Multifocality and multicentricity in breast cancer and survival outcomes.

BACKGROUND: The clinicopathological characteristics and the prognostic significance of multifocal (MF) and multicentric (MC) breast cancers are not well established. PATIENTS AND METHODS: MF and MC were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. The Kaplan-Meier product limit was used to calculate recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. RESULTS: Of 3924 patients, 942 (24%) had MF (n = 695) or MC (n = 247) disease. MF/MC disease was associated with higher T stages (T2: 26% versus 21.6%; T3: 7.4% versus 2.3%, P < 0.001), grade 3 disease (44% versus 38.2%, P < 0.001), lymphovascular invasion (26.2% versus 19.3%, P < 0.001), and lymph node metastases (43.1% versus 27.3%, P < 0.001). MC, but not MF, breast cancers were associated with a worse 5-year RFS (90% versus 95%, P = 0.02) and BCSS (95% versus 97%, P = 0.01). Multivariate analysis shows that MF or MC did not have an independent impact on RFS, BCSS, or OS. CONCLUSIONS: MF/MC breast cancers were associated with poor prognostic factors, but were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.

[Depressive states and chronic asthenic syndromes in general practice]. / Les états dépressifs et les syndromes d'asthénie chronique en médecine praticienne.

It has been shown in Great Britain that general practitioners fail to recognize as many as 50% of the cases of depressive illness that present to them. The diagnosis is missed particularly when it is the physical type of symptom, such as asthenia, that is prominent. The Royal College of Psychiatrists, in association with the Royal College of General Practitioners, has launched the "Defeat Depression" campaign which includes amongst its aims the intention to provide up-to-date educational materials to family doctors on the recognition and treatment of depression. We have held two consensus meetings jointly with psychiatrists and primary care physicians and the results have been published in the British Medical Journal (2). One of our key recommendations is that, when medication is used to treat depressive illness in general practice, the antidepressants should be continued for six months after full remission has taken place. At present patients in general practice take their drugs for a total of three or four weeks. One of the reasons for patients abandoning their medication prematurely has been revealed by surveys that we have carried out on the general public. The lay person has little confidence in the efficacy of antidepressants and, perhaps more importantly, believes that they are addictive. It is therefore no surprise, then, that patients are keen to stop their antidepressants before they become dependent on them.(ABSTRACT TRUNCATED AT 250 WORDS)

Monospot and VP1 tests in chronic fatigue syndrome and major depression.

Thirty-four patients with chronic fatigue syndrome (CFS) were compared with controls with DSM-III-R major depression on the Monospot and VP1 antigen tests. There was no significant difference in the numbers initially VP1 positive in the groups (11/34 and 7/34 positive in the chronic fatigue and major depression group respectively). Four CFS but no depressed patients were Monospot positive initially. No patient was both Monospot and VP1 positive. Patients positive on the tests were offered a repeat 6 months later. Eight of the 11 VP1 positive patients in the CFS group were retested and four remained positive, but none of the four depressed patients retested remained positive. No patient retested remained Monospot positive. The Monospot and VP1 tests appear to have little discriminating ability between these groups as screening tests and their predictive validity is unclear.

Cardenolide content and thin-layer chromatography profiles of monarch butterflies,Danaus plexippus L., and their larval host-plant milkweed,Asclepias asperula subsp.Capricornu (woods.) woods., in north central Texas.

This paper is the second in a series on cardenolide fingerprinting of monarch butterflies and their host-plant milkweeds in the eastern United States. Spectrophotometric determinations of the gross cardenolide content ofAsclepias asperula plants in north central Texas indicated wide variation ranging from 341 to 1616 µg/0.1 g dry weight. The mean plant cardenolide concentration (886 µg/0.1 g) is the highest for any milkweed species on which monarch cardenolide profiles have been produced. Forty-one butterflies reared individually on these plants contained a skewed distribution of cardenolide concentrations ranging from 231 to 515 µg/0. 1 g dry weight with a mean of 363µg/0.1 g. The uptake of cardenolide by the butterflies was independent of plant concentration, suggesting that saturation occurs in cardenolide sequestration by monarchs when feeding on cardenolide-rich host-plants. Female monarchs contained significantly greater mean cardenolide concentrations (339 µg/0.1 g) than did males (320 µg/0.1 g). The mean dry weight of the male butterflies (0.211 g) was significantly greater than the female mean (0.191) so that the mean total cardenolide contents of males (675 fig) and females (754 µg) were not significantly different. Butterfly size was not significantly correlated to butterfly cardenolide concentration when differences due to sex and individual host-plant concentration were removed. Thin-layer chrornatograms of 24 individual plant-butterfly pairs developed in two solvent systems resolved 22 individual spots in the plants and 15 in the butterflies.A. asperula plants appear to contain several relatively nonpolar cardenolides of the calotropagenin series which are metabolized to more polar derivatives in the butterflies. Quantitative evaluation of theR f values, spot intensities, and probabilities of occurrence in the chloroform-methanol-formamide TLC system produced a cardenolide fingerprint clearly distinct from those previously established for monarchs reared on otherAsclepias species. Our data support the use of fingerprints to make ecological predictions concerning larval host-plant utilization.A. asperula subsp.capricornu andA. viridis Walt, are the predominant early spring milkweeds throughout most of the south central United States. Cardenolide-rich monarchs reared on these two species may be instrumental in establishing and reinforcing visual avoidance of adults by naive predators throughout their spring and summer breeding cycle in eastern North America.

Cardenolide content and thin-layer chromatography profiles of monarch butterflies,danaus plexippus L., and their larval host-plant milkweed,asclepias viridis walt., in northwestern louisiana.

This paper is the first in a series on cardenolide fingerprinting of monarch butterflies and their host-plant milkweeds in the eastern United States. Spectrophotometric determinations of the gross cardenolide content of 60Asclepias viridis plants in northwestern Louisiana indicate a positively skewed variation ranging from 95 to 432 υg/0.1 g dry weight with a mean of 245 υg/0.1 g. Butterflies reared individually on these plants contained a normal cardenolide distribution ranging from 73 to 591 υg/0.1 g dry weight with a mean of 337 υg/0.1 g. The uptake of cardenolide by the butterflies best fit a logarithmic function of the plant concentration. Female monarchs (385 υg/0.l g) contained significantly greater mean cardenolide concentrations than did males (287 υg/0.1 g). No indications of a metabolic cost for either cardenolide ingestion or storage were adduced from size or dry weight data. Thin-layer chromatograms of 24 individual plant-butterfly pairs developed in two solvent systems resolved 21 individual spots in the plants and 15 in the butterflies.A. viridis plants appear to contain several relatively nonpolar cardenolides of the calotropagenin series which are metabolized to the more polar 3'-hydroxy derivatives calactin and calotropin as well as to calotropagenin in the butterflies. The epoxy cardenolides labriformin and labriformidin were absent, although desglucosyrioside (a 3'-hydroxy derivative) appeared present in both plants and butterflies. Quantitative evaluation of theR f values, spot intensities, and probabilities of occurrence in the chloroform-methanol-formamide TLC system produced a cardenolide fingerprint clearly distinct from those previously established for monarchs reared on otherAsclepias species, supporting the use of fingerprints to make ecological predictions concerning larval host-plant utilization.A. viridis is the predominant early spring milkweed throughout most of the south central United States and may be important in providing chemical protection to spring and early summer generation monarchs in the eastern United States.

Plant-determined variation in cardenolide content and thin-layer chromatography profiles of monarch butterflies,Danaus plexippus reared on milkweed plants in California : 3. Asclepias californica.

Variation in gross cardenolide concentration of the mature leaves of 85Asclepias californica plants collected in four different areas of California is a positively skewed distribution ranging from 9 to 199 µg of cardenolide per 0.1 g dry weight with a mean of 66 µg/0.1 g. Butterflies reared individually on these plants in their native habitats contained a normal distribution of cardenolide ranging from 59 to 410 µg of cardenolide per 0.1 g dry weight with a mean of 234 µg. Cardenolide uptake by the butterflies was a logarithmic function of plant concentration. Total cardenolide per butterfly ranged from 143 to 823 µg with a mean of 441 µg and also was normally distributed. Populational variation of plant cardenolide concentrations occurs within subspecies, but the northern subspeciesA. c. greenei does not differ significantly from the southernA. c. californica. Generally higher concentrations occur in butterflies from northern populations and in females. No evidence was adduced that cardenolides in the plants adversely affected the butterflies. Low cardenolide concentrations in the leaves and the absence of cardenolides in the latex characterize bothA. californica andA. speciosa, but notA. eriocarpa. Thin-layer chromatography in two solvent systems isolated 24 cardenolide spots in the plants, of which 18 are stored by the butterflies. There was a minor difference in the cardenolide spot patterns due to geographic origin of the plants, but as in our previous studies, none in the sexes of the butterflies. UnlikeA. eriocarpa andA. speciosa, A. californica plants lack cardenolides withRf values greater than digitoxigenin. Overall, the cardenolides of bothA. californica andA. speciosa are more polar than those inA. eriocarpa. A. californica plants contain cardenolides of the calotropagenin series including calotropin, calactin, and uscharidin, and the latter is metabolically transformed by monarch larvae to calactin and calotropin. Cardenolides of this series also occur inA. vestita, andA. cordifolia from California, the neotropicalA. curassavica, and the AfricanCalotropis procera, Gomphocarpus spp., andPergularia extenso; they therefore cross established taxonomic lines.A. californica is the predominant early season milkweed in California and may be important in providing chemical protection to the spring generation of monarchs in the western United States.A. speciosa, A. eriocarpa, andA. californica each imparts distinctive cardenolide fingerprints to the butterflies, so that ecological predictions are amenable to testing.

Plant-determined variation in the cardenolide content, thin-layer chromatography profiles, and emetic potency of monarch butterflies,Danaus plexippus L. Reared on milkweed plants in California: 2.Asclepias speciosa.

The pattern of variation in gross cardenolide concentration of 111Asclepias speciosa plants collected in six different areas of California is a positively skewed distribution which ranges from 19 to 344 µg of cardenolide per 0.1 g dry weight with a mean of 90 µg per 0.1 g. Butterflies reared individually on these plants in their native habitats ranged from 41 to 547 µg of cardenolide per 0.1 g dry weight with a mean of 179 µg. Total cardenolide per butterfly ranged from 54 to 1279 µg with a mean of 319 µg. Differences in concentrations and total cardenolide contents in the butterflies from the six geographic areas appeared minor, and there were no differences between the males and the females, although the males did weigh significantly more than females. The uptake of cardenolide by the butterflies was found to be a logarithmic function of the plant concentration. This results in regulation: larvae which feed on low-concentration plants produce butterflies with increased cardenolide concentrations relative to those of the plants, and those which feed on high-concentration plants produce butterflies with decreased concentrations. No evidence was adduced that high concentrations of cardenolides in the plants affected the fitness of the butterflies. The mean emetic potencies of the powdered plant and butterfly material were 5.62 and 5.25 blue jay emetic dose fifty units per milligram of cardenolide and the number of ED50 units per butterfly ranged from 0.28 to 6.7 with a mean of 1.67. Monarchs reared onA. speciosa, on average, are only about one tenth as emetic as those reared onA. eriocarpa. UnlikeA. eriocarpa which is limited to California,A. speciosa ranges from California to the Great Plains and is replaced eastwards byA. syriaca L. These two latter milkweed species appear to have a similar array of chemically identical cardenolides, and therefore both must produce butterflies of relatively low emetic potency to birds, with important ecological implications. About 80% of the lower emetic potency of monarchs reared on A. speciosa compared to those reared onA. eriocarpa appears attributable to the higher polarity of the cardenolides inA. speciosa. Thin-layer Chromatographie separation of the cardenolides in two different solvent systems showed that there are 23 cardenolides in theA. speciosa plants of which 20 are stored by the butterflies. There were no differences in the cardenolide spot patterns due either to geographic origin or the sex of the butterflies. As when reared onA. eriocarpa, the butterflies did not store the plant cardenolides withR f values greater than digitoxigenin. However, metabolic transformation of the cardenolides by the larvae appeared minor in comparison to when they were reared onA. eriocarpa. AlthoughA. eriocarpa andA. speciosa contain similar numbers of cardenolides and both contain desglucosyrioside, the cardenolides ofA. speciosa overall are more polar. ThusA. speciosa has no or only small amounts of the nonpolar labriformin and labriformidin, whereas both occur in high concentrations inA. eriocarpa. A. speciosa plants and butterflies also contain uzarigen, syriogenin, and possibly other polar cardenolides withR f values lower than digitoxin. The cardenolide concentration in the leaves is not only considerably less than inA. eriocarpa, but the latex has little to immeasurable cardenolide, whereas that ofA. eriocarpa has very high concentrations of several cardenolides. Quantitative analysis ofR f values of the cardenolide spots, their intensities, and their probabilities of occurrence in the chloroform-methanol-formamide TLC system produced a cardenolide fingerprint pattern very different from that previously established for monarchs reared onA. eriocarpa. This dispels recently published skepticism about the predictibility of chemical fingerprints based upon ingested secondary plant chemicals.

Plant-determined variation in the cardenolide content, thin-layer chromatography profiles, and emetic potency of monarch butterflies,Danaus plexippus reared on the milkweed,Asclepias eriocarpa in California.

This paper is the first in a series on cardenolide fingerprinting of the monarch butterfly. New methodologies are presented which allow both qualitative and quantitative descriptions of the constituent cardenolides which these insects derive in the wild from specificAsclepias foodplants. Analyses of thin-layer Chromatographic profiles ofAsclepias eriocarpa cardenolides in 85 individual plant-butterfly pairs collected at six widely separate localities in California indicate a relatively invariant pattern of 16-20 distinct cardenolides which we here define as theAsclepias eriocarpa cardenolide fingerprint profile. Cardenolide concentrations vary widely in the plant samples, but monarchs appear able to regulate total storage by increasing their concentrations relative to their larval host plant when reared on plants containing low concentrations, and vice versa. Forced-feeding of blue jays with powdered butterfly and plant material and with one of the constituent plant cardenolides, labriformin, established that theA. eriocarpa cardenolides are extremely emetic, and that monarchs which have fed on this plant contain an average of 16 emetic-dose fifty (ED50) units. The relatively nonpolar labriformin and labriformidin in the plant are not stored by the monarch but are metabolized in vivo to desglucosyrioside which the butterfly does store. This is chemically analogous to the way in which monarchs and grasshoppers metabolize another series of milkweed cardenolides, those found inA. curassavica. It appears that the sugar moiety through functionality at C-3' determines which cardenolides are metabolized and which are stored. The monarch also appears able to store several lowR f cardenolides fromA. eriocarpa without altering them. Differences in the sequestering process in monarchs and milkweed bugs (Oncopeltus) may be less than emphasized in the literature. The monarch is seen as a central organism involved in a coevolutionary triad simultaneously affecting and affected by both its avian predators and the secondary chemistry of the milkweeds with which it is intimately involved.