high insufficiency or even deficiency when sun exposure protection would be recommended on the basis of the simulated ultraviolet index.

<b>Conclusion Vitamin D insufficiency is common over a wide latitude range in Australia. Season appears to be more important than latitude, but both accounted for less than one-fifth of the variation in serum 25(OH)D levels, highlighting the importance of behavioral factors. Current sun exposure guidelines do not seem to fully prevent vitamin D insufficiency, and consideration should be given to their modification or to pursuing other means to achieve vitamin D adequacy.

Prevalence of vitamin D deficiency and its determinants in Australian adults aged 25 years and older : a national, population-based study

Objective  Vitamin D deficiency is recognized as a global public health problem, but the population-based prevalence of deficiency and its determinants in Australian adults is not known. This study evaluated the vitamin D status of Australian adults aged ≥25 years and risk factors associated with vitamin D deficiency in this population.

Design and Patients  We studied a national sample of 11 247 Australian adults enrolled in the 1999/2000 Australian Diabetes, Obesity and Lifestyle (AusDiab) study drawn from 42 randomly selected districts throughout Australia.

Measurements  Serum concentrations of 25-hydroxyvitamin D [25(OH)D] were measured by immunoassay. Vitamin D deficiency was defined as a concentration <50 nmol/l. Information on demographic and lifestyle factors was derived from interview-administered questionnaires.

Results  The mean serum 25(OH)D concentration was 63 nmol/l (95% CI: 59&ndash;67 nmol/l). Only 4% of the population had a level <25 nmol/l, but the prevalence of vitamin D deficiency (<50 nmol/l) was 31% (22% men; 39% women); 73% had levels <75 nmol/l. The prevalence of vitamin D deficiency increased significantly with age, was greater in women, in those of non-Europid origin, in the obese and those who were physically inactive and with a higher level of education. Deficiency was also more common during winter and in people residing in southern Australia (latitude >35&deg;S); 42% of women and 27% of men were deficient during summer&ndash;autumn, which increased to 58% and 35%, respectively, during winter&ndash;spring.

<b>Conclusion  Vitamin D deficiency is common in Australia affecting nearly one-third of adults aged ≥25 years. This indicates that strategies are needed at the population level to improve vitamin D status of Australians.

Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.

Patients and methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m2 dose every three weeks

Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6&ndash;99 weeks) and 1-year survival was 71%.

<b>Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma

Background In this phase II trial, we investigated the efficacy of a metronomic temozolomide schedule in the treatment of recurrent malignant gliomas (MGs).

Methods Eligible patients received daily temozolomide (50 mg/m2) continuously until progression. The primary endpoint was progression-free survival rate at 6 months in the glioblastoma cohort (N = 37). In an exploratory analysis, 10 additional recurrent grade III MG patients were enrolled. Correlative studies included evaluation of 76 frequent mutations in glioblastoma (iPLEX assay, Sequenom) aiming at establishing the frequency of potentially &ldquo;drugable&rdquo; mutations in patients entering recurrent MG clinical trials.

Results Among glioblastoma patients, median age was 56 y; median Karnofsky Performance Score (KPS) was 80; 62% of patients had been treated for ≥2 recurrences, including 49% of patients having failed bevacizumab. Treatment was well tolerated; clinical benefit (complete response + partial response + stable disease) was seen in 10 (36%) patients. Progression-free survival rate at 6 months was 19% and median overall survival was 7 months. Patients with previous bevacizumab exposure survived significantly less than bevacizumab-naive patients (median overall survival: 4.3 mo vs 13 mo; hazard ratio = 3.2; P = .001), but those patients had lower KPS (P = .04) and higher number of recurrences (P < .0001). Mutations were found in 13 of the 38 MGs tested, including mutations of EGFR (N = 10), IDH1 (N = 5), and ERBB2 (N = 1).

<b>Conclusions In spite of a heavily pretreated population, including nearly half of patients having failed bevacizumab, the primary endpoint was met, suggesting that this regimen deserves further investigation. Results in bevacizumab-naive patients seemed particularly favorable, while results in bevacizumab-failing patients highlight the need to develop further treatment strategies for advanced MG.

Environmental and genetic determinants of vitamin D insufficiency in 12-month-old infants

We aimed to investigate the relationship between genetic and environmental exposure and vitamin D status at age one, stratified by ethnicity. This study included 563 12-month-old infants in the HealthNuts population-based study. DNA from participants' blood samples was genotyped using Sequenom MassARRAY MALDI-TOF system on 28 single nucleotide polymorphisms (SNPs) in six genes. Using logistic regression, we examined associations between environmental exposure and SNPs in vitamin D pathway and filaggrin genes and vitamin D insufficiency (VDI). VDI, defined as serum 25-hydroxyvitamin D3(25(OH)D3) level ≤50 nmol/L, was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infants were stratified by ethnicity determined by parent's country of birth. Infants formula fed at 12 months were associated with reduced odds of VDI compared to infants with no current formula use at 12 months. This association differed by ethnicity (P;bsubesub;= 0.01). The odds ratio (OR) of VDI was 0.29 for Caucasian infants (95% CI, 0.18-0.47) and 0.04 for Asian infants (95% CI, 0.006-0.23). Maternal vitamin D supplementation during pregnancy and/or breastfeeding were associated with increased odds of infants being VDI (OR, 2.39; 95% CI, 1.11-5.18 and OR, 2.5; 95% CI, 1.20-5.24 respectively). Presence of a minor allele for any GC SNP (rs17467825, rs1155563, rs2282679, rs3755967, rs4588, rs7041) was associated with increased odds of VDI. Caucasian infants homozygous (AA) for rs4588 had an OR of 2.49 of being associated with VDI (95% CI, 1.19-5.18). In a country without routine infant vitamin D supplementation or food chain fortification, formula use is strongly associated with a reduced risk of VDI regardless of ethnicity. There was borderline significance for an association between filaggrin mutations and VDI. However, polymorphisms in vitamin D pathway related genes were associated with increased likelihood of being VDI in infancy. © 2014 Elsevier B.V. All rights reserved.

The effect of insulin and exercise on c-Cbl protein abundance and phosphorylation in insulin-resistant skeletal muscle in lean and obese Zucker rats.

Aims/hypothesis: Recruitment of the protein c-Cbl to the insulin receptor (IR) and its tyrosine phosphorylation via a pathway that is independent from phosphatidylinositol 3prime-kinase is necessary for insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes. The activation of this pathway by insulin or exercise has yet to be reported in skeletal muscle. Methods: Lean and obese Zucker rats were randomly assigned to one of three treatment groups: (i) control, (ii) insulin-stimulated or (iii) acute, exhaustive exercise. Hind limb skeletal muscle was removed and the phosphorylation state of IR, Akt and c-Cbl measured.  Results:   Insulin receptor phosphorylation was increased 12-fold after insulin stimulation (p<0.0001) in lean rats and threefold in obese rats. Acute exercise had no effect on IR tyrosine phosphorylation. Similar results were found for serine phosphorylation of Akt. Exercise did not alter c-Cbl tyrosine phosphorylation in skeletal muscle of lean or obese rats. However, in contrast to previous studies in adipocytes, c-Cbl tyrosine phosphorylation was reduced after insulin treatment (p<0.001). <b>Conclusions/interpretation: We also found that c-Cbl associating protein expression is relatively low in skeletal muscle of Zucker rats compared to 3T3-L1 adipocytes and this could account for the reduced c-Cbl tyrosine phosphorylation after insulin treatment. Interestingly, basal levels of c-Cbl tyrosine phosphorylation were higher in skeletal muscle from insulin-resistant Zucker rats (p<0.05), but the physiological relevance is not clear. We conclude that the regulation of c-Cbl phosphorylation in skeletal muscle differs from that previously reported in adipocytes.

Stability of 2-D characteristic polynomials

This paper derives some new conditions for the bivariate characteristic polynomial of an uncertain matrix to be very strict Hurwitz. The uncertainties are assumed of the structured and unstructured type. By using the two-dimensional (2-D) inverse Laplace transform, the bounds on the uncertainties are derived which will ensure that the bivariate characteristic polynomial to be very strict Hurwitz. Two numerical examples are given to illustrate the results.