Phylogeny of the Alismatales (Monocotyledons) and the relationship of Acorus (Acorales?)

A phylogenetic analysis of the early branching lineages of the monocotyledons is performed using data from two plastid genes (rbcL and matK), five mitochondrial genes (atp1, ccmB, cob, mttB and nad5) and morphology. The complete matrix includes 93 terminals representing Acorus, the 14 families currently recognized within Alismatales, and numerous lineages of monocotyledons and other angiosperms. Total evidence analysis results in an almost completely resolved strict consensus tree, but all data partitions, genomic as well as morphological, are incongruent. The effects of RNA editing and potentially processed paralogous sequences are explored and discussed. Despite a decrease in incongruence length differences after exclusion of edited sites, the major data partitions remain significantly incongruent. The 14 families of Alismatales are all found to be monophyletic, but Acorus is found to be included in Alismatales rather than being the sister group to all other monocotyledons. The placement is strongly supported by the mitochondrial data, atp1 in particular, but it cannot be explained as an artifact caused by patterns of editing or by sampling of processed paralogues.     

Revision of the Cambrian Agnostina (Trilobita?) from Russia

Cambrian genera and species of Agnostina (?Trilobita) found in Russia are revised. Agnostid trilobite species are used as index taxa in chronostratigraphic subdivisions of the traditional Middle and Upper Cambrian in both regional and global stratigraphic scales. The correlation of the regional and international stratigraphic schemes largely depends on the state of knowledge of the regional agnostid fauna. Therefore, an up-to-date revision of this group based on the Russian collections taking into account their global diversity is very timely. For this study we reexamined the type collections of agnostids, including the holotypes of species described by Russian authors. This paper contains new photographic images of the holotypes housed in Russian museums. The compiled data offered solutions for some difficult taxonomic problems of the families Agnostidae, Ptychagnostidae, Peronopsidae, and some genera of Pseudagnostidae, Diplagnostidae. Apart from listing the diversity, this paper serves as the basis for studying the biogeography and evolution of this interesting arthropod group.     

PEG-ing down (and preventing?) the cause of pegloticase failure

Pegloticase is a powerful but underutilized weapon in the rheumatologist’s armamentarium. The drug’s immunogenicity leads to neutralizing antibody formation and rapid loss of efficacy in roughly one-half of all patients, which remains an impediment to broader use. New data, however, suggest that drug survival might improve with concomitant immunosuppressive agent (s), which merits further study. Efficacy appears to be unchanged when pegloticase is infused at 3-week (rather than 2-week) intervals. Stretching the time between infusions may also improve patient adherence and allow for earlier identification of transient responders.In the previous issue of Arthritis Research and Therapy, Hershfield and colleagues published a study putting forth a number of novel and potentially important findings regarding pegloticase, a powerful but underutilized weapon in the small but growing anti-hyperuricemic arsenal [1].The study examined the efficacy of pegloticase in a cohort of 30 patients with severe gout (93% tophaceous) utilizing an every 3-week infusion regimen, rather than the every 2-week schedule employed in previously published phase 3 trials. Despite the longer interval between infusions in the current study, the effectiveness of pegloticase is no worse (17/30 patients are persistent responders), and the pharmacokinetics of the drug suggest this should come as no surprise. The authors correctly note that a 3-week interval would be significantly more convenient for patients, and notably that such a regimen would also prove less costly to payors. Hershfield and colleagues’ dosing schedule would also help to identify transient responders earlier in the course of treatment – only four of 12 transient responders had uric acid >6 mg/dl 2 weeks after the first infusion (three of whom had previously been exposed to pegloticase in earlier phase 1 and 2 studies), whereas 11 of 12 transient responders had uric acid >6 mg/dl at 3 weeks (vs. only one of 17 persistent responders). For the reasons just elaborated upon, the paper demonstrates that dosing every 3 weeks may not just be as good as the current protocol, but may in some ways be superior.Hershfield and colleagues also upend the assumption that neutralizing antibodies to pegloticase are formed against uricase itself. Their paper clearly demonstrates that neutralizing antibodies develop in response to the polyethylene glycol (PEG) moiety of the drug, a finding that rebuffs a recent commentary which suggested antibodies to PEG are not pathogenic [2]. A septe and larger study (169 patients exposed to pegloticase) published in the previous issue Arthritis Research and Therapy by Lipsky and colleagues reaches the same conclusion regarding anti-pegloticase antibodies: anti-PEG antibodies are responsible for loss of efficacy rather than antibodies to the uricase enzyme itself, the latter of which rarely occur (positive more than once in only 11 subjects) and occur much later during the course of treatment, long after neutralizing anti-pegloticase antibodies have developed [3]. This larger study also demonstrates that an anti-pegloticase antibody titer >1:2,430 generally predicts loss of efficacy to the drug.Finally, and not least of all, Hershfield and colleagues’ smaller study included post-transplant patients (who were excluded from the phase 3 studies), a population particularly susceptible to developing gout. Of seven post-transplant subjects in the study, six proved to be persistent responders (86%) [1]. Although this is an admittedly small number of patients upon which to base any conclusion, it does raise the intriguing question of whether immunosuppression might lead to less of a mounted antibody response against pegloticase, and thus to more favorable outcomes. This is no small point; patients who are placed on pegloticase generally have severe, long-standing, and refractory gout, and should be given every chance to optimize their response to a potentially transformative therapy.While this signal is worth pursuing, some questions are immediately raised: how immunosuppressed must patients be to prevent neutralizing anti-PEG antibody formation, and with what should this be accomplished? Of the small subcohort in this trial, all patients were on cyclosporine or mycophenolate mofetil, and five of seven patients were on a combination of immunosuppressive agents. In choosing an immunosuppressant for the express purpose of preventing neutralizing antibodies, the risk of these drugs would very probably outweigh any proposed benefit (cyclosporine in particular might be the least desirable immunosuppressant for a patient with severe gout, because it both increases serum uric acid levels and decreases the glomerular filtration rate).If a trial was designed to investigate this line of query, a reasonable immunosuppressive agent of choice might be methotrexate. This drug has been shown to effectively prevent neutralizing antibodies from forming against monoclonal antibodies to anti-tumor necrosis factor [4,5]. Methotrexate’s inhibitory effect may not extend to preventing antibody formation against PEG, although methotrexate has also been shown to inhibit antibody formation against the polysaccharide 23-valent pneumococcal vaccine [6]. Methotrexate might also yield the unintended benefit of acting as an anti-inflammatory agent to suppress gouty attacks. However, because patients with severe gout have multiple comorbidities that place them at higher risk for medication side effects, methotrexate should not be considered in the clinical setting in the absence of data to support its use [7]. Nevertheless, methotrexate therapy is an avenue of inquiry that is clinically relevant and needs exploration to increase the likelihood that patients who begin this powerful drug can remain on it.     

Use of the γ-H2AX Assay to Investigate DNA Repair Dynamics Following Multiple Radiation Exposures

Radiation therapy is one of the most common and effective strategies used to treat cancer. The irradiation is usually performed with a fractionated scheme, where the dose required to kill tumour cells is given in several sessions, spaced by specific time intervals, to allow healthy tissue recovery. In this work, we examined the DNA repair dynamics of cells exposed to radiation delivered in fractions, by assessing the response of histone-2AX (H2AX) phosphorylation (γ-H2AX), a marker of DNA double strand breaks. γ-H2AX foci induction and disappearance were monitored following split dose irradiation experiments in which time interval between exposure and dose were varied. Experimental data have been coupled to an analytical theoretical model, in order to quantify key parameters involved in the foci induction process. Induction of γ-H2AX foci was found to be affected by the initial radiation exposure with a smaller number of foci induced by subsequent exposures. This was compared to chromatin relaxation and cell survival. The time needed for full recovery of γ-H2AX foci induction was quantified (12 hours) and the 1:1 relationship between radiation induced DNA double strand breaks and foci numbers was critically assessed in the multiple irradiation scenarios.     

The anthropology of ontology (religious science?)

Through engagement with a range of recent publications, this article offers a mini‐ethnography of wonder discourses in the anthropology of ontology, leading to a rethink of the concept of religion. It has sometimes been suggested that science and religion are antithetical orientations to the experience of wonder: whereas science seeks to banish wonder by replacing it with knowledge, religion remains open to wonder in the face of the unknowable. With this criterion of difference in view, this article identifies certain trends in the anthropology of ontology that appear to enjoin and pursue open‐ended wonder in ways that might be read as constituting anthropology as religious science. This coincidence of supposed opposites recommends, I conclude, a relational account of religion.     

Substitution Reaction on the Indole Ring of ( – )-Indolactam V,the Fundamental Structure of Teleocidins

We isolated a temperature-sensitive mutant which did not exhibit derepression of acid phosphatase and invertase at the restrictive temperature. The mutation was mapped in the cryl gene, the structural gene for the catalytic subunit of adenylate cyclase. On electron microscopic observation of the mutant cells at the restrictive temperature, it was observed that they accumulated carbohydrate particles in the cytoplasm. Isolated particles had a rosette-like structure of 40 to 60 nm in diameter, and were identified as glycogen. After 2 hr incubation at the restrictive temperature, glycogen particles occupied most of the cytoplasmic space and the vacuoles were observed to be fragmented.     

TRICHOMONIASIS—Clinical Trial of Metronidazole (Flagyl?)

Metronidazole was given in various dosage regimens to 97 patients having microscopically diagnosed trichomoniasis.At the first examination after treatment all 97, including 76 to whom metronidazole had been given orally only, were found by culture and wet smear to be free of trichomonads.Reexamination of the 65 patients followed up for periods ranging from two weeks to 14 months revealed reappearance of trichomonads in eight cases.Nineteen husbands were treated. No patient had a recurrence after treatment of the husband.No effect of metronidazole on pregnancy or on fetal development was seen. Side effects, noted in 19 cases (20 per cent), generally were mild and transient and in no case were severe enough to terminate therapy before cure was effected.     

NITROFURANTOIN (FURADANTIN?)—Use of Intravenous Forms in Resistant Surgical Infections; a Preliminary Report on 25 Patients

Twenty-five patients with severe and unusually resistant bacterial infections were treated with nitrofurantoin given intravenously.Twelve patients were classified as cured and seven as improved. In two cases there was no observable benefit. The other four patients, all moribund at the beginning of nitrofurantoin therapy, died. No significant toxic reaction to the drug was noted except for a tendency to metabolic acidosis in five patients in a state of shock after treatment with nitrofurantoin (Furadantin® intravenous solution). In no case was there evidence of impaired hematopoiesis.From this preliminary report it appeared that nitrofurantoin for intravenous use is justified in the treatment of gravely ill patients with surgical infections resistant to other antimicrobial drugs.     

Cytochemical demonstration of catalasepositive particles (peroxisomes?) in fibroblasts

Summary The connective tissue of the mucosa of the respiratory tract, of the gastric mucosa and of the mucosa of the tongue was investigated in mice. The tissue was fixed in glutaraldehyde and incubated in an alkaline DAB-medium to demonstrate the peroxidatic activity of catalase. In fibroblasts and fibrocytes, as well as in lymphoid cells, membrane bounded particles from 0.10 to 0.25 m in diameter were found, whose matrices were intensely stained by the histochemical reaction. The reaction is inhibited by the addition of 2×10^–2 M 3-amino-1,2,4-triazole. In connective tissue cells of specimens, which were not reacted to demonstrate catalase activity, these organelles show a granular matrix of moderate electron density. They lack a crystalline core. The possibility that these catalase-positive particles (CPs) represent peroxisomes is discussed.This investigation was kindly supported by a grant of Hochschuljubiläumsstiftung der Stadt Wien.     

Use of”Tcm for the Routine Assessment of Thyroid Function

⁹⁹Tc^m-pertechnetate is concentrated in the thyroid in the same way as iodide but it does not become organically bound. The uptake of ⁹⁹Tc^m is a measure of the thyroid trap, and this measurement is satisfactory as a routine test in the diagnosis of thyrotoxicosis. The reproducibility of the method is such that suppression tests can be carried out when necessary even when uptake is within the normal range of 0·4-3%. ⁹⁹Tc^m gives a low radiation dose to the thyroid and has certain other advantages over radioactive isotopes of iodine for early thyroid uptake measurements. It is particularly suitable when serial tests of thyroid function are required during treatment with an antithyroid drug.