Mega-dose vitamins and minerals in the treatment of non-metastatic breast cancer: an historical cohort study.

BACKGROUND: Alternative therapies such as mega-dose vitamins and minerals are commonly used by women with breast cancer, but their effect on recurrence and survival have rarely been evaluated. METHODS: Survival and recurrence outcomes for 90 women with unilateral non-metastatic breast cancer diagnosed between 1989 and 1998, and who had been prescribed mega-doses of beta-carotene, vitamin C, niacin, selenium, coenzyme Q10, and zinc in addition to standard therapies were compared with matched controls. The 90 treated patients were prescribed combinations from three to six of the vitamins and minerals listed above. The controls were matched (2:1) to the vitamin/mineral patients for age at diagnosis, presence of axillary lymph node metastasis, tumor stage, grade, estrogen receptor status, year of diagnosis, and prescription of systemic therapy. All subjects were patients of the British Columbia Cancer Agency, Vancouver Island Centre. FINDINGS: Median follow-up of surviving patients was 68 months (minimum 20 months, 133 months maximum). The vitamin/mineral patients and controls were well matched. Two endpoints were considered. Breast cancer-specific survival (p = 0.19) and disease-free survival (p = 0.08) times for the vitamin/mineral treated group were shorter, after adjusting for diagnostic variables using a Cox proportional hazards model. The hazard ratios for the vitamin/mineral treated group versus the control group were estimated at 1.75 (95% CI = 0.83-2.69) for disease-specific survival and 1.55 (95% CI = 0.94-2.54) for disease-free survival. Overall survival was similar for the two groups (log-rank test, p = 0.36). INTERPRETATION: Breast cancer-specific survival and disease-free survival times were not improved for the vitamin/mineral treated group over those for the controls.

Jung's analysis of Sabina Spielrein and his use of Freud's free association method.

This paper examines Jung's use of Freud's free association method and his own association experiments in his analysis of Sabina Spielrein in 1904-1905. Jung's gradual rejection of the Freudian free association method is noted. By the time of their split in 1913, Jung came to view Freud's method of using associations to analyse personal complexes as reductive, limiting and backward-looking. He also felt that the Freudian method threatened the analysand by creating confusion and a regressive dependency on the analyst. Jung's early approach inclined away from personal pain in favour of analysing autonomous, impersonal and collective phenomena. The historical question is raised whether Jung's rejection of the use of the free associations of the individual analysand might be as fundamental as their well-known disagreement about Freud's belief in the central role of sexuality in neurosis.

Ferenczi's fatal illness in historical context.

In August 1932, Ferenczi was already manifesting symptoms of his fatal illness, pernicious anemia. This was diagnosed between September 20 and October 2 of that year, less than a month after the Twelfth International Psychoanalytic Congress in Wiesbaden. Despite seemingly successful treatment with injectable liver extract, he underwent an acute psychotic episode in March 1933, triggered by the neurological symptoms of his illness. These facts substantiate the subsequent claim of Freud and Jones that Ferenczi suffered from paranoia near the end of his life, but they do not support the commonly-held view that the writings and experiments in psychoanalytic technique of his last five years were symptomatic of a progressive mental illness.

Sustained increase in intracellular free calcium and activation of cyclooxygenase-2 expression in mouse hepatoma cells treated with dioxin.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a non-genotoxic environmental pollutant that causes multiple adverse effects in experimental animals and in humans. We show here that TCDD treatment of mouse hepatoma cells causes a rapid mobilization of intracellular calcium both in wild type Hepa-1 cells and in its c2 variant, a cell line that has highly reduced levels of functional aromatic hydrocarbon (Ah) receptor (AHR). In wild type cells, but not in the c2 variant, TCDD treatment leads to a sustained elevation of cytosolic free calcium. TCDD also induces elevated levels of cyclooxygenase-2 (COX-2) mRNA in wild type and in c37, a CYP1A1-deficient cell line, but not in c2 cells. Induction of Cox-2 is in fact dependent on the presence of a functional Ah receptor, since it can be blocked by antisense oligonucleotides to Ah receptor mRNA. Most likely as a consequence of Cox-2 induction, we find a significant increase in the level of 12-hydroxyheptadecatrienoic acid (12-HHT) secreted from TCDD-treated Hepa-1 cells. In addition, we observe elevated levels of 6-keto prostaglandin F1alpha in c2 cells and high levels of secreted prostaglandin F2alpha in c2, c37 and c4, the variant cell line lacking aromatic hydrocarbon nuclear translocator protein. These data suggest that Cox-2 activation by TCDD leads to the release of prostaglandins, eicosanoids and other mediators which may have an important role in the biological and toxic effects of TCDD.

Cholecystokinin increases GABA release by inhibiting a resting K+ conductance in hippocampal interneurons.

Cholecystokinin (CCK) is found co-localized with the inhibitory neurotransmitter GABA in interneurons of the hippocampus. Also, CCK receptors are found in abundance in this brain region. The possibility that CCK alters interneuron activity was examined using whole-cell current- and voltage-clamp recordings from visualized interneurons in the stratum radiatum of area CA1 in rat hippocampal slices. The effect of CCK on GABA-mediated IPSCs was also determined in pyramidal neurons. The sulfated octapeptide CCK-8S increased action potential frequency or generated inward currents in the majority of interneurons. These effects of CCK persisted in the presence of tetrodotoxin and cadmium, suggesting that they were direct. Current-voltage plots revealed that CCK-8S inhibited a conductance that was linear across command potentials and reversed near the equilibrium potential for K+ ions. The K+ channel blocker tetraethylammonium (10 mM) generated inward currents similar to those initiated by CCK, and it occluded the effect of the peptide. BaCl2 (1 mM) and 4-aminopyridine (2 mM) did not alter the effect of CCK. The CCKB receptor antagonist PD-135,158 completely blocked the inward currents generated by CCK-8S. CCK also resulted in an increase in spontaneous action potential-dependent IPSC frequency, but no changes in action potential-independent miniature IPSCs or evoked IPSCs in pyramidal neurons. These results provide evidence that CCK can depolarize hippocampal interneurons through the inhibition of a resting K+ conductance, leading to increased tonic inhibition of pyramidal neurons. This action of CCK may contribute to its anticonvulsant properties, as observed in limbic seizure models.

Dioxin induces transcription of fos and jun genes by Ah receptor-dependent and -independent pathways.

Halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin), and polycyclic aromatic hydrocarbons, such as benzo[a]pyrene, are environmental contaminants that cause many apparently unrelated toxic effects. In a previous study, we have shown that treatment of mouse hepatoma cells with TCDD or B(a)P results in an increase in mRNA levels of the immediate-early protooncogenes c-fos, c-jun, junB, and junD, and the concomitant increase of the DNA-binding activity of the transcription factor AP-1, a dimer of FOS and JUN proteins. To analyze the mechanism of fos/jun activation by TCDD we have used electrophoretic mobility shift and transient expression assays of reporter gene constructs containing response elements for 12-O-tetradecanoyl-phorbol-13-acetate (TRE), serum (SRE), cAMP (CRE), and aromatic hydrocarbons (AhRE) from the fos and jun genes fused to the firefly luciferase gene under the control of the SV40 minimal promoter. In mouse hepatoma Hepa-1 cells, which have Ah receptor (AHR) and Ah receptor nuclear translocator (ARNT) proteins, inclusion of TRE, SRE, and the AhRE motifs from c-jun and junD, but not CRE or the AhREs from c-fos, fosB, and junB, causes a large TCDD-dependent increase in luciferase expression. In agreement with these results, c-jun and junD, but not c-fos, fosB, and junB AhREs, competed with a canonical Cyp1A1 AhRE for binding to the AHR ARNT heterodimeric complex. In African Green Monkey CV-1 cells, which lack AHR, expression plasmids with AhRE motifs require coexpression of AHR and ARNT for TCDD to stimulate luciferase expression. In contrast, SRE-containing expression plasmids respond equally well to TCDD whether or not AHR and ARNT are coexpressed. These results suggest that TCDD induces expression of the immediate-early response genes fos and jun by activation of possibly three separate signal transduction pathways, at least one of which does not require a functional Ah receptor complex.

Dioxin activates HIV-1 gene expression by an oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme.

We have studied the effect of several environmental chemicals on the transient expression of a chloramphenicol acetyltransferase (cat) reporter gene linked to the promoter sequences in the long terminal repeat (LTR) of the human immunodeficiency virus type 1 (HIV-1). Aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyrene cause a significant increases in CAT expression in mouse hepatoma Hepa-1 cells. The induction of CAT after TCDD treatment is abolished by administration of N-acetyl-L-cysteine or 2-mercaptoethanol and does not take place in a mutant cell line that lacks CYP1A1 enzymatic activity. Linker-scanning mutational analysis of transcription factor binding sites in the promoter revealed that both the NF kappa B and an adjacent aromatic hydrocarbon response element (AhRE) are required for TCDD-dependent CAT expression. In addition, mutation of the NFAT/AP-1 binding sites in the negative regulatory region of the promoter increases the magnitude of the TCDD effect. We conclude that induction of a functional CYP1A1 monooxygenase by TCDD stimulates a pathway that generates thiol-sensitive reactive oxygen intermediates which, in turn, are responsible for the TCDD-dependent activation of genes linked to the LTR. These data might provide an explanation for findings that TCDD increases infectious HIV-1 titers in experimental systems and for epidemiologic reports suggesting that exposure to aromatic hydrocarbons, such as found in cigarette smoke, is associated with an acceleration in AIDS progression.

[Asymmetry and mutuality in the analytic relationship: lessons for today from the relationship between Freud and Ferenczi]. / Asymmetrie und Gegenseitigkeit in der analytischen Beziehung: Lektionen für heute aus der Beziehung zwischen Freud und Ferenczi.

Against the background of the controversy between Freud and Ferenczi on the nature of the psychoanalytic relationship, Hoffer examines the perennial issue of the way in which analysts come to terms with the warring claims of asymmetry (Freud) and mutuality (Ferenczi) in analysis. While discerning an inherent tendency towards mutuality in the psychoanalytic constellation, the author nevertheless calls for the upholding of asymmetry because the psychoanalytic relationship is not a relationship "of the usual kind". The analyst, he contends, must sustain the tension between mutuality and asymmetry and use this reflected tension as a therapeutic instrument for fathoming the patient's psychic reality.

Clinical significance of various ELISA assays for detecting antiphospholipid antibodies.

We have compared the prevalence of antiphospholipid antibodies (APA) measured by enzyme-linked immunosorbent assay (ELISA), in 119 selected patients using five different antigens: bovine cardiolipin, phosphatidylserine, phosphatidylinositol, bovine partial thromboplastin and human brain partial thromboplastin. All the plasmas have been evaluated for the presence of lupus anticoagulant (LA) activity by clotting techniques. We found a significant association between the incidence of LA and APA (p less than 0.001), only moderate agreement between the prolongation of the activated partial thromboplastin time (APTT) and ELISAs (r around 0.50) and a good agreement between the ELISAs (r around 0.80). The combination of antibodies against cardiolipin (ACA) and human brain partial thromboplastin (AHPTA) allowed the detection of antibodies in most of the LA positive cases. ACA, AHPTA and antiphosphatidylinositol antibodies detected all the positive samples. Six patients (5%) had a single APA detected. The clinical associations of APA according to phospholipid specificity, immunoglobulin isotype and titer are shown.

Ultrastructural studies on the development of the blood-epididymis barrier in immature rats.

The development of the blood-epididymis barrier in immature rats (8, 11, 14, 18, and 21 days old) was examined with an electron microscope using lanthanum nitrate as an electron dense tracer. A gradual increase in the development of the blood-epididymis barrier was noted with age. On Day 8, lanthanum was frequently detected in both the intercellular spaces and the lumen. On day 14, no lanthanum penetration into the lumen was observed in 75% of the junctions in the caput, 40.3% in corpus, and 30% in cauda epididymidis. On Day 18, only 7.5%, 9%, and 15%, of the junctions in the caput, corpus, and cauda epididymidis, respectively, remained permeable to lanthanum. No lanthanum was observed in the lumen of any tubules in the 21-day-old rat epididymis. These findings indicate that the postnatal development of the blood-epididymis barrier is gradual, and that its formation is virtually completed by Day 21. As with adult rats, the zonula occludens is the ultimate structural component of the blood-epididymis barrier in immature rats (Agarwal and Hoffer, 1985).