Pharmacokinetic considerations in testing hypoxic cell radiosensitizers in mouse tumours.

Bilateral kidney ligation of mice immediately before injection of misonidazole (MIS) prolongs the plasma half-life of this radiosensitizer from about 2 h (in normal mice) to 10-11 h, similar to that in man. Kidney ligation does not, however, change the relative proportions of MIS and its O-demethylated metabolite, Ro-05-9963, for the first 12 h after MIS injection. Kidney ligation was used with the two radiosensitizers, MIS and Ro-05-9963, to investigate the influence of plasma half-life both on peak plasma levels and on the tumour/plasma ratio of sensitizer concentration in the EMT6 mouse tumour. Although the acute LD50 of Ro-05-9963 in normal mice was twice that of MIS, this apparent advantage was offset by peak tumour levels 50% or less of those achieved by equimolar injected doses of MIS. However, by comparing the plasma and tumour levels in mice in which the drug half-lives were prolonged by bilateral kidney ligation, it was concluded that the lower plasma and tumour levels of Ro-05-9963 were a result of its shorter plasma half-life, rather than of an intrinsic barrier to tumour penetration. Because of this rapid clearance, the radiosensitization produced by Ro-05-9963 was less than that produced by equimolar injected doses of MIS. As this difference did not occur in kidney-ligated mice, and hence would not be expected to occur in man, the comparison of MIS and Ro-05-9963 in mice produces an artificially low radiosensitization for Ro-05-9963 and possibly also for other compounds with short plasma half-lives. Although the short plasma half-life of Ro-05-9963 appeared to be responsible for its low peak plasma concentration, it did not produce a low tumour/plasma ratio. Within the limits of plasma nitroimidazole half-lives investigated (0.5-10 h) the tumour/plasma ratio was insensitive to plasma half-life, being 50-70% for both MIS and Ro-05-9963 in both normal and kidney-ligated mice. It is concluded that the common assumption that tumour/plasma ratios of MIS in the mouse are less than those in man is unjustified

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p < 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits

Toward a unified description of hadro- and photoproduction: S-wave pi- and eta-photoproduction amplitudes

The Chew-Mandelstam parameterization, which has been used extensively in the two-body hadronic sector, is generalized in this exploratory study to the electromagnetic sector by simultaneous fits to the pion- and eta-photoproduction S-wave multipole amplitudes for center-of-mass energies from the pion threshold through 1.61 GeV. We review the Chew-Mandelstam parameterization in detail to clarify the theoretical content of the SAID hadronic amplitude analysis and to place the proposed, generalized SAID electromagnetic amplitudes in the context of earlier employed parameterized forms. The parameterization is unitary at the two-body level, employing four hadronic channels and the gamma-N electromagnetic channel. We compare the resulting fit to the MAID parameterization and find qualitative agreement though, numerically, the solution is somewhat different. Applications of the extended parameterization to global fits of the photoproduction data and to global fits of the combined hadronic and photoproduction data are discussed.Comment: 9 pages, 9 figures; added figures and tex

Viewership footprint for a low-resource, student-centred collaborative video platform to teach orthopaedics in southern Africa

Background. Institutions are increasingly using technology to augment the class learning experience of medical students. Especially in Africa, local content is key to allow insights and knowledge to emerge and build transformative capacity for students and patients. There is currently no peer-reviewed video content produced by students with the aim of providing education on orthopaedic topics for medical students and patients in this region.Objectives. To evaluate the demographic and geographical viewership as well as video-specific statistics of orthopaedic teaching videos for medical students on a YouTube channel, with the expressed aim of informing future content production.Methods. Videos were produced by South African (SA) medical students as a problem-based collaborative project. Student-owned smartphones and various types of free video editing software were used to produce these videos, which were then assessed by a group of orthopaedic specialists and uploaded onto a YouTube channel (UCTeach). The analytical reports of this channel generated by Google and YouTube were analysed regarding watch time per day (minutes), average view duration (minutes), most watched videos, top geographies, age and gender.Results. A total of 83 videos were uploaded to the UCTeach Ortho channel during a 2-year period, with a total watch time of 857 062 minutes and 337 983 views. The majority of viewers were between the ages of 18 and 34 years (85%). India had the most views (n=69 089), followed by the USA (n=66 257) and SA (n=21 882). Most of the videos were watched on mobile phones (n=183 299) and computers (n=128 228). The most watched video, produced in April 2016, was on physiological and pathological gait, with 51 314 views.Conclusions. Our study provides proof of concept for a new educational material creation and dissemination strategy. A low-cost local collaborative orthopaedic video project by medical students for medical students can lead to high view counts and watch time on YouTube. It is accessible to audiences in low-, middle- and high-income countries. The students’ educational videos also reached a global audience consistently over a 3-year period

Light Baryon Resonances: Restrictions and Perspectives

The problem of nucleon resonances N' with masses below the Delta is considered. We derive bounds for the properties of such states. Some of these are new, while others improve upon existing limits. We discuss the nature of N' states, and their unitary partners, assuming their existence can be verified.Comment: 11 pages, 11 figur

In vivo pharmacology and anti-tumour evaluation of the tyrphostin tyrosine kinase inhibitor RG13022.

Amplification and increased expression of many growth factor receptors, including the epidermal growth factor receptor (EGFR), has been observed in human tumours. One therapeutic strategy for overcoming EGF autocrine control of tumour growth is inhibition of EGFR protein tyrosine kinase (PTK). A series of low molecular weight molecules have been identified which inhibit the EGFR PTK in vitro and demonstrate antiproliferative activity against human cancer cell lines with high expression of EGFR. A significant growth delay in squamous cancer xenografts has been reported for one of these compounds, the tyrphostin RG13022. Based on these encouraging results, we sought to confirm the activity of RG13022 in vivo and relate the effects to the in vivo plasma disposition. RG13022 and three additional peaks were detected by HPLC following intraperitoneal administration of 20 mg kg-1 RG13022 in MF1 nu/nu mice. RG13022 demonstrated rapid biexponential elimination from plasma with a terminal half-life of 50.4 min. RG13022 plasma concentrations were less than 1 microM by 20 min post injection. A primary product was identified as the geometrical isomer (E)-RG13022. Both RG13022 and its geometrical isomer inhibited DNA synthesis in HN5 cells after a 24 h in vitro incubation (IC50 = 11 microM and 38 microM respectively). Neither RG13022 nor its geometrical isomer displayed significant cytotoxicity. RG13022 had no influence on the growth of HN5 tumours when administered chronically, starting either on the day of tumour inoculation or after establishment of tumour xenografts. The rapid in vivo elimination of RG13022 has potential significance to the development of this and other related tyrphostin tyrosine kinase inhibitors, as plasma concentrations fell below that required for in vitro activity by 20 min post injection. The lack of in vivo tumour growth delay suggests that a more optimal administration schedule for RG13022 would include more frequent injections or continuous administration. An improved formulation for RG13022 is therefore required before further development of this or other similar protein tyrosine kinase inhibitors can be made. Alternative strategies should also be sought which display longer lasting in vivo exposures

Nucleon Polarizibilities for Virtual Photons

We generalize the sum rules for the nucleon electric plus magnetic polarizability $\Sigma=\alpha+\beta$ and for the nucleon spin-polarizability $\gamma$, to virtual photons with $Q^2>0$. The dominant low energy cross sections are represented in our calculation by one-pion-loop graphs of relativistic baryon chiral perturbation theory and the $\Delta(1232)$-resonance excitation. For the proton we find good agreement of the calculated $\Sigma_p(Q^2)$ with empirical values obtained from integrating up electroproduction data for $Q^2<0.4 GeV^2$. The proton spin-polarizability $\gamma_p(Q^2)$ switches sign around $Q^2= 0.4 GeV^2$ and it joins smoothly the "partonic" curve, extracted from polarized deep-inelastic scattering, around $Q^2=0.7 GeV^2$. For the neutron our predictions of $\Sigma_n(Q^2)$ and $\gamma_n(Q^2)$ agree reasonably well at $Q^2=0$ with existing determinations. Upcoming (polarized) electroproduction experiments will be able to test the generalized polarizability sum rules investigated here.Comment: 12 pages, 5 figures, submittes to Nuclear Physics

Reconnecting the Sciences

During the last three years at the Illinois Mathematics and Science Academy, we have been working on a partial reconstruction of Whitehead\u27s one subject matter, a course reconnecting biology, chemistry, earth and space sciences, and physics into an Integrated Science program