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.

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.

[Treatment of perivascular extravasation of cytostatic agents]. / Paravenöse Zytostatikainjektion: Prophylaxe und Sofortmassnahmen im Notfall.

In the intravenous administration of cytostatic drugs, top priority is given to preventive measures, and to immediate countermeasures in the event of an accidental paravenous injection. In contrast to earlier recommendations, the use of antidotes has been minimized. Only those with proven efficacy and no tissue toxic potential are to be used. The intradermal application of sodium bicarbonate and sodium thiosulfate, and the subcutaneous administration of glucocorticoids are no longer applicable. As a specific antidote in the case of anthracycline, topical dimethylsulfoxide (DMSO) is used, and for perivascular injection of vinca alkaloid, subcutaneous hyaluronidase is administered.

Spatiotemporal calcium signaling in a Drosophila melanogaster cell line stably expressing a Drosophila muscarinic acetylcholine receptor.

A muscarinic acetylcholine receptor (mAChR), DM1, expressed in the nervous system of Drosophila melanogaster, has been stably expressed in a Drosophila S2 cell line (S2-DM1) and used to investigate spatiotemporal calcium changes following agonist activation. Carbamylcholine (CCh) and oxotremorine are potent agonists, whereas application of the vertebrate M1 mAChR agonist, McN-A-343, results in a weak response. Activation of S2-DM1 receptors using CCh resulted in an increase in intracellular calcium ([Ca(2+)](i)) that was biphasic. Two distinct calcium sources were found to contribute to calcium signaling: (1) internal stores that are sensitive to both thapsigargin and 2-aminoethoxydiphenyl borate and (2) capacitative calcium entry. Spatiotemporal imaging of individual S2-DM1 cells showed that the CCh-induced [Ca(2+)](i) transient resulted from a homogeneous calcium increase throughout the cell, indicative of calcium release from internal stores. In contrast, ionomycin induced the formation of a "calcium ring" at the cell periphery, consistent with external calcium influx.

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.

["Folie a deux" in the age of lasers]. / "Folie à deux" im Laserzeitalter.

We report on a 59-year-old teacher suffering for approximately 5 years from multiple dermatological changes, some of which are artificially induced and some of which are imaginary. The patient believes these manifestations are the result of neighbors shooting at her with lasers. Her husband is also convinced of the veracity of these impressions. We interpret her notion of almost daily laser attacks to a skin-related paranoid/hallucinatory psychosis with the involvement of her husband in a "folie à deux".

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.

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.

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.

Pharmacology of skeletal muscle GABA-gated chloride channels in the cockroach Periplaneta americana.

The pharmacology of -aminobutyric acid (GABA)-gated chloride channels of the coxal levator (182c,d) muscle of the cockroach Periplaneta americana has been investigated and the data compared with similar findings for the cell body of the cockroach fast coxal depressor motor neurone (Df). Muscle GABA receptors resembled those of the motor neurone cell body in their sensitivity to picrotoxinin and insensitivity to bicuculline. However, muscle GABA receptors were insensitive to the neuronal GABA receptor agonists isoguvacine (10(-4) mol l-1) and 3-aminopropane sulphonic acid (10(-3 )mol l-1). The benzodiazepine flunitrazepam, which at 10(-6 )mol l-1 greatly enhances the amplitude of the motor neurone GABA-induced responses, failed to affect muscle responses to GABA when tested at the same and at a higher (10(-4 )mol l-1) concentration. The convulsant t-butylbicyclophosphorothionate was a weak antagonist of cockroach muscle GABA receptors, whereas several cyclodienes were much more effective antagonists. Thus, studies using a benzodiazepine and several convulsant antagonists reveal differences in the pharmacology of muscle and neuronal GABA receptors of the cockroach Periplaneta americana.

Polycyclic dinitriles: a novel class of potent GABAergic insecticides provides a new radioligand, [3H]BIDN.

The polycyclic dinitriles are a potent class of insecticides which are non-competitive GABA (gamma-aminobutyric acid) antagonists acting at the convulsant site. Comparison with other classes of GABA convulsant site ligands using molecular modelling has shown significant structural similarities. We have developed a pharmacophore model which unifies this class and some previous classes of GABA convulsants. Key pharmacophore elements are a polarizable functionality separated by a fixed distance from two H-bond accepting elements. This model is based on information from X-ray crystal structures and Sybyl using the Tripos force field. Using this pharmacophore model, numerous structural modifications were explored to enhance understanding of structure-activity relationships at the GABA receptor convulsant site of insects and mammals. A radiolabelled bicyclic dinitrile, [3H]BIDN [3H]3,3-bis-trifluoromethyl-bicyclo[2,2,1]heptane-2,2-dicarbonitrile+ ++), was prepared from this area of chemistry and was used as a probe for the interaction of polycyclic dinitriles at the target site.

[The aortic arch as an embolism source for cerebral infarcts]. / Der Aortenbogen als Emboliequelle zerebraler Infarkte.

Atherosclerotic plaques in the aortic arch are a potential source of cerebral emboli in patients with cryptogenic stroke (Amarenco et al., 1994). We report on seven patients with cerebral infarction, who had atherosclerotic plaques in the aortic arch, diagnosed by transesophageal echocardiography (TEE). Cardiovascular risk factors as hypertension, diabetes, hypercholesterolemia or cigarette smoking were found in all cases. Carotid disease was present in four patients, one patient had atrial fibrillation with left atrial spontaneous echo contrast, which might have been an additional potential embolic source. Intraluminal protrusion of the plaques ranged from five to twenty-four millimeters. In conclusion, even in patients with carotid or heart disease, the aortic arch may be an important source of cerebral emboli. In cases with mobile and pedunculated protruding atheromas anticoagulation should be considered.

Adolescents' reasons for and experience after discontinuation of the long-acting contraceptives Depo-Provera and Norplant.

PURPOSE: The objectives of this study were to examine the reasons for discontinuation of the long-acting contraceptives Depo-Provera and Norplant in adolescents, and to assess the adolescents' experience after discontinuation of the methods. METHODS: A total of 35 adolescents [gynecologic age 4.7 +/- 0.3 years, and body mass index (BMI) 24.2 +/- 0.6] who discontinued Depo-Provera, and 31 adolescents (gynecologic age 3.4 +/- 0.3 years, BMI 24.1 +/- 0.9) who discontinued Norplant were periodically assessed during use of the methods and up to 12 months after discontinuation. RESULTS: The most common reasons for discontinuation of both Norplant (after 21.8 +/- 1.6 months of use) and Depo-Provera (9.2 + 0.9 months of use) were irregular menstrual bleeding (64%), weight gain (41%), and increased headaches (30%). Resumption of menstrual regularity and dysmenorrhea was noted sooner after discontinuation of Norplant, compared with Depo-Provera. The increase in BMI noted at discontinuation of Depo-Provera (1.1, P = .0005) and Norplant (1.3, P = .03) persisted up to 6 months after discontinuation of either method (0.6, P = .01 post-Depo-Provera discontinuation; and 0.9, P = 0.02 post-Norplant discontinuation). Only 62% of the adolescents reported no break in contraceptive practice. The condom was the most popular method (37%) after discontinuation of Depo-Provera, and oral contraceptive (39%) after discontinuation of Norplant. The cumulative conception proportion reached 0.93 at 12 months after discontinuation of Norplant, and was significantly higher (P = .01) compared with the cumulative proportion of conception after discontinuation of Depo-Provera (P = .50). CONCLUSIONS: Health care providers should aggressively manage physical problems associated with Depo-Provera and Norplant use, and expedite the transition to a new contraceptive method to minimize the high pregnancy rate observed after discontinuation of these methods in adolescents.

PIP: The authors present their findings from the study of adolescents' reasons for discontinuing the use of Norplant and Depo-Provera. Their experiences after method discontinuation were also assessed. 35 adolescents of mean gynecologic age 4.7 years and body mass index (BMI) 24.2 who discontinued Depo-Provera, and 31 adolescents of mean gynecologic age 3.4 years and BMI 24.1 who discontinued Norplant were periodically assessed during use of the methods and up to 12 months after discontinuation. The most common reasons for discontinuation of both Norplant and Depo-Provera after mean periods of 21.8 and 9.2 months use, respectively, were irregular menstrual bleeding (64%), weight gain (41%), and increased headaches (30%). The resumption of menstrual regularity and dysmenorrhea was noted sooner after discontinuation of Norplant, compared to Depo-Provera. The increase in BMI noted at the discontinuation of Depo-Provera persisted up to 6 months after discontinuation of either method. 62% of adolescents reported no break in contraceptive practice. The condom was the most popular method (37%) after discontinuation of Depo-Provera, and oral contraceptives (39%) after discontinuation of Norplant. The authors conclude that health care providers should aggressively manage physical problems associated with Depo-Provera and Norplant use, and expedite the transition to new contraceptive methods in an effort to minimize the high pregnancy rates observed after discontinuation of these methods in adolescents.

Immunocytochemical mapping of a C-terminus anti-peptide antibody to the GABA receptor subunit, RDL in the nervous system in Drosophila melanogaster.

An antibody raised against a peptide based on the C-terminal derived amino acid sequence from a cloned Drosophila melanogaster (fruit fly) gene, Rdl (resistant to dieldrin), was used to investigate localization of a GABA receptor subunit in adult male D. melanogaster. Many regions in the brain and thoracic ganglia were stained with this antibody. For example, staining was detected in the medulla, lobula and lobular plate optic neurpiles. Also stained were the antennal lobe glomeruli, the ellipsoid body of the central complex and the mushroom bodies. These results suggest possible roles for an RDL-like GABA receptor subunit in the processing of olfactory, visual and mechanosensory information in the nervous system of D. melanogaster.

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.

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.

[Rhombencephalitis caused by Listeria monocytogenes]. / Rhombenzephalitis durch Listeria monocytogenes.

We report the case of a 57-year-old man with Listeria rhombencephalitis. This had been ascertained by means of Listeria isolation from the cerebrospinal fluid. After an nonspecific prodromial period with nausea and headache, he developed fever, meningism, brain stem dysfunction and an organic psychosis. With early antibiotic therapy (ampicillin/gentamycin), it was possible to bring about a restitio ad integrum. Different brain-imaging methods (computed tomography, MRI, brain SPECT) in the acute and follow-up stages are discussed.

The pediatrician's role in assisting teenagers to avoid the consequences of adolescent pregnancy.

There are ways in which the practicing pediatrician can help adolescent prevent pregnancy or improve the outcome of pregnancy. Clearly, each practitioner will have to decide what services will work best within his or her practice as well as for the community.

PIP: The high rate of adolescent pregnancy remains one of the world's major medical/social problems. In the US, teens most at risk are young, Black or Hispanic, and poor. Serious medical and social sequelae may follow teen pregnancy. Comprehensive prenatal care provided by staff sensitive to the needs and concerns of adolescents; nutritional assessment and support services; schools for pregnant teens; and contraceptive and abortion services, however, reduce the seriousness of these sequelae and improve the quality of life for mothers and children over the long term. 4 realistic scenarios are offered in which practicing pediatricians have opportunities to help adolescents prevent pregnancy or improve its outcome. Ultimately, however, individual practitioners must decide which services will work best in the context of their practice and community.