Surface modification of a screen-printed electrode with a flower-like nanostructure to fabricate a guanine DNA-based electrochemical biosensor to determine the anticancer drug pemigatinib.

The present study developed a DNA biosensor to determine pemigatinib for the first time. Three-dimensional carnation flower-like Eu3+:ß-MnO2 nanostructures (3D CF-L Eu3+:ß-MnO2 NSs) and a screen-printed electrode (SPE) modified with polyaniline (PA) were employed. The double-stranded DNA was also immobilized completely on the PA/3D CF-L Eu3+:ß-MnO2 NSs/SPE. Then, electrochemical techniques were used for characterizing the modified electrode. After that, the interaction between pemigatinib and DNA was shown by a reduction in the oxidation current of guanine using differential pulse voltammetry (DPV). According to the analysis, the dynamic range of pemigatinib was between 0.001 and 180.0 µM, indicating the new electrode has a low limit of detection (LOD = 0.23 nM) for pemigatinib. Afterwards, pemigatinib in real samples was measured using the PA/3D CF-L Eu3+:ß-MnO2 NSs/SPE loaded with ds-DNA. The proposed DNA biosensor showed good selectivity toward pemigatinib in the presence of other interference analytes, such as other ions, structurally related pharmaceuticals, and plasma proteins. In addition, the interaction site of pemigatinib with DNA was predicted by molecular docking, which showed the interaction of pemigatinib with the guanine bases of DNA through a groove binding mode. Finally, we employed the t-test to verify the capability of the ds-DNA/PA/3D CF-L Eu3+:ß-MnO2 NSs/SPE for analyzing pemigatinib in real samples.

Autonomous atmospheric water seeping MOF matrix.

The atmosphere contains an abundance of fresh water, but this resource has yet to be harvested efficiently. To date, passive atmospheric water sorbents have required a desorption step that relies on steady solar irradiation. Since the availability and intensity of solar radiation vary, these limit on-demand desorption and hence the amount of harvestable water. Here, we report a polymer-metal-organic framework that provides simultaneous and uninterrupted sorption and release of atmospheric water. The adaptable nature of the hydro-active polymer, and its hybridization with a metal-organic framework, enables enhanced sorption kinetics, water uptake, and spontaneous water oozing. We demonstrate continuous water delivery for 1440 hours, producing 6 g of fresh water per gram of sorbent at 90% relative humidity (RH) per day without active condensation. This leads to a total liquid delivery efficiency of 95% and an autonomous liquid delivery efficiency of 71%, the record among reported atmospheric water harvesters.

Fap2 of Fusobacterium nucleatum is a galactose-inhibitable adhesin involved in coaggregation, cell adhesion, and preterm birth.

Fusobacterium nucleatum is a common oral anaerobe involved in periodontitis that is known to translocate and cause intrauterine infections. In the oral environment, F. nucleatum adheres to a large diversity of species, facilitating their colonization and creating biological bridges that stabilize the multispecies dental biofilm. Many of these interactions (called coadherences or coaggregations) are galactose sensitive. Galactose-sensitive interactions are also involved in the binding of F. nucleatum to host cells. Hemagglutination of some F. nucleatum strains is also galactose sensitive, suggesting that a single galactose-sensitive adhesin might mediate the interaction of fusobacteria with many partners and targets. In order to identify the fusobacterial galactose-sensitive adhesin, a system for transposon mutagenesis in fusobacteria was created. The mutant library was screened for hemagglutination deficiency, and three clones were isolated. All three clones were found to harbor the transposon in the gene coding for the Fap2 outer membrane autotransporter. The three fap2 mutants failed to show galactose-inhibitable coaggregation with Porphyromonas gingivalis and were defective in cell binding. A fap2 mutant also showed a 2-log reduction in murine placental colonization compared to that of the wild type. Our results suggest that Fap2 is a galactose-sensitive hemagglutinin and adhesin that is likely to play a role in the virulence of fusobacteria.

High sensitivity troponin T in acute medicine; more questions than answers?

BACKGROUND: Troponin testing in acute medicine is routine. The introduction of a high sensitivity assay (hs Tn T) has created uncertainty regarding the clinical significance of 'abnormal' troponin T levels. The previous assay could not detect troponin levels <30 ng/l. AIMS AND METHODS: To characterize those with a hs Tn T ≥14 ng/l. Prospective cohort study of consecutive admissions to an acute medical unit. RESULTS: Troponin was measured in 564 consecutive patients (∼50% of all admissions) over 1 month; was ≥14 ng/l in 224 (40%) of which 220 patients had demographic data for this analysis. Median (inter-quartile range) peak troponin was 47.5 ng/l (24-130) and 36% had a Tn T between 14 and 30 ng/l. Mean [standard deviation (SD)] age was 72 (12) years and 57% were male. Only 44 patients (20%) had an acute myocardial infarction, reflecting the increased sensitivity but reduced specificity of the assay. Prognosis was poor with 31% mortality at 1 year. Over a mean (SD) follow-up of 648 (61) days, there were 87 deaths (40%). Those with a primary non-cardiac diagnosis (n = 126) had poorer survival than those with a primary cardiac diagnosis (n = 94). Troponin elevation related to sepsis conferred a very poor prognosis with 24 deaths (70%) over the follow-up period. CONCLUSION: Elevated hs Tn T is very common in acute medicine, but myocardial infarction as an explanation is uncommon. Overall, the prognosis is poor with a tendency to worse outcomes in those with a primary 'non-cardiac' diagnosis.

Abnormal apical-to-basal transport of dietary ovalbumin by secretory IgA stimulates a mucosal Th1 response.

In celiac disease, enhanced permeability to gliadin peptides can result from their apico-basal transport by secretory immunoglobulin A1 (SIgA1) binding to the CD71 receptor ectopically expressed at the gut epithelial surface. Herein, we have established a mouse model in which there is apico-basal transport of the model antigen ovalbumin (OVA) by specific SIgA1 and have analyzed local T-cell activation. Transgenic DO11.10 mice were grafted with a hybridoma-secreting OVA-specific humanized IgA1, which could bind mouse CD71 and which were released in the intestinal lumen as SIgA. CD71 expression was induced at the gut apical surface by treating the mice with tyrphostin A8. Following gavage of the mice with OVA, OVA-specific CD4⁺ T cells isolated from the mesenteric lymph nodes displayed higher expression of the activation marker CD69 and produced more interferon gamma in mice bearing the hybridoma-secreting OVA-specific IgA1, than in ungrafted mice or in mice grafted with an irrelevant hybridoma. These results indicate that the protective role of SIgA1 might be jeopardized in human pathological conditions associated with ectopic expression of CD71 at the gut surface.

Dialyzer reuse impact on dialyzer efficiency, patient morbidity and mortality and cost effectiveness.

Since the introduction of dialyzer reuse more than three decades ago, several studies have reported its safety, efficacy and cost effectiveness. Reuse of hemodialyzer was prospectively studied in ten chronic hemodialysis (HD) patients recruited from the renal unit, the King Khalid University Hospital, Riyadh, Saudi Arabia, for three months. During the study period, 66 dialyzers were used for 408 sessions of HD, with a mean reuse of 6.2 +/- 5.3 episodes per dialyser, the mean of maximum reuse episodes being 13.7 +/- 8.0. The urea reduction ratio was maintained between 73 +/- 5% at baseline to 71.2 +/- 9.03% (p=0.53) at the maximum reuse. Similarly phosphate reduction with each HD session was maintained; mean decrease in phosphate levels was 0.67 mmol/L. Significant increase in heparin requirement was noted; however, the risk of bleeding was not increased. Hematocrit levels increased from 30.4 +/- 4.1% to 33.2 +/- 3.6% at the end of the study (p=0.6). Albumin leak in dialysate decreased with each reuse; baseline 8.27 +/- 7.93 mg/L to 2.8 +/- 0.4 mg/L at maximum reuse (p=0.04). Serum albumin levels remained stable. No short-term adverse effects on patients' morbidity and mortality were noted. Total cost savings of 53% was achieved with the reuse of dialyzers, excluding capital equipment used for preparation for reuse. In conclusion, dialyzer reuse seems to be safe and may provide an economical and efficient dialysis. Studies involving larger number of patients is required to validate this observation.

Developing a framework for comprehensive cancer prevention and control in the United States: an initiative of the Centers for Disease Control and Prevention.

The Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, is working with state health agency staff and other stakeholders to develop a comprehensive and integrated approach to cancer control. To help stakeholders visualize the approach, a graphic model was developed based on stakeholder input and a literature review of existing models. Phases of the model include setting optimal objectives (data driven), determining optimal strategies (science driven), establishing feasible priorities (capacity driven), and implementing effective strategies (outcome driven). The model currently is being validated through case studies of state-level cancer planning in six states.

Comprehensive cancer control initiative of the Centers for Disease Control and Prevention: an example of participatory innovation diffusion.

Site-specific and risk factor-specific cancer programs can point to impressive accomplishments, but coordination among them often is lacking. The Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, is working with state health agency staff and other stakeholders to develop a comprehensive, integrated, nationwide approach to cancer control. The participatory innovation diffusion model may help this complex public health innovation be adopted. The participants in the process identified problematic aspects of the innovation and steps that the division can take to ameliorate these problems before the innovation is implemented.

Long-term effect of intravenous calcitriol on the treatment of severe hyperparathyroidism, parathyroid gland mass and bone mineral density in haemodialysis patients.

We conducted this study on 15 chronic haemodialysis patients to evaluate the efficacy of i.v. calcitriol over a 1-year period in the treatment of severe secondary hyperparathyroidism (HPT), in particular its effect on bone mineral density (BMD) and parathyroid gland mass. Mean age was 39 +/- 11.9 (20-65) years and dialysis duration was 58 +/- 3 (19-130) months. i.v. calcitriol was given at a dose of 1 microg post-dialysis 3 times/week for 3 weeks; the dose was then adjusted to maintain the total serum calcium at less than 2.88 mmol/l. The maximum dose was 3 microg 3 times/week. Serum calcium (Ca) and phosphorus (P) were determined prior to treatment, then weekly for 6 weeks and every 2 weeks thereafter. Skeletal survey, dual photon densitometry and parathyroid ultrasound (US) were done prior to treatment and after 1 year. Bone biopsy was done in 10 patients at the beginning of treatment. There was a significant reduction (p < 0.01) in pre-treatment mid-region serum parathyroid hormone (PTH) from 1,476 +/- 895 to 489 +/- 485 P mol/l, as well as alkaline phosphatase (p < 0.04) from 236.5 +/- 221 to 116.3 +/- 49 U/l. This was without a significant increase in serum Ca (2.15 +/- 0.25 to 2.44 +/- 0.26 mmol/l, p = 0.08). Three patients had recurrent hypercalcaemia which responded to reduction of Ca in dialysate. There was a significant increase in BMD over the spine from 1.071 +/- 0.25 to 1.159 +/- 0.22 g/cm2 (p < 0.003) with a percent increase of 9.3 +/- 8.9% as well as over the femoral neck from 0.834 +/- 0.002 to 0.89 +/- 0.09 g/cm2 (p < 0.001) with a percent increase of 7.45 +/- 6.81%. Five patients had enlarged parathyroid glands by US and in 3 of these, there was a significant reduction to normal with treatment. Bone biopsy was done in 10 patients. Six patients had predominant hyperparathyroid bone disease and 4 had mixed uraemic osteodystrophy. In conclusion, long-term i.v. treatment with calcitriol is effective in the treatment of severe secondary HPT. PTH decreased without a significant increase in serum Ca. BMD also increases during this therapy.

Pharmacodynamics of local heparin infusion in a canine renal allograft model.

Inasmuch as heparin has demonstrated immunosuppressive activity in vivo and in vitro, we utilized a canine renal transplant model to estimate the first-pass extraction of heparin during renal artery infusion and to examine the effect of regional heparin delivery on the histologic features of rejection and allograft survival. Four autotransplanted mongrel dogs with programmable, implantable pump/catheter systems received a continuous intrarenal heparin infusion which was increased daily in stepwise fashion. Activated coagulation time (ACT) rose linearly with local heparin dose, indicating that heparin clearance remained constant over the dosage range studied. Comparison of these ACT values with those measured during same-dose i.v. infusion and those predicted from i.v. bolus studies revealed that there was little or no first-pass renal extraction of heparin by the transplanted kidney. In nine allografted dogs, the heparin infusion rate was adjusted according to daily ACT to maximize local heparin delivery but still maintain the ACT close to 125% of base line. There was no difference in overall survival between the heparin-treated dogs and a group of 14 untreated controls, and vascular rejection was significantly more intense in the heparin-treated animals. We conclude that intrarenal dosing of heparin to the point of producing systemic anticoagulation is limited by failure of the transplanted kidney to eliminate drug and does not prolong canine renal allograft survival.

Retrograde infusion of blood into a pulmonary vein promotes natriuresis in anaesthetized dogs.

Retrograde infusion of blood into a pulmonary vein raised the pressure by 0.5-1 kPa in the cannulated vein. There were no changes in heart rate, arterial blood pressure, left atrial pressure, right atrial pressure or the pressure in the other pulmonary veins. The rise in pulmonary venous pressure was associated with an increase in urinary sodium concentration and excretion. However, there was no change in urine volume. The natriuresis was abolished by cooling the vagi to 9 degrees C. It is argued that receptors up-stream in the pulmonary veins themselves may be involved in the increase in sodium excretion that follows a rise in left atrial pressure.

Class III action of beta-blocking agents.

We have studied the effect of the intravenous administration of the following drugs on ventricular refractoriness in 35 experiments in open chested beagle dogs: atenolol 0.2 mg X kg-1; nadolol 0.05 mg X kg-1; oxprenolol 0.2 mg X kg-1; pindolol 0.04 mg X kg-1; propranolol 0.2 mg X kg-1; sotalol 0.6 mg X kg-1 and timolol 0.1 mg X kg-1. The animals were anaesthetised with chloralose and urethane. Measurements were made of left ventricular epicardial monophasic action potentials (MAP) (n = 35) and the left ventricular paced evoked response (PER) (n = 25) at a fixed paced cycle length of between 220 and 310 ms. The animals were initially beta-blocked with iv pindolol or propranolol and the drug under study then administered iv 10 min later. The results were as follows: (control and post drug administration) MAP: nadolol 151 +/- 12 SD to 172 +/- 13 SD (p less than 0.001); oxprenolol 153 +/- 21 to 178 +/- 20 (p less than 0.001); sotalol 153 +/- 19 to 176 +/- 20 (p less than 0.001); atenolol 152 +/- 25 to 153 +/- 23 (NS); pindolol 149 +/- 11 to 152 +/- 10 (NS); propranolol 152 +/- 26 to 155 +/- 26 (NS); timolol 144 +/- 23 to 144 +/- 21 (NS). PER: nadolol 172 +/- 14 to 190 +/- 20 (p less than 0.001); oxprenolol 164 +/- 16 to 188 +/- 15 (p less than 0.001); propranolol 166 +/- 22 to 173 +/- 18 (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Study of the electrophysiological effects of early or subendocardial ischaemia with intracavitary electrodes in the dog.

The early electrophysiological patterns of regional subendocardial ischaemia were studied by using the paced endocardial evoked response and simultaneous endocardial monophasic action potential recordings in 16 experiments in open chested dogs. Ischaemia was produced by transient (1-3 min) coronary artery occlusion. Regional subendocardial isochaemia caused asynchronous activation due to differential conduction delay and shortened repolarization as evaluated by the duration of the paced evoked response from 175 +/- (SD) 18.7 ms to 167 +/- 16 ms (P less than 0.001). These changes occurred within 60 s of occlusion and reversed rapidly after release of the occlusion. In simultaneous endocardial monophasic action potentials there was a decrease in plateau amplitude and the duration of repolarization shortened from 180 +/- (SD) 21.2 ms to 167 +/- 20.4 ms (P less than 0.001). The delay in endocardial activation after 2 min ischaemia was 5.5 ms, which is considerably shorter than the conduction delay previously reported in the subepicardial layers. The calcium-channel blocking drug verapamil (infused at 0.4 mg/kg) altered the rate at which shortening of repolarization and asynchronous activation occurred during ischaemia in six experiments. These experiments suggest that intracavitary electrodes could provide earlier and more sensitive detection of regional subendocardial ischaemia and may permit the assessment of therapy on the early electrical changes in the intact heart.