The effect of DCIS grade on rate, type and time to recurrence after 15 years of follow-up of screen-detected DCIS.

BACKGROUND: The incidence of ductal carcinoma in situ (DCIS) rose rapidly when the NHS Breast Screening Programme (NHSBSP) started in 1988. Some authorities consider that this represents both over-diagnosis and over-treatment. We report long-term follow-up of DCIS diagnosed in the first 10 years (April 1988 to March 1999) of the West Midlands NHSBSP. METHODS: 840 noninvasive breast cancers were recorded on the national breast screening computer system. Following exclusions, and thorough case note and pathology review, 700 DCIS cases were identified for follow-up. RESULTS: After a median follow-up of 183 (range 133 to 259) months, 102 (14.6%) first local recurrences were identified, 49 (48%) were invasive. Median time to first noninvasive recurrence was 15 months, and 60 months for invasive recurrence. Median time to invasive recurrence was 76 months from initially high-grade DCIS, and 131 months from low/intermediate grade DCIS. For the seven women, presenting with metastasis as their first event, the median time was 82 (range 15 to 188) months. The cumulative proportion developing recurrence at 180 months was twice as high as at 60 months. INTERPRETATION: Short-term follow-up of patients diagnosed with DCIS will miss significant numbers of events, especially invasive local recurrences.

Excitation of the venus night airglow.

The strongest spectral features in the Venus night airglow between 3000 and 8000 angstroms are identified as the Herzberg. II (c(1)Sigma(-)(u) - X(3)Sigma(-)(a)) bands of molecular oxygen. These bands have been produced in a laboratory afterglow by the recombination of oxygen atoms in the presence of carbon dioxide molecules. It is hypothesized that the same mechanism produces this emission in the upper atmosphere of Venus.

Non-operative diagnosis--effect on repeat-operation rates in the UK breast screening programme.

Non-operative diagnosis rates in the UK breast screening programme have improved dramatically from 48.8% in 1994/95 (only nine units achieved the then minimum standard of 70%) to 94% in 2005/06 (only seven units failed to achieve the target of 90%). Preoperative and operative history of all 120,550 women diagnosed with screen-detected breast cancer in the UK between April 1994 and March 2006 was derived from different national databases. In 2005/06, 2,790 (17.8%) of the 15,688 women having surgery needed two or more operations. In 2001/02 (non-operative diagnosis rate 87%), the re-operation rate was 23.8% (2,377 of 9,969). Extrapolation backwards to 1994/95 (non-operative diagnosis rate 48.8%) suggests a re-operation rate of 62%. Analysis over the 4 years from April 2002 (n=34,198) demonstrates that 4,089 (12%) women with a correct non-operative diagnosis of invasive disease required additional surgery compared to 1,166 (48%) of women who were under-staged (diagnosed as non-invasive based on core biopsy, but actually suffering from invasive disease). Failure to achieve a non-operative diagnosis of invasive disease (n=1,542) or non-invasive disease (n=2,247) resulted in re-operation rates of 65 and 43% respectively. Given the impact of not having a diagnosis pre-operatively, or of under-staging invasive carcinoma, it seems timely to introduce more sophisticated standards.

Antigenic cross-reactivities between mammalian hexokinases.

Immunoelectrophoresis and gel diffusion techniques have demonstrated that, contrary to previous reports, antigenic cross-reactivity does exist between the three major rat hexokinase isoenzymes. Immune inhibition and immune precipitation assays performed in parallel generally failed to detect this cross-reactivity and possible reasons for this failure are discussed. The inability of the latter assay systems to detect cross-reactivity would seem to account for the discrepancies between the present results and those obtained in earlier studies.

Analysis of the solution structure of human interleukin-4 determined by heteronuclear three-dimensional nuclear magnetic resonance techniques.

Human interleukin-4 (IL-4) is a member of the family of haemopoietic cytokines that modulate cell proliferation and differentiation within the immune system. It has a four-helix-bundle structure, and possesses a high degree of mobility in certain regions, notably in the two long loops running the length of the bundle in its up-up-down-down topology. Information from a variety of three-dimensional heteronuclear NMR experiments, including chemical shifts, coupling constants and NOE data, is analysed in terms of the solution structure of IL-4. In addition, structure calculations with and without specific restraints such as hydrogen bond location or torsion angle restrictions are compared in the light of the dynamic behaviour of the polypeptide chain. Particular emphasis is placed on defining the lengths and positions of secondary structure elements, and on the likely structural preferences within the less well ordered loop regions. The overall topology of IL-4 is compared with those defined in recent structure determinations of related proteins. This analysis is combined with recent mutagenesis data to propose a possible mode of interaction of IL-4 with its receptor.

Human interleukin 4. The solution structure of a four-helix bundle protein.

Heteronuclear 13C and 15N three-dimensional nuclear magnetic resonance (n.m.r.) techniques have been used to determine the solution structure of human interleukin 4, a four-helix bundle protein. A dynamical simulated annealing protocol was used to calculate an ensemble of structures from an n.m.r. data set of 1735 distance restraints, 101 phi angle restraints and 27 pairs of hydrogen bond restraints. The protein structure has a left-handed up-up-down-down topology for the four helices with the two long overhand loops in the structure being connected by a short section of irregular antiparallel beta-sheet. Analysis of the side-chains in the protein shows a clustering of hydrophobic residues, particularly leucines, in the core of the bundle with the side-chains of charged residues being located on the protein surface. The solution structure has been compared with a recent structure prediction for human interleukin 4 and with crystal structures of other helix bundle proteins.

Thioacetamide-induced changes in hepatic hexokinase isoenzymes.

In the 48 h following a single i.p. injection of 200 mg of thioacetamide/kg body wt there is a progressive rise in low-Km hexokinase activity and a concomitant decrease in high-Km glucokinase activity. Loss of glucokinase activity occurs as a consequence of its predominantly perivenous zonal distribution in normal liver since it is hepatocytes in this region of the acinus that are selectively damaged by thioacetamide. Increased low-Km activity is mainly present in inflammatory infiltrates which invade perivenous and mid-zone regions in response to tissue injury. Low- and high-Km hexokinase activities return to control levels 10 days after thioacetamide treatment when the infiltration zones disappear and necrotic perivenous hepatocytes are replaced by cells with normal morphology. Changes in low- and high-Km hexokinase activities induced by thioacetamide thus appear to primarily reflect alterations in cell population rather than changes in gene expression within existing hepatocytes.

Interval breast cancers in the NHS Breast Screening Programme: does the current definition exclude too many?

OBJECTIVES: To examine the impact of the definition of interval breast cancers on interval cancer rates arising from the prevalent (first) screening round. DESIGN: Interval breast cancers arising from the prevalent (first) screening round at the Warwickshire, Solihull and Coventry Breast Screening Unit (17 April 1989 to 31 March 1992) were identified by comparison of data held at the unit with records at the West Midlands Cancer Intelligence Unit. Exclusion criteria used in National statistics were applied to this sample to quantify their impact on achieved interval cancer rates. The round lengths experienced by individual women at the unit were determined from the prevalent and incident invitation dates for 155 women with incident (re-screen) breast cancers detected in the second round. SETTING: Warwickshire, Solihull and Coventry Breast Screening Unit. SUBJECTS: 59,017 women screened between 17 April 1989 and 31 March 1992 with a negative screening result and 155 women with incident screen detected cancers. RESULTS: A total of 278 interval cancers were identified, giving an overall rate from the prevalent screening round of 47.1/10,000 women screened. Of these, 213 met the criteria used in the definition of interval cancers for National statistics and were termed "core" interval cancers. The overall "core" interval rate was 36.1/ 10,000 women screened, similar to interval cancer rates found in the north west of United Kingdom. Thus applying commonly used exclusion criteria produced a 23.4% reduction in the apparent interval cancer rate, with the largest decrease resulting from the exclusion of cancers arising at 36 months or more from the last screen. CONCLUSIONS: The exclusion criteria used in the definition of interval cancers have a significant impact on observed interval cancer rates. Of particular concern is the exclusion in the current National definitions of cancers arising at 36 months or more from the last screen, which may mask a problem with significant implications for the success of the NHSBSP.

Slippage in the NHS breast screening programme: an assessment of whether a three year screening round is being achieved.

BACKGROUND: The NHS breast screening programme (NHSBSP) was established in 1987 to screen women aged 50-64 every three years to achieve a significant reduction in breast cancer mortality. Ensuring that women are re-invited every three years (that is, a three year screening round is in operation) is becoming increasingly difficult as pressure on the service rises. Coverage measures the proportion of eligible women receiving a screen in the previous three years and is currently used as an NHS performance indicator, while uptake measures the proportion of invited women who attend for screening. Data for 1996/1997 for the West Midlands NHSBSP show that, although uptake among 50-64 year olds was in excess of the 70% target at 78%, coverage was 10% below this at 68%. The discrepancy between coverage and uptake is likely to in part reflect "round slippage" in which women are re-invited at three years or more from their previous screen. To investigate the extent to which slippage is occurring in the region a technique for assessing round length independently of coverage was developed. METHODS: Records for women receiving routine recall (incident) screens between 1994 and 1997 in the West Midlands NHSBSP were examined and the time between the most recent screen and the previous screen measured in months. FINDINGS: Of 73,785 women screened in 1996/1997, 46.3% had a round length of under three years, although 74.9% had been re-screened within 38 months of the previous screen. Overall the regional programme was estimated to have a round slippage of approximately two months. CONCLUSIONS: The West Midlands NHSBSP operates to high standards in terms of uptake and cancer detection, but round slippage must be reduced. The lack of quantitative data with which to assess round length has hindered assessment in the past. The simple technique developed in this study will allow assessment of round length to be used routinely as the key quality assurance measure for the programme.

Epithelial expression of major histocompatibility complex (MHC) antigens in normal rat salivary and lacrimal glands.

The presence and distribution of MHC class I and class II antigens within these glands of Wistar and Lewis rats was studied using monoclonal antibodies and an indirect immunoperoxidase technique. In rats of both strains and sexes, MHC class 1 antigens were expressed by ductal epithelium in addition to vascular endothelium and other connective tissue elements. Except for a small proportion of secretory cells within lacrimal glands, acini were uniformly negative for class I antigen. MHC class II immune response-associated (Ia) antigens were expressed by stromal dendritic cells in all glands. Glandular expression of Ia was limited to submandibular glands of the two strains. In Lewis rats, staining was detected in some striated and collecting ducts, whereas positive glandular reactivity in Wistar rats was predominantly within the granular-cell tubules. Quantitative histomorphometric studies of Wistar submandibular glands, taken from 2.5-60-week-old male and female animals, demonstrated a close relationship between the extent of glandular Ia reactivity and postnatal granular-cell tubule development. These results indicate that whilst constitutive expression of Ia is a feature of rat submandibular epithelium, the glandular components involved are strain dependent.

The effect of diurnal rhythms on the hepatotoxicity of thioacetamide in male and female rats.

Single 200 mg/Kg body weight i.p. injections of thioacetamide administered to litter mate male and female rats at 09.00, 13.00, 17.00 and 21.00 h caused body weight losses, elevated plasma glutamate pyruvate transaminase (GPT) levels, decreases in hepatic glycogen, zone 3-specific necrosis and leucocyte infiltration. All of these changes were more marked in males. The effects of thioacetamide on females were more severe at later injection times while no diurnal variations were apparent in males. Decreases in hepatic glycogen were most obvious in necrotic perivenous hepatocytes and correlated with increases in active glycogen phosphorylase which were probably caused by raised cytosolic calcium concentrations resulting from thioacetamide induced damage to cell membranes.

Contraceptive practice among New Zealand women.

In May 1976 the contraceptive practices of New Zealand women were surveyed among a national random probability sample of 1200 women aged 15 years and over. The survey found 93 percent of women aged 15-44 years considered themselves at risk of pregnancy. Of all women surveyed, almost half (two-thirds of those at risk) currently practised contraception. The highest incidence was among women aged 25-44 years. Single women at risk contracepted less frequently than did married women. The most frequently used method was the contraceptive pill, favoured particularly by younger women. It was followed by sterilisation of either partner, which was most frequent among women aged 25-44 years.

Abortion experiences among New Zealand women.

In May 1976 the incidence of abortion among New Zealand women was surveyed over a national random probability sample of 1200 women aged 15 years and over. Of the respondents who had ever been pregnant, 16.6 percent had at some stage considered terminating their pregnancy, and one-third of them subsequently attempted to obtain an abortion with 84 percent success. Single women and/or women in the 15-24 year age group were more likely than married or older women to have considered abortion when pregnant, and were more likely to have followed through with an abortion attempt after considering abortion. Prior to 1974, 62 percent of the abortion attempts involved an unqualified operator, in contrast to only 5 percent of those attempted or obtained from 1974-1976. Women with abortion experiences shifted from a low incidence of contraception and reliance on inadequate methods prior to the abortion attempt, to a higher incidence and use of more adequate methods subsequent to the abortion attempt. Extrapolation from the survey data yielded a median estimated incidence of 8000 abortions per annum on New Zealand women.

Hex-square moire patterns in imagers using microchannel plates.

In electronic imaging detectors using microchannel plates, the mismatch between the pixels on a square mesh and the microchannels on a hexagonal mesh produces moire image defects. Theoretical statistical estimates of the sizes of the microposition offsets and the flat field intensity errors are calculated, showing the trade-off between resolution and position accuracy. A distinction is made between moments of spot images and moments of the single pixel response functions. As the resolution between the hex and square meshes is improved, the detector resolution is improved but at the expense of an ~10% moire pattern. These moire patterns will not be properly corrected by dividing by the flat field image.

Effect of strain and sex on the induction of hyperalbuminaemic proteinuria in the rat.

1. Male and female rats representing the four inbred strains [Wistar (albino), Sprague-Dawley (albino), DA (brown) and PVG (hooded) rats] were injected intraperitoneally with 4 . 5-5 . 5 mg of Cohn V bovine albumin day-1 g-1 body wt. 2. The levels of proteinuria and glomerular ultrastructural damage induced in response to hyperalbuminaemia varied widely with the strain and sex of rat studied, being highest in the male Wistar and lowest in the male Sprague-Dawley. 3. A survey of the relevant literature shows that these results probably explain most of the reported inconsistencies and anomalies concerning the effect of parenteral protein injection in the rat.

Normal urinary protein composition in the female Wistar rat and its relationship to the proteinuria induced by intraperitoneal bovine albumin.

1. Normal female Wistar rats showed a wide range of baseline protein excretion and albuminuria and could be divided into two distinct groups: (a) low-to-intermediate excretors, where daily baseline albumin excretion was below 1.8 mg/24 h and (b) high excretors, where daily baseline albumin excretion was 1.8-22 mg/24 h. 2. In low-to-intermediate excretors "sex-associated' by urinary specific proteins, supposedly present only in male rat urine, were excreted in larger quantities than albumin which constituted only 10-15% of the total urinary protein. 3. In high excretors up to 50% of the urinary protein was albumin and other serum proteins were also present in relatively larger quantities than the urinary specific proteins. 4. Baseline albumin excretion appeared to be a good indicator of the inherent efficiency of the glomerular filter and this was reflected in the response to intraperitoneal injection of heterologous serum albumin since, during periods where no significant glomerular epithelial cell foot-process loss had been incurred, the levels of proteinuria induced correlated well with baseline albuminuria.

A biochemical and immunological investigation into the physiological basis of the increased albumin filtration induced in hyperalbuminaemic female Wistar rats.

1. The level of proteinuria induced in female Wistar rats after bovine albumin injection intraperitoneally was highly dose dependent. 2. The proteinuria remained highly selective, with albumin constituting approximately 90% of the total protein excreted, even in the most severely affected rats. 3. Calculations relating the amount of bovine albumin available in the serum for filtration to the amount excreted in the urine indicated that complete saturation of the reticuloendothelial and tubular protein reabsorption systems may have occurred during the course of the 5 day injection period in rats given more than 3.5 mg of bovine albumin day-1 g-1 body wt. 4. When this situation was attained there appeared to be no further increase in glomerular permeability to either rat or bovine albumin and an equilibrium state seemed to exist where, when serum albumin levels were raised above the normal level, all the excess albumin passed across the glomerular filter to be excreted in the urine. 5. The passage of these large quantities of albumin across the glomerular filter may have resulted not from ultrastructural damage to the filter itself but rather from the generation of vastly increased concentration gradients across the glomerular basement membrane, which were sufficiently large to overcome the electrostatic repulsive forces which normally severely restrict albumin filtration.

Studies on the relationship between proteinuria and glomerular ultrastructural change in hyperalbuminaemic female Wistar rats.

Increased albumin filtration was shown to cause glomerular epithelial cell foot process loss in female Wistar rats made hyperalbuminaemic by means of a series of intraperitoneal bovine albumin injections. It appeared to act by stimulating glomerular epithelial cell endocytosis with the result that protein droplets and vacuoles accumulated within the epithelium causing marked cytoplasmic swelling which forced the foot processes to spread out and fuse. The severity of this glomerular ultrastructural damage rose with increasing bovine albumin dose and correlated well with induced proteinuria.

Effect of molecular charge on the induction of proteinuria and glomerular ultrastructural damage in hyperalbuminaemic female Wistar rats.

Intraperitoneal injection of anionic carbamylated bovine albumin derivatives induced glomerular epithelial cell foot process loss and increased urinary protein excretion, the severity of which rose with the dose administered. The effects induced at a given albumin dose were significantly lower than those previously measured after the administration of normal bovine albumin. The amount of epithelial cell foot process loss induced after the injection of carbamylated bovine albumin derivatives correlated well with the level of induced proteinuria but, at a given level of proteinuria, the amount of foot process was lower in these rats compared with those given normal bovine albumin. The results obtained are consistent with the interpretation that the more anionic carbamylated bovine albumin derivatives were not only filtered less readily at the glomerulus than their less negatively charged counterparts but were also reabsorbed to a lesser extent by the tubular epithelium.

Hexokinase isoenzymes: antigenic cross-reactivities and amino acid compositional relatedness.

Previously undetected antigenic cross-reactivities have been demonstrated between yeast and rat hexokinase isoenzymes using an enzyme-linked immune sorbent assay. The levels of structural homology between the isoenzymes have been assessed in terms of their relative antigenic cross-reactivities and their amino acid compositional relatedness. The three major rat hexokinases appear, despite their differing molecular sizes, to have a close evolutionary background and to share a common but distant ancestry with yeast and wheat-germ forms.