A re-audit of the technical quality of undergraduate root canal treatment after the introduction of new technology and teaching practices.

AIM: To revaluate through re-audit the technical quality of undergraduate nonsurgical root canal treatment (RCTx) in a dental teaching hospital as a result of recommended changes to teaching practices. METHODOLOGY: The technical quality of undergraduate RCTx was evaluated radiographically after educational changes and the mandatory introduction of new technologies (nickel-titanium files, apex locators, greater taper gutta-percha points) in 182 root canals. Evaluation was based on four criteria: presence of voids, root canal filling termination (0-2 mm of radiographic apex), all roots filled and the prepared canal contained the original anatomy. Chi-squared analysis was used to determine statistically significant improvements in quality between the respective audits (P < 0.05). RESULTS: Twenty-three of the 40 canals in single-rooted teeth (57.5%) and 68 of the 129 (52.7%) canals in multirooted teeth analysed had an acceptable root filling. This compared with 48% of canals in single-rooted teeth and 38% of canals in multirooted teeth in the original audit. Specifically, the frequency of root canal voids and unsatisfactory apical root filling termination were reduced in multirooted teeth by 23% and 14% and in single-rooted teeth by 11% and 12%, respectively, compared with the original audit. When multirooted teeth were taken as one unit, 45.2% were considered to be acceptable, significantly better than the 18.8% multirooted teeth in the original audit (P = 0.042). Deviations from the canal anatomy on radiographic examination were rare findings in both audits. CONCLUSIONS: Changes to endodontic teaching practices significantly improved the technical standards of undergraduate root filling in multirooted teeth. The regular auditing of undergraduate teaching practice is necessary to inform current teaching, instigate change and improve standards.

Epidemiology & management of complex ankle fractures in the United Kingdom: A multicentre cohort study.

BACKGROUND: Patient factors are known to contribute to decision making and treatment of ankle fractures. The presence of poor baseline mobility, diabetes, neuropathy, alcoholism, cognitive impairment, inflammatory arthritis or polytrauma can result in a higher risk of failure or complications. Limited evidence is available on the optimum management for this challenging cohort of patients herein described as complex ankle fractures. This UK multicentre study assessed and evaluated the epidemiology of ankle fractures complicated by significant comorbidity and patient factors and use of specialist surgical techniques such as hindfoot nails (HFN) / tibiotalarcalcaneal (TCC) nails and enhanced open reduction and internal fixation (ORIF). PATIENTS AND METHODS: A UK-wide collaborative study was performed of adult distal AO43/AO44 fractures, associated with 1 or more of the patient factors listed above. Primary outcomes included patient demographics, comorbidities, surgical technique and implants. Secondary outcomes included surgical complications and early post-operative weight bearing instructions. Statistical analysis was performed to assess patient and fracture characteristics on outcome, including propensity matching. RESULTS: One-thousand three hundred and sixty patients, with at least one of the above complex factors, from 56 centres were included with a mean age of 53.1 years. 90.2% (1227) patients underwent primary fixation which included 78.9% (1073) standard open reduction internal fixations (ORIF), 3.25% (43) extended ORIF and 8.1% (111) primary HFN / TCC. Overall wound complications and thromboembolic events were similar in the hindfoot nail group and the ORIF group (11.7% vs 10.7%). Wound complications were greater in diabetic patients versus non-diabetic patients independent of fixation method (15.8% vs 9.0%). After propensity matching for comorbidities and fracture type, overall complications were lower in the hindfoot nail (11.8%) and extended ORIF groups (16.7%), than the standard ORIF group (18.6%). CONCLUSION: Only a minority of complex ankle fractures are treated with specialised techniques (HFN/TCC or extended ORIF). Though more commonly used in older and frail patients their perceived advantages are often negated by a reluctance to bear weight early. These techniques demonstrated a better complication profile to standard ORIF but hindfoot nail with joint preparation for fusion was associated with more complications than hindfoot nail for fixation. LEVEL OF EVIDENCE: III.

Follow-up arrangements in head and neck cancer clinics during the COVID-19 pandemic: results from two tertiary UK head and neck cancer centres.

INTRODUCTION: The aim of this paper is to report the pattern of follow-up that occurred for a cohort of head and neck cancer (HNC) patients across two large centres in the UK (Aintree and Leeds), as a consequence of the COVID-19 pandemic. METHODS: Patients had been treated for HNC with curative intent between April 2017 and October 2019 by 14 oral and maxillofacial (OMFS) and ear nose and throat (ENT) oncology surgeons in the Patient Concerns Inventory intervention trial. In October 2020, hospital records were reviewed, and information collected on the timing and mode (face-to-face/telephone/video) of follow-up consultations. In addition, recurrence, second primary tumours and deaths were recorded. RESULTS: At the start of 'lockdown', 212 members of the cohort were known to be alive. During the post-lockdown period (follow-up appointment data comprised 5 months in Aintree and 7 months in Leeds) 7 died and 13 were identified as palliative/recurrence/new primary/metastases ('new event'). In Aintree, the first ENT/OMFS consultations after lockdown were 51 (67%) telephone and 25 (33%) face-to-face appointments. In Leeds, 46 (78%) consultations were by telephone and 13 (22%) were face-to-face. The second ENT/OMFS consultations post lockdown included 11 (44%) telephone and 14 (56%) face-to-face in Aintree, and 21 (75%) telephone and 7 (25%) face-to-face in Leeds. CONCLUSIONS: These data suggest that clinicians favoured remote consultations. Variations in practice were observed but reached a point of a 'hybrid follow-up approach' that included both face-to-face and remote consultations. With the emergence of telemedicine, clinicians may consider a follow-up model tailored to risk stratification. The development of the mode of such a consultation model needs further evaluation.

A general swimming response in exhausted obligate swimming fish.

Marine organisms normally swim at elevated speeds relative to cruising speeds only during strenuous activity, such as predation or escape. We measured swimming speeds of 29 ram ventilating sharks from 10 species and of three Atlantic bluefin tunas immediately after exhaustive exercise (fighting a capture by hook-and-line) and unexpectedly found all individuals exhibited a uniform mechanical response, with swimming speed initially two times higher than the cruising speeds reached approximately 6 h later. We hypothesized that elevated swimming behaviour is a means to increase energetic demand and drive the removal of lactate accumulated during capture via oxidation. To explore this hypothesis, we estimated the mechanical work that must have been spent by an animal to elevate its swim speed and then showed that the amount of lactate that could have been oxidized to fuel it comprises a significant portion of the amount of lactate normally observed in fishes after exhaustive exercise. An estimate for the full energetic cost of the catch-and-release event ensued.

Nuclear matrix. Isolation and characterization of a framework structure from rat liver nuclei.

A nuclear framework structure termed the nuclear matrix has been isolated and characterized. This matrix forms the major residual structure of isolated nuclei and consists largely of protein with smaller amounts of RNA, DNA, carbohydrate, and phospholipid. The nuclear matrix can be further resolved by combined treatment with DNase and RNase. The remaining nuclear protein structure, after extraction of 90 percent of the nuclear protein, 99.9 percent of the DNA, and 98 percent of the RNA and phospholipid, is termed the nuclear protein matrix. Electron microscopy of this final nuclear protein matrix reveals an interior framework structure composed of residual nucleolar structures associated with a granular and fibrous internal matrix structure. The internal matrix framework is derived from the interchromatinic structures of the nucleus, and is connected to a surrounding residual nuclear envelope layer containing residual nuclear pore complex structures. Sodium dodecyl sulfate-acrylamide gel electrophoresis of the nuclear matrix proteins demonstrates three major polypeptide fractions, P-1, P-2, and P-3, with average molecular weights of approximately 69,000, 66,000 and 62,000, as well as several minor polypeptides which migrate at approximately 50,000 and at higher molecular weights (>100,000). Polypeptides with molecular weights identical to those of P-1, P-2 and P-3 are also components of isolated nuclear envelopes and nucleoli, whereas isolated chromatin contains no detectable matrix polypeptides. This suggests that the major matrix polypeptides are localized in specific structural regions of the nucleus, i.e., nuclear envelope, nucleoli, and interchromatinic structures. The presence of cytochrome oxidase activity in the isolated nuclear matrix indicates that at least some integral proteins of the nuclear membrane are associated with the matrix.

Cyclosporine A, an in vitro calmodulin antagonist, induces nuclear lobulations in human T cell lymphocytes and monocytes.

Cyclosporine A is a noncytotoxic, natural, 11 amino acid cyclic peptide used clinically as an immunosuppressant to prevent organ rejection after transplantation. Cyclosporine A is an in vitro calmodulin antagonist. At the low concentrations required to inhibit calmodulin-dependent phosphodiesterase in vitro, cyclosporine A causes a dramatic alteration in the nuclear morphology of 23% of human peripheral blood mononuclear leukocytes in vitro without loss of viability. The shape of the nucleus changes from ovoid to a distinctive, radially splayed lobulated structure. The changes occur in a dose-dependent manner in 60 min at 37 degrees C. Specific monoclonal antibodies to human leukocytes identify the cells susceptible to nuclear lobulation by cyclosporine A as OKT4 antigen-positive T cell lymphocytes and monocytes. The lobulated nuclei are 2N as determined by flow cytometric measurement of ethidium bromide fluorescence of DNA. The cyclosporine A-induced lobulation of T cell nuclei requires both physiologic temperature and metabolic energy. Although structurally different than cyclosporine A, the calmodulin antagonists R24571 and W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide] also produce T cell nuclear lobulations that are indistinguishable from the nuclear lobulations caused by cyclosporine A. These data indicate that nonmitotic structural elements that govern normal nuclear morphology in a subset of mononuclear leukocytes appear to require a calmodulin-mediated process. Cyclosporine A may be a useful noncytotoxic inhibitor of calmodulin-dependent systems that influence nuclear structure and function.

Structural alteration in isolated rat liver nuclei after removal of template restriction by polyanions.

Specific polyanions release DNA template restrictions for DNA synthesis in isolated rat liver nuclei. The degree to which DNA synthesis is enhanced can be correlated with a spectrum of changes in nuclear structure Each polyanion which is effective in the release of template restriction produces a characteristic alteration in nuclear ultrastructure. Polyanions which have no effect on DNA synthesis do not appear to cause any change in nuclear organization or ultrastructure. Parallel measurements of nuclear DNA release and nuclear volume changes also indicate that template-activating polyanions cause remarkable changes in the structural organization of the treated nuclei. These results indicate that DNA template activation involves direct interactions between polyanions and nuclear constituents and suggest the possibility that naturally occurring polyanions might have a role in the control of gene activity

Nuclear protein matrix: association with newly synthesized DNA.

The residual structural framework of the cell nucleus termed the nuclear protein matrix, is associated with newly synthesized DNA in regenerating rat liver. One minute after rats are injected with [3-H] thymidine, more than 90 percent of the total tritium in nuclear DNA is associated with the matrix DNA although this DNA comprises only 25 percent of the total nuclear DNA. In contrast, the bulk DNA, 75 percent of total nuclear DNA, contains less than 8 percent of the total labeled DNA. The percentage of total labeled DNA associated with the bulk DNA increases for 30 minutes after injection and decreases correspondingly in the matrix DNA.

Measuring the ionisation fraction in a jet from a massive protostar.

It is important to determine if massive stars form via disc accretion, like their low-mass counterparts. Theory and observation indicate that protostellar jets are a natural consequence of accretion discs and are likely to be crucial for removing angular momentum during the collapse. However, massive protostars are typically rarer, more distant and more dust enshrouded, making observational studies of their jets more challenging. A fundamental question is whether the degree of ionisation in jets is similar across the mass spectrum. Here we determine an ionisation fraction of ~5-12% in the jet from the massive protostar G35.20-0.74N, based on spatially coincident infrared and radio emission. This is similar to the values found in jets from lower-mass young stars, implying a unified mechanism of shock ionisation applies in jets across most of the protostellar mass spectrum, up to at least ~10 solar masses.

Publisher Correction: Measuring the ionisation fraction in a jet from a massive protostar.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Comparison of spontaneous and experimentally induced canine prostatic hyperplasia.

Spontaneous prostatic hyperplasia in the beagle appears to progress with age from a glandular to a cystic histological appearance. Prostatic hyperplasia can be induced in young beagles with intact testes by treatment for 4 mo with either dihydrotestosterone or 5 alpha-androstane-3 alpha, 17 beta-diol, alone, or with either of these steroids in combination with 17 beta-estradiol. In contrast, the induction of prostatic hyperplasia in young castrated beagles, in which the gland had been allowed to involute for 1 mo, requires the administration of both 17 beta-estradiol and either 5 alpha-androstane-3 alpha, 17 beta-diol or dihydrotestosterone. Testosterone and 17 beta-estradiol, either singly or in combination, did not produce the hyperplastic condition in intact or castrated beagles. The experimentally induced prostatic hyperplasia is identical in pathology to the glandular hyperplasia that occurs naturally in the aging dog with intact testes. However, cystic hyperplasia was not produced by any of the treatments tested in young animals.

Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate.

This paper is a cross-sectional study of spontaneous benign prostatic hyperplasia (BPH) in a single canine species. The effects of aging and hormonal changes on the growth, histology, and glandular secretory function of the canine prostate were studied in 42 male beagles ranging in age from 8 mo to 9 yr. The beagle prostate enlarges for at least 6 yr, whether normal or hyperplastic. In contrast, prostatic secretory function, determined by ejaculate volume and total ejaculate protein, declines markedly after 4 yr of age. These reciprocal growth and functional changes in the prostate are closely associated with a progressive increase in the incidence of BPH, which is already apparent in some dogs by age two. With age there is a modest decrease in serum androgen levels with no apparent change in serum 17 beta-estradiol levels. This suggests that the growth and functional changes that are associated with the development of BPH and are initiated very early in life reflect an altered sensitivity of the prostate to serum androgens or a response to the relative decrease in the serum androgen to estrogen ratio.

Preneoplastic alterations in nuclear morphology that accompany loss of tumor suppressor phenotype.

Alterations of nuclear shape are frequently observed in tumor cells, but the genes controlling these changes and the stage in the neoplastic process at which they occur are unknown. We have studied nuclear shape changes in chemically immortalized, nontumorigenic Syrian hamster embryo cell clones that had either retained (supB+) or lost (supB-) the ability to suppress the tumorigenic phenotype when they were hybridized with a tumor cell line (BP6T). Quantitative morphometric analysis of the nuclei of cells from each of two pairs of supB+/supB- variants indicated that the nuclei of supB- cells were significantly more out of round than those of their corresponding supB+ clones. These data indicate that modification of nuclear structure may represent an early, preneoplastic event in multistep chemical carcinogenesis and that loss of a tumor suppressor gene function may regulate alterations in nuclear morphology.

Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma.

The Dunning R-3327-H rat prostatic adenocarcinoma is a well-differentiated, slow-growing, serially transplantable tumor of spontaneous origin. When intact male rats bearing such an exponentially growing H-tumor s.c. are castrated, tumor growth abruptly stops, demonstrating the initial androgen sensitivity of this tumor. Eventually, however, after an extended period, the tumor invariably relapses and once again appears to grow exponentially. At the time of relapse, the tumor is no longer androgen sensitive but has irreversibly progressed to a completely insensitive state. The mechanism responsible for this irreversible progression has been demonstrated by fluctuation analysis not to be due to environmentally induced adaptation of initially androgen-dependent H-tumor cells to a new androgen-independent state. Instead, the progression is due to the basic heterogeneity of the original H-tumor (i.e., it is composed of a mixture of preexisting clones of both androgen-dependent and androgen-independent tumor cells). Following castration, only the preexisting clones of androgen-independent tumor cells are able to continue exponential growth; the androgen-dependent tumor cells stop proliferating and die. Thus, androgen ablation creates a host environment in which the androgen-independent tumor cells have a highly selective growth advantage over the androgen-dependent cells. Eventually, with time, this selective growth advantage results in a tumor which is completely composed of androgen-independent cells. It is the continuous proliferative growth of these androgen-independent tumor cells which leads to the relapse phenomenon.

Organ site specificity for cancer in chromosomal instability disorders.

DNA rearrangement rather than point mutation is an emerging hypothesis for human carcinogenesis. Although there is no direct evidence for this hypothesis, indirect evidence is provided by cancer cytogenetics and genetics. It has been suggested that patients with Bloom's syndrome, a disorder of spontaneous chromosomal rearrangement, develop the common fatal internal cancers and thus that genetic rearrangements, rather than chemical mutagens, cause most internal human cancers. To test this observation, we have derived age- and sex-adjusted cancer incidence rate ratios for specific organ sites in patients with three chromosomal instability disorders (Bloom's syndrome, xeroderma pigmentosum, and dyskeratosis congenita) and have found that the increased incidence of cancer in all three disorders is limited to specific and often uncommon organ sites. We conclude that chromosomal instability disorders do not predispose patients to the common fatal internal cancers. Although DNA rearrangement remains a promising concept in human carcinogenesis, the organ site specificity of cancers associated with Bloom's syndrome, xeroderma pigmentosum, and dyskeratosis congenita cannot be used as evidence to implicate this mechanism.

Models for development of nonreceptor methods for distinguishing androgen-sensitive and -insensitive prostatic tumors.

From the original Dunning R-3327 rat prostatic adenocarcinoma, several distinct sublines have been obtained. These sublines include a well-differentiated, slow-growing, androgen-sensitive tumor (R-3327-H); a well-differentiated, slow-growing, androgen-insensitive tumor (R-3327-HI); and a fast-growing, androgen-insensitive, anaplastic tumor (R-3327-AT). These three sublines were compared in order to develop new model methods for the prediction of the androgen sensitivity and the degree of differentiation of prostatic adenocarcinomas. The R-3327-AT was very distinct in all parameters examined except the tissue protein electrophoretic patterns which contained a uniform pattern in all tumors. The significant differences between R-3327-H and -HI sublines were (a) the inability of testosterone to stimulate DNA synthesis in the R-3327-HI tumor and (b) the difference in the enzymatic profiles of these sublines. The specific activity of three enzymes (3 alpha-hydroxysteroid dehydrogenase, leucine aminopeptidase, lactic dehydrogenase) increased while the activity of another three enzymes (6 alpha,7 alpha-hydroxylase, 5 alpha-reductase, alkaline phosphatase) decreased in the sublines which are androgen insensitive and less differentiated. An arbitrary index was constructed, based upon these enzyme differences, which clearly discriminates the degree of androgen sensitivity and differentiation of these R-3327 rat prostatic adenocarcinomas.

Chaotic oscillations in cultured cells: rat prostate cancer.

Normal prostate epithelial cells exhibit uniformity of structure, function, and DNA content. This uniformity is dramatically perturbed in cancer with the development of variance associated with tumor cell heterogeneity. The development of this kind of diversity is paralleled in models of chaotic oscillators that produce multiple pseudosteady states. We have tested prostatic cancer cells in culture for the presence of chaos by comparing the micromotion of two related rat prostate cancer cell lines that exhibited large differences in motility and metastatic potential. In these extremes of cancer cell types, our data suggest that the three criteria which characterize a chaotic oscillation are fulfilled by their cellular micromotions: (a) absence of defined regularity in the time series as evidenced using Fourier analysis and visual inspection; (b) determinism as evidenced by attractor reconstruction; and (c) sensitive dependence on initial conditions as evidenced by a positive Lyapunov exponent. Cellular motion was studied by using an electronic cell impedance sensor which records, in real time, the fluctuations in the resistive and capacitive properties of cells cultured on recording electrodes. Our data and a preliminary screen of other cell types support a model of established cell lines in culture as chaotic oscillators.

Synergistic enhancement by tumor necrosis factor of in vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II.

Recombinant human tumor necrosis factor (rHTNF) alone had no effect on L929 tumor cells at 100 units/ml for 20 h of continuous exposure. However, under the same conditions, rHTNF markedly enhanced the cytotoxicity of Adriamycin, actinomycin D, 4'-(9-acridinylamino)-methanesulfon-m-anisidide, teniposide (VM 26), and etoposide (VP 16), all targeted at DNA topoisomerase II. The rHTNF had a minimally enhancing effect on the cytotoxicity of bleomycin, hydroxyurea, and 1-beta-D-arabinofuranosylcytosine and no effect on the cytotoxicity of cis-platinum, mitomycin C, vincristine, and vinblastine, all chemotherapeutic drugs with dose-related cytotoxic effects on L929 cells but mechanisms of action which do not appear to involve topoisomerase II. Treatment with rHTNF first and then topoisomerase-targeted drugs yielded no enhanced cytotoxicity, whereas pretreatment with drug followed by rHTNF yielded marked enhancement of cytotoxicity. Topoisomerases have previously been implicated in cell kill phenomena following treatment with certain chemotherapeutic agents [K.M. Tewey, et al., Science (Wash. DC), 226:466-468, 1984]. The data suggest that the lethality to the cell from topoisomerase-targeted drug treatment is increased by rHTNF in vitro. We suggest that rHTNF may be a useful adjuvant to this class of drugs which has well-known antitumor activity.