Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study.

AIMS/HYPOTHESIS: The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). METHODS: Participants with type 2 diabetes (HbA(1c) 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n = 30) or placebo (n = 30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. RESULTS: Compared with placebo, colesevelam improved HbA(1c) (mean change from baseline of 0.3 [SD 1.1]% for placebo [n = 28] and -0.3 [1.1]% for colesevelam [n = 26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. CONCLUSIONS/INTERPRETATION: Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents. TRIAL REGISTRATION: ClinicalTrials.gov NCT00596427 FUNDING: The study was funded by Daiichi Sankyo.

Valuing gene testing in children with possible neurofibromatosis 1.

With the growing number of clinical guidelines recommending genetics tests in routine clinical care, the value of these tests should be evaluated. We examined the economic value of offering genetic testing to children with possible neurofibromatosis 1 (NF1) in British Columbia. Diagnosis of NF1 is usually made based on diagnostic clinical criteria, but molecular diagnostic testing, currently offered on a case-by-case basis in BC, now reliably diagnoses NF1 in 95% of cases. Children who present with some clinical features but whose findings are insufficient to meet the diagnostic criteria are labelled as having 'possible NF1'. Current guidelines call for these children to be followed as they have NF1, leading to annual ophthalmologic examinations and screening for complications; thus, there are increased costs to health care system. We created a model to account for these costs to the health care system, comparing the current protocol with one that would offer all children diagnosed with possible NF1 with genetic testing. Focusing on the incremental cost allowed us to determine that genetic testing provides good value, and patient interviews provided insight into the qualitative benefits of an earlier firm diagnosis. These findings may be helpful in guiding health policy decision-making.

Sequence of therapy and survival in patients with advanced pancreatic neuroendocrine tumours.

Background: Pancreatic neuroendocrine tumours (pnets) often present as advanced disease. The optimal sequence of therapy is unknown. Methods: Sequential patients with advanced pnets referred to BC Cancer between 2000 and 2013 who received 1 or more treatment modalities were reviewed, and treatment patterns, progression-free survival (pfs), and overall survival (os) were characterized. Systemic treatments included chemotherapy, small-molecule therapy, and peptide receptor radionuclide therapy. Results: In 66 cases of advanced pnets, median patient age was 61.2 years (25%-75% interquartile range: 50.8-66.2 years), and men constituted 47% of the group. First-line therapies were surgery (36%), chemotherapy (33%), and somatostatin analogues (32%). Compared with first-line systemic therapy, surgery in the first line was associated with increased pfs and os (20.6 months vs. 6.3 months and 100.3 months vs. 30.5 months respectively, p < 0.05). In 42 patients (64%) who received more than 1 line of therapy, no difference in os or pfs between second-line therapies was observed. Conclusions: Our results confirm the primary role of surgery for advanced pnets. New systemic treatments will further increase options.

Prenatal exposures to LTP-patterned magnetic fields: quantitative effects on specific limbic structures and acquisition of contextually conditioned fear.

Weak (<1 microT) complex magnetic fields (CMFs) may exert their behavioral influences through the hippocampus by resonating by accident or design with intrinsic electrical patterns. Rats were exposed prenatally to one of four intensities of a CMF (either <5 nanoTesla [nT], 10-50 nT, 50-500 nT, or 500-1000 nT) designed to interact with the process of Long-Term Potentiation (LTP) in the hippocampus. Rats then underwent testing in the forced swim, open field, and fear-conditioning procedures. The cell densities of all amygdaloid nuclei, specific hypothalamic structures, and the major regions of the hippocampus were quantified. Results showed that acquisition of conditioned fear was strongly inhibited in animals exposed to LTP-CMFs. Rats exposed to intensities above 10 nT showed decreased cell density in the CA2 fields of the hippocampus; more neurons were present in the CA1 fields of rats exposed to the 10-50 nT intensities compared to all other groups. A decrease in cell density in the medial preoptic nucleus was linearly dependent on field intensity. In the forced-swim test, swimming was decreased in rats that had been exposed to low (10-50 nT) and medium intensity (50-500 nT) LTP-CMFs in a manner consistent with monoamine modulation. In the open field, exposed rats were indistinguishable from controls. These findings support the hypothesis that continuous exposure during prenatal development to CMFs designed to simulate intrinsic LTP within the hippocampus can affect adult behaviors specific to this structure and produce quantitative alterations in neuronal density.

Second-line systemic therapies for metastatic urothelial carcinoma: a population-based cohort analysis.

Introduction: Patients with urothelial carcinoma (uc) have a poor prognosis after progression on first-line cisplatin-based chemotherapy. Real-world data about second-line cytotoxic therapies are limited. We sought to characterize patients with metastatic uc who receive more than 1 line of systemic therapy and to describe their treatments and outcomes. Methods: Using BC Cancer's pharmacy database, we identified patients with documented metastatic uc who had received more than 1 line of systemic therapy. A retrospective chart review was then performed to collect clinicopathologic, treatment, and outcomes data. Results: The 51 included patients, of whom 42 were men (82%), had a median age of 65 years (range: 38-81 years). Sites of metastasis included lymph nodes (n = 30), bone (n = 7), lung (n = 9), and peritoneum (n = 2). Second-line chemotherapy regimens included gemcitabine-cisplatin [gc (n = 14)], paclitaxel (n = 24), docetaxel (n = 12), and an oral topoisomerase i inhibitor (n = 1). Median time to progression (ttp) and overall survival (os) were 2.0 and 6.83 months respectively. Compared with patients who received a different agent, patients who had experienced a prior response to first-line gc and who were re-challenged with second-line gc had a better median ttp (11.0 months vs. 6.0 months, p = 0.02) and survived longer (4.0 months vs. 1.0 months, p = 0.02). No differences in os between non-gc regimens were evident. Conclusions: In patients with metastatic uc, overall outcomes remain poor, but compared with patients receiving other agents, the subgroup of patients re-challenged with second-line gc demonstrated improved ttp. Conventional chemotherapy regimens provide only modest benefits in the second-line setting and have largely been replaced with immunotherapy.

Myocardial expression of endothelin-1 in murine Trypanosoma cruzi infection.

Chagas' disease, caused by Trypanosoma cruzi, is an important cause of myocarditis and chronic cardiomyopathy and is accompanied by microvascular spasm and myocardial ischemia. We reported previously that infection of cultured endothelial cells with T. cruzi increased the synthesis of biologically active endothlein-1 (ET-1). In the present study, we examined the role of ET-1 in the cardiovascular system of CD1 mice infected with the Brazil strain of T. cruzi and C57BL/6 mice infected with the Tulahuen strain during acute infection. In the myocardium of infected mice myonecrosis and multiple pseudocysts were observed. There was also an intense vasculitis of the aorta, coronary artery, smaller myocardial vessels and the endocardial endothelium. Immunohistochemistry studies employing anti-ET-1 antibody revealed increased expression of ET-1 that was most intense in the endocardial and vascular endothelium. Elevated levels of mRNA for preproET-1, endothelin converting enzyme and ET-1 were observed in the same myocardial samples. Plasma ET-1 levels were significantly elevated in infected CD1 mice 10-15 days post infection. These observations suggest that increased levels of ET-1 are a consequence of the initial invasion of the cardiovascular system and provide a mechanism for infection-associated myocardial dysfunction.

Application of free-radical chromogens to determination of nitrite and nitrate ions by EPR spectrometry.

Various azines and substituted phenylene diamines are oxidized by the nitrite ion to give stable radicals in an autocatalytic reaction. This finding has now been developed into highly sensitive methods for nitrite determination by EPR spectrometry. Thus, when the reagent is phenothiazine, the detection limit for nitrite is 0.012 ppm, the relative standard deviation at 0.05 ppm is 1.9%, and the analytical range is 0-1.5 ppm. With N,N,N',N'-tetramethyl-p-phenylenediamine as the reagent, the corresponding values are 0.025 ppm, 2.6%, and 0-1.3 ppm. Nitrate can be determined after prior reduction to nitrite. A mixture of nitrite and nitrate ions can also be quantitatively analysed. The EPR methods were applied to the determination of the nitrite and nitrate contents of prepacked cooked ham and of soft-spreading cheese. The results agreed well with those obtained by ISO and AOAC standard methods for these samples. ca*|Author for correspondence.

A comparative study on similarity-based fuzzy reasoning methods.

If the given fact for an antecedent in a fuzzy production rule (FPR) does not match exactly with the antecedent of the rule, the consequent can still be drawn by technique such as fuzzy reasoning. Many existing fuzzy reasoning methods are based on Zadeh's Compositional Rule of Inference (CRI) which requires setting up a fuzzy relation between the antecedent and the consequent part. There are some other fuzzy reasoning methods which do not use Zadeh's CRI. Among them, the similarity-based fuzzy reasoning methods, which make use of the degree of similarity between a given fact and the antecedent of the rule to draw the conclusion, are well known. In this paper, six similarity-based fuzzy reasoning methods are compared and analyzed. Two of them are newly proposed by the authors. The comparisons are two-fold. One is to compare the six reasoning methods in drawing appropriate conclusions for a given set of FPRs. The other is to compare them based on five issues: 1) types of FPR handled by these methods; 2) the complexity of the methods; 3) the accuracy of the conclusion drawn; 4) the accuracy of the similarity measure; and 5) the multi-level reasoning capability. The results have shed some lights on how to select an appropriate fuzzy reasoning method under different environments.

Tuning certainty factor and local weight of fuzzy production rules by using fuzzy neural network.

Approximate reasoning in a fuzzy system is concerned with inferring an approximate conclusion from fuzzy and vague inputs. There are many ways in which different forms of conclusions can be drawn. Fuzzy sets are usually represented by fuzzy membership functions. These membership functions are assumed to have a clearly defined base. For other fuzzy sets such as intelligent, smart, or beautiful, etc., it would be difficult to define clearly its base because its base may consist of several other fuzzy sets or unclear nonfuzzy bases. A method to handle this kind of fuzzy set is proposed. A fuzzy neural network (FNN) is also proposed to tune knowledge representation parameters (KRPs). The contributions are that we are able to handle a broader range of fuzzy sets and build more powerful fuzzy systems so that the conclusions drawn are more meaningful, reliable, and accurate. An experiment is presented to demonstrate how our method works.

A comparative study on heuristic algorithms for generating fuzzy decision trees.

Fuzzy decision tree induction is an important way of learning from examples with fuzzy representation. Since the construction of optimal fuzzy decision tree is NP-hard, the research on heuristic algorithms is necessary. In this paper, three heuristic algorithms for generating fuzzy decision trees are analyzed and compared. One of them is proposed by the authors. The comparisons are twofold. One is the analytic comparison based on expanded attribute selection and reasoning mechanism; the other is the experimental comparison based on the size of generated trees and learning accuracy. The purpose of this study is to explore comparative strengths and weaknesses of the three heuristics and to show some useful guidelines on how to choose an appropriate heuristic for a particular problem.

Enhanced power within a specific band of theta activity in one person while another receives circumcerebral pulsed magnetic fields: a mechanism for cognitive influence at a distance?

Four pairs of adult siblings served once as either the stimulus or the response person in two sessions separated by one week. While the brain of the stimulus person, who was seated in a closed chamber, was exposed successively to six different complex magnetic fields for 5 min. each quantitative monopolar electroencephalographic measurements over the frontal, temporal, parietal, and occipital lobes were collected by computer for the response person who was seated in another room. The six configurations of fields served as different stimulus patterns and had been designed to affect consciousness. As predicted theoretically, a significant increase in electroencephalographic power within the 5.0-Hz to 6.0-Hz band over the frontal and occipital lobes was noted for the response persons when the stimulus persons received one of the six specific patterns of weak (1 microTesla range) magnetic fields. This magnetic stimulus was presented for 100 msec. with changes in rate of 20 msec. to each of the eight solenoids that were equally spaced in the horizontal plane around the head of the stimulus person. Derivatives within this narrow frequency band had been hypothesized to be a source of the "binding factor" for the cohesive cerebrogenic electromagnetic fields producing consciousness. The results suggest that an appropriate altered state of one brain can effect specific predictable frequencies of the electroncephalographic activity of another distant brain which is genetically related.

Subthalamic deep brain stimulation at individualized frequencies for Parkinson disease.

OBJECTIVES: The oscillation model of Parkinson disease (PD) states that, in the subthalamic nucleus (STN), increased θ (4-10 Hz) and ß (11-30 Hz) frequencies were associated with worsening whereas γ frequencies (31-100 Hz) were associated with improvement of motor symptoms. However, the peak STN frequency in each band varied widely from subject to subject. We hypothesized that STN deep brain stimulation (DBS) at individualized γ frequencies would improve whereas θ or ß frequencies would worsen PD motor signs. METHODS: We prospectively studied 13 patients with PD. STN local field potential (LFP) was recorded after electrode implantations, in the OFF and then in ON dopaminergic medication states while patients performed wrist movements. Six individual peak frequencies of the STN LFP power spectra were obtained: the greatest decrease in θ and ß and greatest increase in γ frequencies in the ON state (MED) and during movements (MOVE). Eight DBS frequencies were applied including 6 MED and MOVE frequencies, high frequency (HF) used for chronic stimulation, and no stimulation. The patients were assessed using the motor Unified Parkinson's Disease Rating Scale (mUPDRS). RESULTS: STN DBS at γ frequencies (MED and MOVE) and HF significantly improved mUPDRS scores compared to no stimulation and both γ frequencies were not different from HF. DBS at θ and ß frequencies did not worsen mUPDRS scores compared to no stimulation. CONCLUSION: Short-term administration of STN DBS at peak dopamine-dependent or movement-related γ frequencies were as effective as HF for reducing parkinsonian motor signs but DBS at θ and ß frequencies did not worsen PD motor signs. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that STN DBS at patient-specific γ frequencies and at usual high frequencies both improved mUPDRS scores compared to no stimulation and did not differ in effect.

Involvement of the human pedunculopontine nucleus region in voluntary movements.

OBJECTIVE: The pedunculopontine nucleus region (PPNR) is being investigated as a target for deep brain stimulation (DBS) in Parkinson disease (PD), particularly for gait and postural impairment. A greater understanding of how PPNR activities and oscillations are modulated with voluntary movements is crucial to the development of neuromodulation strategies. METHODS: We studied 7 patients with PD who underwent DBS electrode implantations in the PPNR. PPNR local field potential and EEG were recorded while patients performed self-paced wrist and ankle movements. RESULTS: Back-averaging of the PPNR recording showed movement-related potentials before electromyography onset. Frequency analysis showed 2 discrete movement-related frequency bands in the theta (6- to 10-Hz) and beta (14- to 30-Hz) ranges. The PPNR theta band showed greater event-related desynchronization with movements in the ON than in the OFF medication state and was coupled with the sensorimotor cortices in the ON state only. Beta event-related desynchronization was observed in the PPNR during the premovement and movement execution phases in the OFF state. In contrast, premovement PPNR beta event-related synchronization occurred in the ON state. Moreover, beta band coherence between the PPNR and the midline prefrontal region was observed during movement preparation in the ON but not the OFF state. CONCLUSIONS: Activities of PPNR change during movement preparation and execution in patients with PD. Dopaminergic medications modulate PPNR activities and promote the interactions between the cortex and PPNR. Beta oscillations may have different functions in the basal ganglia and PPNR, and may be prokinetic rather than antikinetic in the PPNR.

Contribution of the MexAB-OprM multidrug efflux system to the beta-lactam resistance of penicillin-binding protein and beta-lactamase-derepressed mutants of Pseudomonas aeruginosa.

Deletion of the mexAB-oprM multidrug efflux operon substantially compromised the beta-lactam resistance of beta-lactamase-derepressed mutants of Pseudomonas aeruginosa, although it had only a modest impact on resistance of a penicillin-binding protein mutant. This highlights the multifactorial nature of beta-lactam resistance in this organism. Moreover, the contribution of efflux to the net resistance seen in some beta-lactam-resistant mutants suggests that inhibition of MexAB-OprM-mediated drug efflux might be an effective approach to overcoming beta-lactam resistance attributed to efflux as well as to other mechanisms of beta-lactam resistance.

Power increases within the gamma range over the frontal and occipital regions during acute exposures to cerebrally counterclockwise rotating magnetic fields with specific derivatives of change.

A total of 11 men and women were exposed for 5 min each to six different temporal configurations of pulsed magnetic fields that were delivered through serial activation of 8 solenoids in a counterclockwise direction around the head within the horizontal plane above the ears. Twenty-second samples of quantitative electroencephalographic activity within the delta, theta, lower alpha, upper alpha, beta, and gamma regions were collected after each configuration had been activated for 2.5 min. Only the circumcerebral presentation of the first pulse for 25 ms followed by an acceleration of +2 ms to each of the other 7 solenoids (the last duration = 11 ms) resulted in a significant increase in power within the gamma range (35 Hz to 45 Hz) over both frontal and occipital lobes but not over the parietal or temporal lobes. These results suggest topical application of specific spatial-temporal configurations of magnetic fields may affect the recursive creation of the rostral-caudal waves of cohesive fields that might produce consciousness.

Electrophysiological and quantitative electroencephalographic measurements after treatment by transcerebral magnetic fields generated by compact disc through a computer sound card: the Shakti treatment.

Quantitative electroencephalographic activity over the left and right frontal, temporal, parietal, and occipital lobes was obtained on 4 successive weeks in 12 subjects before they were exposed cerebrally for 30 min to one of two configurations of weak complex magnetic fields or to a sham-field condition. The two configurations were Shakti (c Todd Murphy) and the set of 4 solenoids (Koren boxes) generating a burst-firing magnetic field through the temporal lobes. Compared to baseline measurements there were no statistically significant differences in treatments for relative changes in power over these regions within the delta, theta, low alpha, beta, or gamma ranges. However within the high alpha range (10.5 Hz to 13 Hz), there was a significant interaction between session and type of treatment that was due primarily to the Shakti treatment. These changes were congruent with the subjective experiences reported by some users of the technology.

Transformation of white spruce (Picea glauca) somatic embryos by microprojectile bombardment.

Cotyledonary somatic embryos of white spruce [Picea glauca (Moench) Voss] were subjected to microprojectile bombardment with a gene construct containing a gus::nptll fusion gene. Somatic embryos were used to re-induce the embryogenic tissue after bombardments. Histochemical assay using X-gluc as a substrate showed that all the embryos (100%) were GUS positive 48 h after bombardment. However, only thirteen out of 605 embryos (2.2%) remained GUS positive after two months in culture. Three of those thirteen (23%) embryo-derived tissues consistently showed GUS activity for eight months in culture. These putatively transfomed embryogenic tissues were subjected to Southern blot analysis and the results suggested integration of the gus::nptll gene expression cassette in the white spruce genome.