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Abstract Background The objective of this study was to determine the sedative load and use of sedative and psychotropic medications among older people with dementia living in (residential) care homes. Methods Medication data were collected at baseline and at two further time-points for eligible residents of six care homes participating in the EVIDEM-End Of Life (EOL) study for whom medication administration records were available. Regular medications were classified using the Anatomical Therapeutic Chemical classification system and individual sedative loads were calculated using a previously published model. Results At baseline, medication administration records were reviewed for 115 residents; medication records were reviewed for 112 and 105 residents at time-points 2 and 3 respectively. Approximately one-third of residents were not taking any medications with sedative properties at each time-point, while a significant proportion of residents had a low sedative load score of 1 or 2 (54.8%, 59.0% and 57.1% at baseline and time-points 2 and 3 respectively). More than 10% of residents had a high sedative load score (≥ 3) at baseline (12.2%), and this increased to 14.3% at time-points 2 and 3. Approximately two-thirds of residents (66.9%) regularly used one or more psychotropic medication(s). Antidepressants, predominantly selective serotonin re-uptake inhibitors (SSRIs), were most frequently used, while antipsychotics, hypnotics and anxiolytics were less routinely administered. The prevalence of antipsychotic use among residents was 19.0%, lower than has been previously reported for nursing home residents. Throughout the duration of the study, administration of medications recognised as having prominent sedative adverse effects and/or containing sedative components outweighed the regular use of primary sedatives. Conclusions Sedative load scores were similar throughout the study period for residents with dementia in each of the care homes. Scores were lower than previously reported in studies conducted in long-term care wards which have on-site clinical support. Nevertheless, strategies to optimise drug therapy for care home residents with dementia which rely on clinicians external to the care home for support and medication review are required.

Individuals with social anxiety are sensitive to social hierarchies and tend to compare themselves unfavorably with others, perceiving themselves as inferior or lower in social rank. The current study explores patterns of change in these negative perceptions, and their associated emotional outcomes, in an online social context. Undergraduate students (N = 291) browsed the profiles of eight Instagram influencers and completed a measure of social comparison after viewing each profile, yielding multiple ratings of their own perceived social rank. Participants completed measures of affect and state self-esteem before and after the profile browsing task. Higher social anxiety predicted lower, and greater declines in, social rank self-perceptions during browsing. Higher social anxiety also predicted greater decreases in positive affect, increases in negative affect, and decreases in state self-esteem from the beginning to the end of the browsing task. Low baseline rank perceptions contributed to change in all three emotional variables. Decreases in rank perceptions contributed further to decreases in positive affect and appearance-related self-esteem. This study elaborates on cognitive-evolutionary theory, suggesting that the inferiority self-perceptions of socially anxious individuals translate to online social contexts, may be strengthened with increased exposure to such contexts, and may have a detrimental emotional impact. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Introduction: Adverse childhood experiences contribute to both short- and long-term health issues and negative health behaviors that affect the individual as well as families and communities. Exposure to ≥4 of the 11 adverse childhood experiences (high adverse childhood experiences) compounds the problems in later life. This study assesses the associations among tobacco use, adverse childhood experiences, mental health, and community health., Methods: This study was a secondary data analysis utilizing a large 2019 data set from a Community Health Needs Assessment in Florida (N=14,056). Investigators utilized inferential statistics to determine adverse childhood experiences as a predictor of tobacco use (vaping and cigarette use). In addition, they examined whether a shorter, 2-question adverse childhood experience scale was equivalent to the full scale when predicting tobacco use., Results: The results indicated that parental divorce was the most common household stressor, followed by mental illness and alcoholism. High adverse childhood experiences were found to be most prominent in marginalized individuals. For those individuals experiencing ≥4 adverse childhood experiences, parental divorce continued to rank high, followed by mental illness. Household stressors included emotional and physical abuse as the most prevalent in the ≥4 adverse childhood experience group. High adverse childhood experiences were associated with current cigarette smoking (AOR=1.56) after controlling for individual mental health and social/community health variables. High adverse childhood experiences were also associated with E-cigarette use (AOR=1.81) but not dual cigarette/E-cigarette use. Social and community health was inversely associated with tobacco use. A 2-item adverse childhood experiences measure was sufficient in identifying tobacco users., Conclusions: Including adverse childhood experiences in community needs assessments provides important information for tobacco control efforts and prevention of chronic disease., (Copyright © 2021 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Humans perceive and treat self-resembling others in ways that suggest that self-resemblance is a cue of kinship. However, we know little about how individuals respond to treatment by self-resembling others. Here we approach this problem by connecting facial self-resemblance to social rejection. Given that individuals should expect to cooperate with kin, we hypothesized that (1) social inclusion by perceived kin should elicit lesser feelings of rejection and (2) social exclusion by perceived kin should elicit greater feelings of rejection relative to inclusion or exclusion, respectively, by nonkin. To test these hypotheses, we recruited 90 participants to play two games of Cyberball, a virtual ball-tossing game, with separate pairs of ostensible partners. In one game, the ostensible partners were programed to fully include the participants in group play and, in the other game, they were programed to exclude the participants after a few rounds; the order of inclusion and exclusion was counterbalanced across participants. Partner faces were digitally manipulated to be either self- or nonself-resembling, and these conditions were also counterbalanced. Rejection feelings differed significantly as a function of self-resemblance between the inclusion and exclusion conditions, but only for participants who experienced inclusion first. Moreover, for these individuals, inclusion by self-resembling partners led to significantly lesser feelings of rejection than did inclusion by nonself-resembling partners. To explain this effect, we explore potential mechanisms of kin recognition and social rejection. Although nuanced, our results suggest that perceptions of kinship can moderate psychological responses to the actions of others.

Bone mineral density (BMD) is a complex trait with a strong genetic component and an important predictor of osteoporotic fracture risk. Here we report the use of a cross-species strategy to identify genes that regulate BMD, proceeding from quantitative trait mapping in mice to association mapping of the syntenic region in the human genome. We identified a quantitative trait locus (QTL) on the mouse X-chromosome for post-maturity change in spine BMD in a cross of SAMP6 and AKR/J mice and conducted association mapping of the syntenic region on human chromosome Xp22. We studied 76 single nucleotide polymorphisms (SNP) from the human region in two sets of DNA pools prepared from individuals with lumbar spine-BMD (LS-BMD) values falling into the top and bottom 13th percentiles of a population-based study of 3100 post-menopausal women. This procedure identified a region of significant association for two adjacent SNP (rs234494 and rs234495) within the Xp22 locus (P<0.001). Individual genotyping for rs234494 in the BMD pools confirmed the presence of an association for alleles (P=0.018) and genotypes (P=0.008). Analysis of rs234494 and rs234495 in 1053 women derived from the same population who were not selected for BMD values showed an association with LS-BMD for rs234495 (P=0.01) and for haplotypes defined by both SNP (P=0.002). Our study illustrates that interspecies synteny can be used to identify and refine QTL for complex traits and represents the first example where a human QTL for BMD regulation has been mapped using this approach.

Three mutant mice with pigmentation phenotypes were recovered from a genomewide random mouse chemical mutagenesis study. White toes (Whto; MGI:1861986), Belly spot and white toes (Bswt; MGI:2152776) and Dark footpads 2 (Dfp2; MGI:1861991) were identified following visual inspection of progeny from a male exposed to the point mutagen ethylnitrosourea (ENU). In order to rapidly localize the causative mutations, genome-wide linkage scans were performed on pooled DNA samples from backcross animals for each mutant line. Whto was mapped to proximal mouse chromosome (Mmu) 7 between Cen (the centromere) and D7Mit112 (8.0 cM from the centromere), Bswt was mapped to centric Mmul between D1Mit214 (32.1 cM) and D1Mit480 (32.8 cM) and Dfp2 was mapped to proximalMmu4 between Cen and D4Mit18 (5.2 cM). Whto, Bswt and Dfp2 may provide novel starting points in furthering the elucidation of genetic and biochemical pathways relevant to pigmentation and associated biological processes.

The human RAD52 protein, which exhibits a heptameric ring structure, has been shown to bind resected double strand breaks (DSBs), consistent with an early role in meiotic recombination and DSB repair. In this work, we show that RAD52 binds single-stranded and tailed duplex DNA molecules via precise interactions with the terminal base. When probed with hydroxyl radicals, ssDNA-RAD52 complexes exhibit a four-nucleotide repeat hypersensitivity pattern. This unique pattern is due to the interaction of RAD52 with either a 5' or a 3' terminus of the ssDNA, is sequence independent and is phased precisely from the terminal nucleotide. Hypersensitivity is observed over approximately 36 nucleotides, consistent with the length of DNA that is protected by RAD52 in nuclease protection assays. We propose that RAD52 binds DNA breaks via specific interactions with the terminal base, leading to the formation of a precisely organized ssDNA-RAD52 complex in which the DNA lies on an exposed surface of the protein. This protein-DNA arrangement may facilitate the DNA-DNA interactions necessary for RAD52-mediated annealing of complementary DNA strands.

Mouse mutants have a key role in discerning mammalian gene function and modelling human disease; however, at present mutants exist for only 1-2% of all mouse genes. In order to address this phenotype gap, we have embarked on a genome-wide, phenotype-driven, large-scale N-ethyl-N--nitrosourea (ENU) mutagenesis screen for dominant mutations of clinical and pharmacological interest in the mouse. Here we describe the identification of two similar neurological phenotypes and determination of the underlying mutations using a novel rapid mapping strategy incorporating speed back-crosses and high throughput genotyping. Two mutant mice were identified with marked resting tremor and further characterized using the SHIRPA behavioural and functional assessment protocol. Back-cross animals were generated using in vitro fertilization and genome scans performed utilizing DNA pools derived from multiple mutant mice. Both mutants were mapped to a region on chromosome 11 containing the peripheral myelin protein 22 gene (Pmp22). Sequence analysis revealed novel point mutations in Pmp22 in both lines. The first mutation, H12R, alters the same amino acid as in the severe human peripheral neuropathy Dejerine Sottas syndrome and Y153TER in the other mutant truncates the Pmp22 protein by seven amino acids. Histological analysis of both lines revealed hypo-myelination of peripheral nerves. This is the first report of the generation of a clinically relevant neurological mutant and its rapid genetic characterization from a large-scale mutagenesis screen for dominant phenotypes in the mouse, and validates the use of large-scale screens to generate desired clinical phenotypes in mice.

A vertical cavity surface-emitting laser was studied for gas-sensing applications. Properties of the 962-nm laser that were measured include side-mode suppression, wavelength tuning with temperature and current, power versus injection current, and the amplitude noise spectrum. With wavelength modulation spectroscopy, a rms noise level of 2 x 10(-4) absorbance units was achieved. The large current tuning range (25 cm(-1)) and smaller amplitude modulation (11%/cm(-1)) of the vertical cavity laser compare favorably with Fabry-Perot and distributed feedback diode lasers for spectroscopic gas sensing, especially at atmospheric pressure.

Five patients out of a total of 183 treated with radical radiotherapy for carcinoma of cervix at The Royal Marsden Hospital from 1991 to 1994 inclusive have developed severe pelvic fractures. Two patients had rheumatoid arthritis, one of whom died as a result of the radiation induced damage. This patient developed radiological evidence of radionecrosis within 1 month of completing radiotherapy. There are very few reports in the literature of such a rapid onset. We suggest that the presence of a connective tissue disorder in a patient with other risk factors such as steroid use, old age and osteopenia should alert the clinician to the risk of radionecrosis following radical irradiation.

During genetic recombination a heteroduplex joint is formed between two homologous DNA molecules. The heteroduplex joint plays an important role in recombination since it accommodates sequence heterogeneities (mismatches, insertions or deletions) that lead to genetic variation. Two Escherichia coli proteins, RuvA and RuvB, promote the formation of heteroduplex DNA by catalysing the branch migration of crossovers, or Holliday junctions, which link recombining chromosomes. We show that RuvA and RuvB can promote branch migration through 1800 bp of heterologous DNA, in a reaction facilitated by the presence of E.coli single-stranded DNA binding (SSB) protein. Reaction intermediates, containing unpaired heteroduplex regions bound by SSB, were directly visualized by electron microscopy. In the absence of SSB, or when SSB was replaced by a single-strand binding protein from bacteriophage T4 (gene 32 protein), only limited heterologous branch migration was observed. These results show that the RuvAB proteins, which are induced as part of the SOS response to DNA damage, allow genetic recombination and the recombinational repair of DNA to occur in the presence of extensive lengths of heterology.

This retrospective study of 56 patients with carcinoma of the uterine cervix treated with radical radiotherapy at the Royal Marsden Hospital, London, examined whether simple measurements of maximum tumour dimension from computerized axial tomographic (CT) scans have any prognostic significance. Our results indicate that tumour depth (i.e. maximum antero-posterior dimension) of 4 cm or more is associated with a statistically significant increased relative risk of death of 2.4 (95% CI 1.1-5.5; p = 0.045), as compared with tumours with a depth of less than 4 cm. In addition, there was a clear correlation between tumour depth and lymph node involvement (r = 0.36; p < 0.01), and tumour depth and width (r = 0.70; p < 0.005). We suggest that a measurement of maximum tumour depth from the staging CT scan in these patients provides valuable additional information about likely occult lymph node metastases and prognosis, over and above that suggested by the FIGO staging system alone.

The RuvA and RuvB proteins of Escherichia coli, which are induced in response to DNA damage, are important in the formation of heteroduplex DNA during genetic recombination and related recombinational repair processes. In vitro studies show that RuvA binds Holiday junctions and acts as a specificity factor that targets the RuvB ATPase, a hexameric ring protein, to the junction. Together, RuvA and RuvB promote branch migration, an ATP-dependent reaction that increases the length of the heteroduplex DNA. Electron microscopic visualization of RuvAB now provides a new insight into the mechanism of this process. We observe the formation of a tripartite protein complex in which RuvA binds the crossover and is sandwiched between two hexameric rings of RuvB. The Holliday junction within this complex adopts a square-planar structure. We propose a molecular model for branch migration, a unique feature of which is the role played by the two oppositely oriented RuvB ring motors.

In this retrospective study tumour volume was calculated by two different methods from the staging computed tomographic scans obtained in 1987 of 20 patients with carcinoma of the cervix. All patients underwent treatment by radical radiotherapy and the survival figures at 5 years were analysed. The aim was to identify the nature of the relationship between the true tumour volume and tumour volume obtained by measuring the maximum dimensions in each plane ("cuboid" volume). Significant correlation between the product of height x width x depth and true tumour volume was demonstrated (r = 0.983). A multivariate analysis of survival demonstrated a significantly increased relative risk for positive nodes (p < 0.03) and tumour depth > 3.8 cm (p < 0.04) or tumour width > 5.0 cm (p < 0.03). A significant difference (p < 0.02) between the median tumour volumes for early and late stage disease was present irrespective of the method used to calculate tumour volume. This study demonstrates that cuboid tumour volume can be a good reflection of the true volume; in addition, positive nodes, tumour depth and tumour width are significant determinants of survival.

The ruvA and ruvB genes of Escherichia coli encode a novel DNA helicase that interacts with Holliday junctions and promotes branch migration. In this work, we have investigated the protein-DNA complexes formed between RuvA, RuvB and Holliday junctions. As shown previously, RuvA protein binds a synthetic Holliday junction in vitro, to form a specific protein-DNA complex that can be detected by a band-shift assay. We now show that the combined presence of RuvA and RuvB results in a super-shift of this complex indicative of the formation of a RuvAB-Holliday junction complex. In the absence of RuvA, the RuvB protein fails to bind Holliday junctions. The RuvAB-Holliday junction complex was detected by the band-shift assay only under conditions that favoured its stability, e.g. complex formation in the presence of a nucleoside triphosphate that can not be hydrolysed by RuvB (adenosine 5'-[gamma-thio]triphosphate). In contrast, nucleoside triphosphates that can be hydrolysed (ATP, dATP, dCTP or TTP), lead to RuvAB-mediated branch migration of the junction. These results indicate that the formation of a (RuvAB-ATP)-Holliday junction complex represents the first step in the process of branch migration, and that branch migration is dependent upon ATP hydrolysis. In addition, we show that Holliday junction DNA stimulates the ATPase activity of RuvAB to a greater extent than either single-stranded or linear duplex DNA.

This study was undertaken to compare the diagnostic accuracy of mammography in patients under 50 years with that of patients over 50, and with further subdivisions under 35 and 65 years. A retrospective review of the mammograms of 297 sequential patients undergoing mammography prior to surgical breast biopsy at the Breast Unit, Royal Marsden Hospital, London from 1988-1991 was performed. The films were reviewed blind by a single radiologist and correlated with histological findings at biopsy. The sensitivity and specificity of mammography compared with histology in four age-groups was assessed. There were 144 patients in the under-50 age group (< 35 years = 20, 35-49 years = 124), and 153 patients aged over 50 (50-64 years = 96, > 65 years = 57). Of all patients with histologically malignant biopsies 79% of the under-50s and 76% of the over-50s were diagnosed mammographically. Sensitivity of mammography was therefore 3% greater in the under-50 age-group (95% confidence interval (CI): +16% to -10%). Of patients who had benign biopsies, 76% of the under-50s and 75% of the over-50s were correctly diagnosed by mammography. Mammographic specificity was therefore 1% greater in the over-50 age-group (95% confidence interval: +15% to -14%). Accuracy of mammography was also comparable in the four subdivided age-groups. The results suggest that in patients requiring breast biopsy, contemporary mammography is similar in accuracy in the younger patient when compared to the older post-menopausal patient.

The RuvA, RuvB, and RuvC proteins of Escherichia coli are required for the recombinational repair of ultraviolet light- or chemical-induced DNA damage. In vitro, RuvC protein interacts with Holliday junctions in DNA and promotes their resolution by endonucleolytic cleavage. In this paper, we investigate the interaction of RuvA and RuvB proteins with model Holliday junctions. Using band-shift assays, we show that RuvA binds synthetic Holliday structures to form specific protein-DNA complexes. Moreover, in the presence of ATP, the RuvA and RuvB proteins act in concert to promote dissociation of the synthetic Holliday structures. The dissociation reaction requires both RuvA and RuvB and a nucleotide cofactor (ATP or dATP) and is rapid (40% of DNA molecules dissociate within 1 min). The reaction does not occur when ATP is replaced by either ADP or the nonhydrolyzable analog of ATP, adenosine 5'-[gamma-thio]triphosphate. We suggest that the RuvA and RuvB proteins play a specific role in the branch migration of Holliday junctions during postreplication repair of DNA damage in E. coli.

The recombination of DNA molecules has been reconstituted in vitro using two purified enzymes from Escherichia coli. RecA protein catalyses homologous pairing and strand exchange reactions to form intermediate DNA structures that are acted upon by RuvC. The newly identified RuvC protein resolves the intermediates by specific endonucleolytic cleavage to produce recombinant DNA molecules.

In previous studies, Holliday junctions generated during RecA-mediated strand-exchange reactions were resolved by fractionated Escherichia coli extracts. We now report the specific binding and cleavage of synthetic Holliday junctions (50 base pairs long) by a fraction purified by chromatography on DEAE-cellulose, phosphocellulose, and single-stranded DNA-cellulose. The cleavage reaction provided a sensitive assay with which to screen extracts prepared from recombination/repair-deficient mutants. Cells with mutations in ruvC lack the nuclease activity that cleaves synthetic Holliday junctions in vitro. This deficiency was restored by a multicopy plasmid carrying a ruvC+ gene that overexpressed junction-resolving activity. The UV sensitivity and deficiency in recombinational repair of DNA exhibited by ruv mutants lead us to suggest that RuvC resolves Holliday junctions in vivo.

T7 endonuclease I binds specifically to four-way junctions in duplex DNA and promotes their resolution into linear duplexes. Under conditions in which the nuclease activity is blocked by the absence of divalent cations, the enzyme forms a distinct protein-DNA complex with the junction, as detected by gel retardation and filter binding assays. The formation of this complex is structure-specific and contrasts with the short-lived binding complexes formed on linear duplex DNA. The binding complex between T7 endonuclease I and a synthetic Holliday junction analog has been probed with hydroxyl radicals. The results indicate that the nuclease binds all four strands about the junction point.

The binding of a synthetic four-way junction in DNA by T4 endonuclease VII has been studied using gel retardation and footprint analysis. Two specific protein-DNA complexes have been observed, but only one is stable in the presence of moderate concentrations of salt. The footprint of T4 endonuclease VII in the salt-resistant complex has been probed using hydroxyl radicals generated by the reaction of iron(II)/EDTA with hydrogen peroxide. The hydroxyl radical cleavage pattern indicates protection of approximately 5 residues in two strands that are diametrically opposed across the junction point.

This paper reports a retrospective study of 69 breast biopsies carried out for surgically occult but radiologically apparent lesions. Specimen radiography was required to confirm excision. The group included 17 carcinomas. Review of the pre-operative mammogram reports provided by a 'pool' of general radiologists demonstrated a high sensitivity (88%), but poor specificity (32%), with an overall accuracy of 46%. 'Blind' review of the mammograms by one experienced mammographic radiologist showed high sensitivity (100%), good specificity (73%) and overall accuracy of almost 80%. This result shows the need for the most experienced radiologist available to be involved in deciding which of these difficult lesions require biopsy. This will reduce unnecessary breast surgery and highlights the role of clinical and radiological review instead of biopsy, the need for continuing self audit by radiologists and the need for regular communication between clinicians, radiologists and pathologists.

Holliday junctions are intermediate structures that are formed and resolved during the process of genetic recombination. To investigate the interaction of junction-resolving nucleases with synthetic Holliday junctions that contain homologous arm sequences, we constructed substrates in which the junction point was free to branch migrate through 26 base-pairs of homology. In the absence of divalent cations, we found that both phage T4 endonuclease VII and phage T7 endonuclease I bound the synthetic junctions to form specific protein-DNA complexes. Such complexes were not observed in the presence of Mg2+, since the Holliday junctions were resolved by the introduction of symmetrical cuts in strands of like polarity. The major sites of cleavage were identified and found to occur within the boundaries of homology. T4 endonuclease VII showed a cleavage preference for the 3' side of thymine bases, whereas T7 endonuclease I preferentially cut the DNA between two pyrimidine residues. However, cleavage was not observed at all the available sites, indicating that in addition to their structural requirements, the endonucleases show strong site preferences.

The resolution of Holliday junctions in DNA involves specific cleavage at or close to the site of the junction. A nuclease from Saccharomyces cerevisiae cleaves model Holliday junctions in vitro by the introduction of nicks in regions of duplex DNA adjacent to the crossover point. In previous studies [Parsons and West (1988) Cell, 52, 621-629] it was shown that cleavage occurred within homologous arm sequences with precise symmetry across the junction. In contrast, junctions with heterologous arm sequences were cleaved asymmetrically. In this work, we have studied the effect of sequence changes and base modification upon the site of cleavage. It is shown that the specificity of cleavage is unchanged providing that perfect homology is maintained between opposing arm sequences. However, in the absence of homology, cleavage depends upon sequence context and is affected by minor changes such as base modification. These data support the proposed mechanism for cleavage of a Holliday junction, which requires homologous alignment of arm sequences in an enzyme--DNA complex as a prerequisite for symmetrical cleavage by the yeast endonuclease.

A small series of patients underwent radio-isotope lung scanning before and after the bipedal injection of oily contrast medium for abdominal lymphography to assess known malignant disease. After lymphography the lung scans showed an increase of between 12 and 100% in the radioactivity recorded over the anterior chest. No change was recorded over the posterior aspect of the chest. It is suggested that the increase is a result of blockage of posteriorly placed pulmonary capillaries and diversion of blood flow to the anterior segments.

The mammograms of 444 patients who had a breast biopsy leading to a definitive histological diagnosis were reviewed. In 21 cases (4.7%) grouped microcalcifications were identified as the only mammographic abnormality. These groups of microcalcifications were analysed to determine whether there was any quantitative difference between benign and malignant lesions with respect to a shape parameter of the group, the spatial frequency of the particles and neighbour-to-neighbour relationships of the particles. This analysis did not reveal any significant difference between the spatial relationships of the grouped microcalcifications found in benign and malignant breast disease.

Altogether 117 patients with advanced breast cancer were treated with either tamoxifen 10 mg by mouth twice daily or aminoglutethimide 250 mg by mouth four times daily with hydrocortisone 20 mg twice daily in a randomised cross-over trial in which patients who failed to respond to the first treatment or relapsed while receiving it were switched to the other. Eighteen (30%) out of 60 patients initially treated with tamoxifen achieved an objective response and 11 (18%) showed stable disease. Seventeen (30%) out of 57 patients treated initially with aminoglutethimide achieved an objective response and 13 (23%) achieved stable disease. Objective responses in bone metastases were achieved more commonly with aminoglutethimide (11 patients (35%)) than with tamoxifen (five (17%)). The predicted median duration of response for tamoxifen was 15 months and for aminoglutethimide over 15 months (no significant difference). Five (15%) out of 34 patients who failed to respond to tamoxifen and four out of six patients who relapsed after responding to tamoxifen subsequently responded to aminoglutethimide. In contrast, only two (6%) out of 31 patients who failed to respond to aminoglutethimide and none out of four patients who relapsed while receiving aminoglutethimide subsequently responded to tamoxifen. The main side effects occurring in the 97 patients who received aminoglutethimide as first- or second-line treatment were lethargy and drowsiness (36 patients) and rash (29); seven patients had to stop treatment because of side effects. In contrast, side effects were rare and mild with tamoxifen and no patient had to stop treatment because of them. Both tamoxifen and aminoglutethimide appeared from this study to be equally effective in the medical endocrine treatment of advanced breast cancer.

In a phase II study, 42 patients with advanced soft-tissue sarcoma were treated with ifosfamide by 24-h infusion and mesna by 4-h IV bolus, repeated every 3 weeks. Ten patients received ifosfamide 5.0 g/m2, 20 had the dosage increased to 8.0 g/m2, and 12 received 8.0 g/m2 from the outset. Mesna was given in doses of 400 mg/m2 or 600 mg/m2. Of 40 patients evaluable for response, six (15%) achieved complete response and nine (23%) partial response. The overall response rate was 38%. The median duration of response was 11 months. Treatment was associated with falls in peripheral WBC and alopecia in all patients. Most experienced severe nausea and vomiting. In seven nephrotoxicity developed, and two of these died of renal failure. Renal tubular defects and cerebral effects also occurred. Mesna largely prevented haemorrhagic cystitis. Ifosfamide offers a new alternative to previous chemotherapy for advanced soft-tissue sarcoma, but alterations in dose or method will be necessary to reduce toxicity.

Two hundred and thirteen unselected postmenopausal women with advanced breast cancer were treated with aminoglutethimide and hydrocortisone. There were 6 complete responses (CR), 47 partial responses (PR), 25 stable disease (SD) and 3 mixed response. Overall objective response rate was 28%, and with SD 41%. Median duration of objective response was 14 months. Years after menopause, age and tumour-free interval did not affect response rates. Main side-effects were drowsiness and lethargy (33%), rash (23%) and nausea (15%). Eleven patients (5%) stopped treatment because of toxicity. Median survival from start of treatment was 28 months and was the same for CRs, PRs and SD, compared with 10 months for progressive disease (P less than 0.001). Median survival from first metastasis was 43 months for PR/CR, 40 months for SD (not significantly different) and 22 months for progressive disease (P less than 0.001). Aminoglutethimide is an effective endocrine therapy in advanced postmenopausal breast cancer, particularly for bone deposits. Disease stabilization is associated with symptomatic and survival benefit similar to CR/PR.

A clinical study of computed tomography (CT) was undertaken in 35 patients with tumours involving the larynx. Twenty-seven had primary laryngeal neoplasms, five had tumours arising in adjacent structures but invading the larynx and three who had undergone total laryngectomy were investigated for possible recurrence. The findings were compared with conventional radiological methods and clinical assessment. Confirmation was obtained from laryngectomy specimens in four patients and at autopsy in one. CT provided additional preoperative information on 14 occasions. This included better delineation of submucosal tumour extent, invasion of the pre-epiglottic space and cartilage displacement in invasion.

The accuracy of mammography alone and in combination with clinical examination and aspiration cytology was assessed in 402 patients who attended the Early Diagnostic Unit of the Royal Marsden Hospital, London. The sensitivities of mammography, clinical examination and cytology in identifying breast cancer were 76.9%, 81.7% and 63.5% respectively; the specificities of each test were 90.0%, 87.6% and 99.3%. The calculated sensitivity was increased to 96.2% if one positive test out of the three was regarded as an indication to undertake breast biopsy. If this approach was adopted the number of breast cancers missed would be two out of 104 and the yield of positive biopsies would be approximately one in four (27.6%). The implications of proceeding to breast biopsy on the basis of a single positive test are discussed.

Thirty-six patients treated surgically for carcinoma of the rectum were examined by computed tomography (CT) to determine its value in investigating local pelvic recurrence. Thirteen patients with suspected recurrence but no clinical or radiological evidence of disease and 19 patients with known recurrence were scanned. This study indicates that CT is effective for diagnosing local recurrence from carcinoma of the rectum and accurately delineates the extent of tumor spread, as well as organ and muscle involvement. The value of CT for screening patients at high risk of developing pelvic recurrence is discussed.

Axial computed tomography (CT) of the pelvis provides useful information in patients with gynaecological malignancies, both for initial staging, to follow disease progression and to assess response to treatment. Additional useful information may be available from reformatted coronal and sagittal images. Knowledge of normal anatomy is essential for correct interpretation of pathology. The anatomy and technique used to acquire the images are described in this paper.

Alveolar soft part sarcoma is a rare tumour found in musculofasculofascial planes, most often in the lower limbs of young adults. The tumour shows a characteristic orderly cellular arrangement and the few mitoses belie the often rapid progress of the disease. Cytoplasmic crystals unique to this tumour may be demonstrated. The need for thorough investigation of the patient as an initial staging procedure and to provide a prognostic forecast is emphasised. Isotope scanning of the bones, brain and liver is indicated. Two cases are reported which demonstrate the value of lymphography. The nodal features found were: 1. Enlargement of a lymph node of normal interal architecture. 2. Almost complete nodal replacement by tumour. 3. Pseudolymphomatous appearances. Follow up films are required, after an interval, to show the progress of the disease or response to therapy.

An endonuclease specific for cruciform junctions has been purified from yeast cells treated with a DNA-damaging agent. The activity was followed through five chromatographic steps by assaying for the linearization of supercoiled plasmid DNA, which extrudes cruciform structures in vitro. The sites of cleavage on pColIR215 were sequenced, and nicks were located to positions symmetrically opposed across the cruciform junction. The products of cleavage were unit length linear duplexes that contained terminal hairpin loops. In contrast to pColIR215, the cleavage patterns of pXG540 plasmid DNA were found to be complex, and cuts were found up to 40 bases from an (A-T)34 sequence that extrudes into a cruciform. Little or no activity could be detected on single-stranded DNA, linear duplex DNA, or nicked circular duplex DNA. The nuclease was insensitive to RNase but was inactivated by treatment with proteinase K. Mg2+ was required as cofactor and could not be replaced by Mn2+, Ca2+, Co2+, or Cu2+. The native molecular weight of the activity was approximately 200,000 as estimated by gel filtration.

Holliday junctions, in which two double-stranded DNA molecules are linked by single-stranded crossovers, are thought to be central intermediates in genetic recombination. We report here the in vitro specificity of a yeast endonuclease for structures analogous to Holliday junctions. Plasmids that extrude inverted repeat sequences into cruciform junctions are cleaved by the introduction of nicks into strands of like polarity, approximately 4-8 nucleotides from the base of the junction. In all cases, cleavage occurs within homologous sequences, and with precise symmetry across the junction. In contrast, a junction containing four arms of unrelated sequence is cleaved asymmetrically. The dependence upon homology for symmetrical cleavage is not found with T4 endonuclease VII, which cleaves branched structures in vitro. Holliday junction resolution appears to occur in a concerted manner by the introduction of nicks into two homologous DNA helices held in alignment.