Treatment and outcome in metastatic lobular breast cancer in the prospective German research platform OPAL.

PURPOSE: Evidence about routine treatment and outcome of patients with invasive lobular cancer (ILC) is limited, especially regarding metastatic disease. Here we present prospective real-world data of patients with metastatic ILC (mILC) as compared to patients with metastatic invasive ductal cancer (mIDC) receiving systemic therapy in routine care in Germany. METHODS: Prospective data on patient and tumor characteristics, treatments, and outcomes of patients with mILC (n = 466) and mIDC (n = 2100), recruited between 2007 and 2021 into the Tumor Registry Breast Cancer/OPAL were analyzed. RESULTS: Compared to mIDCs, patients with mILC were older at start of first-line treatment (median 69 vs. 63 years) and had more often lower grade (G1/G2: 72.8% vs. 51.2%), hormone receptor (HR)-positive (83.7% vs. 73.2%) and less often HER2-positive (14.2% vs. 28.6%) tumors, which metastasized more frequently to the bone (19.7% vs. 14.5%) or peritoneum (9.9% vs. 2.0%), and less frequently to the lungs (0.9% vs. 4.0%). Median OS of patients with mILC (n = 209) and mIDC (n = 1158) was 30.2 months [95% confidence interval (CI) 25.3, 36.0] and 33.7 months [95% CI 30.3, 37.9], respectively. Multivariate survival analysis did not show a significant prognostic impact of the histological subtype [HR mILC vs. mIDC 1.18 (95% CI 0.97-1.42)]. CONCLUSION: Overall, our real-world data confirm clinicopathological differences between mILC and mIDC breast cancer patients. Despite patients with mILC presenting with some favorable prognostic factors, ILC histopathology was not associated with a better clinical outcome in multivariate analysis, suggesting the need for more tailored treatment strategies for patients with the lobular subtype.

Risk and space: modelling the accessibility of stroke centers using day- & nighttime population distribution and different transportation scenarios.

PURPOSE: Rapid accessibility of (intensive) medical care can make the difference between life and death. Initial care in case of strokes is highly dependent on the location of the patient and the traffic situation for supply vehicles. In this methodologically oriented paper we want to determine the inequivalence of the risks in this respect. METHODS: Using GIS we calculate the driving time between Stroke Units in the district of Münster, Germany for the population distribution at day- & nighttime. Eight different speed scenarios are considered. In order to gain the highest possible spatial resolution, we disaggregate reported population counts from administrative units with respect to a variety of factors onto building level. RESULTS: The overall accessibility of urban areas is better than in less urban districts using the base scenario. In that scenario 6.5% of the population at daytime and 6.8% at nighttime cannot be reached within a 30-min limit for the first care. Assuming a worse traffic situation, which is realistic at daytime, 18.1% of the population fail the proposed limit. CONCLUSIONS: In general, we reveal inequivalence of the risks in case of a stroke depending on locations and times of the day. The ability to drive at high average speeds is a crucial factor in emergency care. Further important factors are the different population distribution at day and night and the locations of health care facilities. With the increasing centralization of hospital locations, rural residents in particular will face a worse accessibility situation.

The Time Course of Dorsal and Rostral-Ventral Anterior Cingulate Cortex Activity in the Emotional Stroop Experiment Reveals Valence and Arousal Aberrant Modulation in Patients with Schizophrenia.

This paper aims to investigate the temporal dynamics within the dorsal anterior cingulate cortex (dACC) and the rostral-ventral (rv) ACC during the interaction of emotional valence and arousal with cognitive control in patients with Schizophrenia (SZ). Although cognitive deficits in SZ are highly relevant and emotional disturbances are common, the temporal relationship of brain regions involved in the interaction of emotional and cognitive processing in SZ is yet to be determined. To address this issue, the reaction time (RT), event-related potential (ERP) and temporal dynamics of the dACC and rvACC activity were compared between SZ subjects and healthy controls (HC), using a modified emotional Stroop experiment (with factors namely congruence, arousal and valence). EEG was recorded with 64 channels and source localisation was performed using the sLORETA software package. We observed slower initial increase and lower peaks of time course activity within the dACC and rvACC in the SZ group. In this particular group, the dACC activity during late negativity was negatively correlated with a significantly higher RT in the high arousal conflict condition. In contrast to HC subjects, at the N450 window, there was no significant valence (ERP and rvACC ROI) modulation effect in the SZ subjects. Using high density EEG and source localisation, it was possible to distinguish various disturbances within the dACC and rvACC in patients with SZ, during emotion-cognition processing.

Calmodulin is a major component of extruded trichocysts from Paramecium tetraurelia.

Extruded trichocysts are composed of a family of proteins with molecular weights between 15,000 and 20,000. We have used heat treatment and affinity chromatography on fluphenazine-Sepharose to purify calmodulinlike proteins from whole cells and from extruded trichocysts. The purified protein from trichocysts is indistinguishable from that of whole cells; it is heat-stable, activates brain phosphodiesterase in a Ca++-dependent fashion, changes mobility on SDS polyacrylamide gels in the presence of Ca++, contains 1 mol of trimethyllysine/17 kdaltons, and has the amino acid composition characteristic of calmodulins. Calmodulin is a major component of purified, extruded trichocysts, of which it represents between 1 and 10% by mass. The other proteins of the trichocyst also resemble calmodulin in several properties. Possible roles for calmodulin in the Ca++-activated extrusion of trichocysts is discussed.

Theta and high-beta networks for feedback processing: a simultaneous EEG-fMRI study in healthy male subjects.

The reward system is important in assessing outcomes to guide behavior. To achieve these purposes, its core components interact with several brain areas involved in cognitive and emotional processing. A key mechanism suggested to subserve these interactions is oscillatory activity, with a prominent role of theta and high-beta oscillations. The present study used single-trial coupling of simultaneously recorded electroencephalography and functional magnetic resonance imaging data to investigate networks associated with oscillatory responses to feedback during a two-choice gambling task in healthy male participants (n=19). Differential associations of theta and high-beta oscillations with non-overlapping brain networks were observed: Increase of high-beta power in response to positive feedback was associated with activations in a largely subcortical network encompassing core areas of the reward network. In contrast, theta-band power increase upon loss was associated with activations in a frontoparietal network that included the anterior cingulate cortex. Trait impulsivity correlated significantly with activations in areas of the theta-associated network. Our results suggest that positive and negative feedback is processed by separate brain networks associated with different cognitive functions. Communication within these networks is mediated by oscillations of different frequency, possibly reflecting different modes of dopaminergic signaling.

A Ca2+-activated ATPase specifically released by Ca2+ shock from Paramecium tetraurelia.

Deciliation of Paramecium tetraurelia by a Ca2+ shock procedure releases a discrete set of proteins which represent about 1% of the total cell protein. Marker enzymes for cytoplasm (hexokinase), endoplasmic reticulum (glucose-6-phosphatase), peroxisomes (catalase), and lysosomes (acid phosphatase) were not released by this treatment. Among the proteins selectively released is a Ca2+-dependent ATPase. This enzyme has a broad substrate specificity which includes GTP, ATP, and UTP, and it can be activated by Ca2+, Sr2+, or Ba2+, but not by Mg2+ or by monovalent cations. The crude enzyme has a specific activity of 2-3 mumol/min per mg; the optimal pH for activity is 7.5. ATPase, GTPase, and UTPase all reside in the same protein, which is inhibited by ruthenium red, is irreversibly denatured at 50 degrees C, and which has a sedimentation coefficient of 8-10 S. This enzyme is compared with other surface-derived ATPases of ciliated protozoans, and its possible roles are discussed.

Pharmacological and biochemical properties of insect GABA receptors.

The first evidence for the existence of GABA receptors in any tissue was provided by studies on an invertebrate preparation but, until recently, characterization of GABA receptors from such lower organisms has advanced slowly. The identification of GABA receptors as putative target sites for a variety of insecticidal agents has contributed to the resurgence of interest in amino acid receptors of insects and other invertebrates. In this review, James Rauh and colleagues describe the properties of GABA receptors of insects and detail some striking pharmacological differences between the well-characterized GABA receptors of vertebrates and those of insects and other invertebrate organisms. A detailed understanding of invertebrate receptor pharmacology will be increasingly important for defining the mode of action of numerous modern pesticides.

Neonicotinoids: insecticides acting on insect nicotinic acetylcholine receptors.

Imidacloprid is increasingly used worldwide as an insecticide. It is an agonist at nicotinic acetylcholine receptors (nAChRs) and shows selective toxicity for insects over vertebrates. Recent studies using binding assays, molecular biology and electrophysiology suggest that both alpha- and non-alpha-subunits of nAChRs contribute to interactions of these receptors with imidacloprid. Electrostatic interactions of the nitroimine group and bridgehead nitrogen in imidacloprid with particular nAChR amino acid residues are likely to have key roles in determining the selective toxicity of imidacloprid. Chemical calculation of atomic charges of the insecticide molecule and a site-directed mutagenesis study support this hypothesis.

Issues in fertility control for mentally retarded female adolescents: II. Parental attitudes toward sterilization.

Knowledge of the issues involving sterilization for mentally retarded adolescents is limited. Data were obtained from 69 interviewed parents whose mentally retarded daughters were attending the Cincinnati Adolescent Clinic. (A companion paper focuses on the experience of these girls with sexual activity, sexual abuse, and contraceptive use.) Forty-six percent of the parents had considered sterilization for their daughters. Twenty-six percent were still seeking the operation. Interest in sterilization especially correlated with increased severity of retardation (P less than .005) and with difficulty teaching menstrual hygiene (P less than .005). Parents of mildly retarded females sought tubal ligation, and those with severely retarded daughters chose hysterectomy and stressed their concern about menstrual management. Eighty-five percent of the parents favored a state statute that would enable sterilization under certain conditions and limitations. In general, few parents supported either an extremely restrictive or permissive position about sterilization.

Issues in fertility control for mentally retarded female adolescents: I. Sexual activity, sexual abuse, and contraception.

Little information is available about sexual activity, sexual assault, and contraceptive use among mentally retarded adolescents. The experience in these areas among 87 mentally retarded females is reviewed. (A companion paper focuses on these patients' parental attitudes toward sterilization.) All subjects attended a multiservice adolescent clinic with a large developmentally disabled patient group. Charts were reviewed and 69 parents were interviewed. The patients had an age range from 11 to 23 years (mean 16.7). Forty-one subjects were mildly retarded (IQ 55 to 69), 23 were moderately retarded (IQ 41 to 54), and 23 were severely retarded (IQ less than 41). Half of the mildly retarded had had sexual intercourse, a proportion comparable to the general adolescent population. Thirty-two percent of the moderately retarded and nine percent of the severely retarded adolescents had had intercourse. One third of the mildly retarded and one fourth of the moderately retarded adolescents had been victims of rape or incest. Continued sexual activity correlated with sexual abuse, but the majority of victims had no prior or subsequent evidence of intercourse. Forty-two subjects (48%) had used contraception at some time; intrauterine devices and injectable medroxyprogesterone acetate were preferred to oral contraceptives. Six of the 14 patients (43%) who continued sexual activity became pregnant, suggesting that currently available contraception is not providing sufficient protection.

Lipids in schoolchildren 6 to 17 years of age: upper normal limits.

As part of a multiclinic U.S. National Heart, Lung, and Blood Institute study of lipid levels of Americans, the University of Cincinnati studied a total school district's population. Out of a total of 8,906 eligible students from all grades, 6 to 17 years of age, 7,337 participated (82%). After fasting for 12 hours or more, plasma cholesterol and triglyceride levels were ascertained in 6,775 children. For white and black boys and girls, normal lipid values are given by age in both fasting and casual (nonfasting) states. This study group closely resembled a normal pediatric practice population, so that the values established may be used as baseline data for the practicing pediatrician. Since sex, race, and age are dominant sources for variations, care must be taken in the interpretation of minor changes that occur over time in a child.

Cross-resistance with dieldrin of a novel tricyclic dinitrile GABA receptor antagonist.

A novel tricyclic dinitrile, KN244, blocked the wild-type (dieldrin-sensitive) homo-oligomeric gamma-aminobutyric acid (GABA)-gated chloride channel of Drosophila melanogaster expressed in Xenopus oocytes. Sensitivity to the block by KN244 of the response to 30 microM GABA (IC50=41.6 nM, wild-type RDLac) was reduced abut 100 fold (IC50=4.5 microM) in the dieldrin-resistant (RDLacA302S) form of RDL.

Effects of [3H]-BIDN, a novel bicyclic dinitrile radioligand for GABA-gated chloride channels of insects and vertebrates.

1. The radiolabelled bicyclic dinitrile, [3H]-3,3-bis-trifluoromethyl-bicyclo[2.2.1]heptane-2,2-dicarbonitrile ([3H]-BIDN), exhibited, specific binding of high affinity to membranes of the southern corn rootworm (Diabrotica undecimpunctata howardi) and other insects. A variety of gamma-aminobutyric acid (GABA) receptor convulsants, including the insecticides heptachlor (IC50, 35 +/- 3 nM) and dieldrin (IC50, 93 +/- 7 nM), displaced [3H]-BIDN from rootworm membranes. When tested at 100 microM, 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct ane(EBOB), 4-t-butyl-2,6,7-trioxa-1-phosphabicy-clo[2.2.2]octane-1-thio ne (TBPS), 1-phenyl-4-t-butyl-2,6,7-trioxabicyclo[2.2.2]octane (TBOB) and picrotoxin failed to displace 50% of [3H]-BIDN binding to rootworm membranes indicating that the bicyclic dinitrile radioligand probes a site distinct from those identified by other convulsant radioligands. 2. Dissociation studies showed that dieldrin, ketoendrin, toxaphene, heptachlor epoxide and alpha and beta endosulphan displace bound [3H]-BIDN from rootworm membranes by a competitive mechanism. 3. Rat brain membranes were also shown to possess a population of saturable, specific [3H]-BIDN binding sites, though of lower affinity than in rootworm and with a different pharmacological profile. Of the insecticidal GABAergic convulsants that displaced [3H]-BIDN from rootworm, cockroach (Periplaneta americana) and rat brain membranes, many were more effective in rootworm. 4. Functional GABA-gated chloride channels of rootworm nervous system and of cockroach nerve and muscle were blocked by BIDN, whereas cockroach neuronal GABA(B) receptors were unaffected. 5. Expression in Xenopus oocytes of either rat brain mRNA, or cDNA-derived RNA encoding a GABA receptor subunit (Rdl) that is expressed widely in the nervous system of Drosophila melanogaster resulted in functional, homo-oligomeric GABA receptors that were blocked by BIDN. Thus, BIDN probes a novel site on GABA-gated Cl- channels to which a number of insecticidally-active molecules bind.

Development of an in vitro cell culture system to mimic the blood-brain barrier.

Primary cultures of brain capillary endothelial cells (BCECs) cocultured together with astroglia cells were used to investigate the induction of blood-brain barrier (BBB) characteristics in vitro. By immunofluorescence, histochemical staining, two-dimensional gel electrophoresis and enzyme activity tests we are able to show that BCECs in vitro loose typical blood-brain barrier properties but not their common endothelial phenotype. Astrocytes induce the expression of the blood-brain barrier characteristic enzymes gamma-glutamyltranspeptidase and alkaline phosphatase but only in a coculture system with direct cell to cell contact between BCECs and astroglia cells. C6-glioma cells also re-establish the BBB phenotype but were less effective compared to astrocytes. The susceptibility of the BCECs to an astroglial stimulus depends on the proliferative state of the BCECs.

[35S]t-butylbicyclophosphorothionate binding sites in susceptible and cyclodiene-resistant houseflies.

4-aminobutyric acid (GABA)-gated chloride ion channels are important molecular targets for a number of polychlorocycloalkane compounds including cyclodiene insecticides. Previous radioligand binding studies have indicated that cyclodiene insecticides are potent inhibitors of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to housefly thorax and abdomen membranes. In the present study, a laboratory-reared, cyclodiene-resistant (CYW) housefly strain (Musca domestica) showed resistance to a number of cyclodiene insecticides. Specific, saturable [35S]TBPS binding was detected in thorax and abdomen membranes prepared from housefly strains susceptible (CSMA) and resistant (CYW) to cyclodienes. Scatchard analysis of [35S]TBPS binding data from CSMA and CYW membranes revealed no significant differences between the two strains in either the affinity (Kd) or the density (Bmax) of specific, saturable binding sites. There were no differences in the comparative effectiveness of a range of polychlorocycloalkanes, including cyclodiene insecticides, as inhibitors of specific [35S]TBPS binding to CSMA and CYW thorax and abdomen membranes. Therefore, if an alteration in target site is a mechanism for resistance to cyclodienes in the CYW strain, it is not readily measurable using [35S]TBPS.

Gorlin's syndrome: ovarian fibromas at adolescence.

An adolescent with bilateral ovarian fibromas associated with Gorlin's or the multiple nevoid basal cell carcinoma syndrome is described. The syndrome should be considered and looked for when bilateral solid ovarian masses are found in young women.

BIDN, a bicyclic dinitrile convulsant, selectively blocks GABA-gated Cl- channels.

BIDN (3,3-bis(trifluoromethyl)bicyclo[2,2,1]heptane-2,2-dicarbonitrile) at 10(-5) M blocked GABA-induced inhibitory postsynaptic potentials (IPSPs) recorded from an identified, giant interneuron (G12) of the cockroach (Periplaneta americana). The same concentration of this bicyclic dinitrile also blocked Cl- -mediated responses of G12 to GABA applied by pressure microinjection into the terminal abdominal ganglion neuropile containing dendrites of G12. BIDN (10(-5) M) was without effect on a response of G12 to GABA known to be mediated by a GABAB type receptor. In studies of the cell body of an identified motor neurone, the fast coxal depressor (Df) in the cockroach metathoracic ganglion, BIDN (10(-5) M) blocked reversibly an extrasynaptic GABA-gated Cl- channel, but not an extrasynaptic L-glutamate-gated Cl- channel. Glycine-gated Cl- channels observed when rat brain messenger RNA was expressed in Xenopus laevis oocytes were unaffected by BIDN at concentrations up to 10(-4) M, whereas this same concentration of BIDN completely blocked GABA-gated Cl- responses recorded from the same preparations. Unlike picrotoxin, which antagonises a variety of ligand-gated Cl- channels, to date BIDN has been found to block only Cl- channels gated by GABA, both in insect and vertebrate preparations.

Blocking actions of BIDN, a bicyclic dinitrile convulsant compound, on wild-type and dieldrin-resistant GABA receptor homo-oligomers of Drosophila melanogaster expressed in Xenopus oocytes.

The receptor antagonist actions are described for a novel bicyclic dinitrile compound (BIDN, 3,3-bis-(trifluoromethyl)-bicyclo [2.2.1] heptane-2,2-dicarbonitrile) on a Drosophila melanogaster homo-oligomeric GABA receptor expressed in Xenopus oocytes. BIDN blocked the wild-type form of the receptor in a neither purely competitive, nor purely non-competitive manner, being dependent on the GABA concentration yet insurmountable, and block was independent of the membrane potential. BIDN was found to be less effective against a mutant (A(302) --> S) form of the receptor resistant to dieldrin and picrotoxinin. This cross resistance of dieldrin-resistant receptors to BIDN is of interest in the light of recent findings that BIDN binding to insect membranes is displaced competitively by dieldrin, but not by picrotoxinin.

Contraception for the teenager.

PIP: Although adolescents are now fecund at an earlier age, they are not ready for parenthood financially, educationally, or socially until a much later time. More and more states directly or indirectly permit minors to consent for their own contraceptive needs, a trend that must be applauded. Studies of adolescent attitudes, knowledge, and use of contraceptives indicate a woeful ignorance and lack of use, even among college students. From a medical and practical point of view, the IUD is considered the most suitable contraceptive for the teen-ager. A well-established menstrual cycle of at least 2 years should be be present if oral contraceptives are used. Abstience, although medically ideal, must be initiated by the patient; otherwise, the failure rate is high. The failure rate for the condom, diaphragm, and spermicidal foam is high, except when 2 methods are used at the same time. Coitus interruptus, douche, and rhythm have no application for adolescents. Girls who have had an abortion should receive contraceptive counseling immediately following the abortion. Sterilization must be considered very cautiously for this age group.^ieng

Experience with side effects and health risks associated with Norplant implant use in adolescents.

Levonorgestrel implants (Norplant) have been recommended as a contraceptive method for teenage women. Our experience suggests that the use of Norplant implants in adolescents is associated with bleeding irregularities and modest weight gain. There is no effect on condom use or STD acquisition. Despite the bleeding irregularities, we documented high continuation rates, suggesting that with appropriate pre-insertion counseling, Norplant implants can be a successful contraceptive method for adolescent women.

PIP: An analysis of the experiences of 72 US adolescents (mean age, 15.5 years) suggests that Norplant implants are an appropriate contraceptive method for this population. All study participants had the implants inserted at a hospital-based adolescent clinic at least 1 year before chart review. The continuation rate was 97% at 12 months and 86% at 24 months. At insertion, 60 adolescents (83%) reported regular menstrual periods. At the various follow-up intervals (e.g., 3, 6, and 12 months), 12-18% had regular periods, 12-16% were amenorrheic, and the remainder had bleeding that was irregular in length and/or interval. Mean weight gains of 3, 4.5, and 5.8 pounds were recorded at 3, 6, and 12 months, respectively; however, there was no consistent trend and a substantial number of young women lost weight during the study period. Finally, there was no clear trend of increase or decrease after Norplant insertion in either condom use or rates of infection with sexually transmitted diseases (STDs). Pre-insertion counseling for adolescent Norplant acceptors should include preparation for menstrual irregularities and encouragement of condom use to prevent STD acquisition.