[Acute hypersensitivity reactions associated with monoclonal antibodies for targeted therapy]. / Akute Überempfindlichkeitsreaktionen auf monoklonale Antikörper zur zielgerichteten Therapie.

The application of biologics such as monoclonal antibodies for targeted therapy may lead to immediate adverse drug reactions with different pathophysiological mechanisms. Some of them are due to the immunogenicity of these drugs and are truly allergic, some of them are non-allergic, some are on-target, and some are off-target. The main example of non-allergic reactions are infusion reactions, mainly induced by cytokine release. They generally occur already at the first application and symptoms may decrease in subsequent applications. Allergic reactions need a preceding sensitization phase and therefore may not occur at first application. However, if the IgE-mediated reaction is due to cross-reactivity, they may occur at the first application of the monoclonal antibody. The management of these reactions depends on their severity and the ultimate need to treat the patient with these drugs.

[Drug-induced angioedema : Focus on bradykinin]. / Arzneimittelassoziierte Angioödeme : Bradykinin im Fokus.

On a pathophysiological level, angioedema can be differentiated into histamine- and bradykinin-mediated types. The prototype drug-associated, bradykinin-mediated form of angioedema is angiotensin-converting enzyme (ACE) inhibitor-induced angioedema. The hypothesized cause is a decrease in bradykinin degradation via ACE inhibition. In this scenario, other bradykinin-degrading enzymes assume major importance. When the effect of these enzymes is also diminished, e. g., due to genetic variants or external factors, compensation for the inhibition of ACE may be insufficient. An increased risk of angioedema has also been reported for other drugs, particularly when prescribed in combination with ACE inhibitors. Here, the suspected cause also relates to the degradation of bradykinin. When angioedema arises within the context of concomitant ACE inhibitor use, additive bradykinin degradation effects may be implicated.

Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

Background: Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity. Methods: Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aß42, Aß40, Aß42/Aß40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics. Results: In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) . Conclusions: Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.

Erratum to: Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

[This corrects the article DOI: 10.14283/jarlife.2024.1.].

Adatoms and clusters of 3d transition metals on graphene: electronic and magnetic configurations.

We investigate the electronic and magnetic properties of single Fe, Co, and Ni atoms and clusters on monolayer graphene (MLG) on SiC(0001) by means of scanning tunneling microscopy (STM), x-ray absorption spectroscopy, x-ray magnetic circular dichroism (XMCD), and ab initio calculations. STM reveals different adsorption sites for Ni and Co adatoms. XMCD proves Fe and Co adatoms to be paramagnetic and to exhibit an out-of-plane easy axis in agreement with theory. In contrast, we experimentally find a nonmagnetic ground state for Ni monomers while an increasing cluster size leads to sizeable magnetic moments. These observations are well reproduced by our calculations and reveal the importance of hybridization effects and intra-atomic charge transfer for the properties of adatoms and clusters on MLG.

Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice.

Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.

Local gating of an Ir(111) surface resonance by graphene islands.

The influence of graphene islands on the electronic structure of the Ir(111) surface is investigated. Scanning tunneling spectroscopy (STS) indicates the presence of a two-dimensional electron gas with a binding energy of -160 meV and an effective mass of -0.18me underneath single-layer graphene on the Ir(111) surface. Density functional calculations reveal that the STS features are predominantly due to a holelike surface resonance of the Ir(111) substrate. Nanometer-sized graphene islands act as local gates, which shift and confine the surface resonance.

Analysis of cytokine secretion from lymphocytes of patients with hypersensitivity reactions to contaminated heparins.

BACKGROUND: Beginning in 2007, anaphylactoid reactions associated with unfractionated heparin (UFH) occurred and resulted in some fatalities. These reactions were reported to be linked to the complement and contact system activation induced by certain batches of UFH containing the adulterant oversulphated chondroitin sulphate (OSCS). OBJECTIVES: Drug-specific secretion of selected cytokines from peripheral blood mononuclear cells (PBMC) of patients with hypersensitivity reactions to contaminated heparin was compared with the respective in vitro cytokine pattern of individuals with or without hypersensitivity to heparin, different glycosaminoglycans or other drugs. METHODS: Study individuals (n = 13) were classified as follows: patients with hypersensitivity reactions to contaminated (OSCS) heparin (n = 3), noncontaminated heparin (n = 1) or other compounds (n = 3) and patients with ongoing heparin therapy without symptoms of intolerance (n = 2). Four healthy individuals served as controls. PBMC were incubated with six different glycosaminoglycan structures. Drug-specific intracellular interleukin (IL)-5, interferon (IFN)-γ and IL-10 production was investigated by flow cytometry, while secretion of IL-5, IL-2 and IFN-γ was analysed by enzyme-linked immunosorbent assay. RESULTS: PBMC from individuals with hypersensitivity reactions to contaminated heparin secreted considerable amounts of IL-2 in vitro. There was a suggestion that ongoing heparin therapy and the Li-heparin in the vials may have an impact on the lymphocyte reactivity of PBMC. CONCLUSIONS: The in vitro lymphocyte reactivity pattern of PBMC from individuals with hypersensitivity reactions to contaminated heparins was neither typical for an immune-mediated nor for a nonimmune-mediated reaction. Possible effects of heparins in the test system itself may require consideration.

In vitro detection and characterization of drug hypersensitivity using flow cytometry.

BACKGROUND: The lymphocyte transformation test (LTT) is the only in vitro test for detecting drug sensitization at the cellular level irrespective of the reaction's phenotype. However, the LTT includes working with radioactive substances and is considered impracticable for routine laboratory investigation. OBJECTIVE: The aim of this study was to assess drug-specific cytokine production by means of flow cytometry as an alternative nonradioactive approach which may be more appropriate for routine testing and may provide in addition more information about the pathophysiology of the reaction than proliferation-based assays, like the LTT. METHOD: Peripheral blood mononuclear cells of 19 patients were incubated with culprit drugs (n = 28) or irrelevant antigens (n = 10). Ten healthy persons served as controls for all different drugs (n = 15). Intracellular interleukin (IL)-5, interferon (IFN)-gamma and IL-10 production was investigated using flow cytometry. Accuracy of the flow cytometry test system was confirmed using different statistical tests, i.e. receiver operating characteristic curve and Mann-Whitney rank test. In addition, drug-specific secretion of IL-5, IL-2 and IFN-gamma were analysed using enzyme-linked immunosorbent assay (ELISA). RESULTS: Drug-specific cytokine production could be demonstrated in 75% of the patients using flow cytometry and in 79% using ELISA respectively. Combining ELISA and flow cytometry increased the sensitivity to 100%. Analysis of involved T-cell subsets [e.g. CD4(+) or CD8(+); T helper (TH) 1 or TH 2] allowed characterization of the in vitro lymphocyte reactivity pattern. CONCLUSIONS: Analysis of drug-specific cytokine production by means of flow cytometry proved a useful and reliable approach for the in vitro detection and characterization of drug hypersensitivities.

Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GALEN platform. The Galenda project.

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.

Photoperiodic control of the cloacal gland of the Japanese quail.

Changes in photoperiod cause correlated changes in testes, cloacal glands, cloacal foam, and reproductive behavior of male Japanese quail. The cloacal protrusion may serve as a convenient external index of androgen, permitting repeated measurement without operation on or killing of the animal.

Sexual behavior: stimulation by painful electrical shock to skin in male rats.

A mildly painful electric shock lasting 0.5 second was delivered every 30 seconds to the skin of male rats while they were with a receptive female rat. Sexual behavior occurred, with brief latency, after shocks; thus, successive shocks resulted in a pacing of sexual behavior. This effect is attributed to periodic augmentation of sexual arousal by a periodic, nonspecific arousing stimulus (that is, shock).

Ejaculatory pattern in female rats without androgen treatment.

Adult female rats receiving long-term estrogen treatment displayed the species-typical motor pattern of ejaculation during copulation. This hormone treatment produced pituitary hypertrophy and concomitant pressure damage to brain areas dorsal to the pituitary, but did not cause clitoral hypertrophy. The demonstration of the ejaculatory pattern in perinatally untreated female rats indicates that the potential for the expression of the ejaculatory or "orgasmic" pattern is not dependent on exogenous androgen at any stage of development and is more widely represented among female mammals than previously believed.

Sexual behavior: normal male patterning in androgenized female rats.

Female rats treated with testosterone as neonates and as adults exhibited a temporal patterning of male copulatory behavior identical to that of normal males, although such females displayed few intromission reflexes and almost no ejaculatory patterns. With prenatal, postnatal, and adult testosterone treatment, female rats displayed all the characteristic masculine responses and intervals, including the ultrasonic postejaculatory vocalization.

Label-inconsistent use of sibutramine in spontaneous adverse drug reaction reports in Germany.

In Germany, reports on adverse drug reactions (ADRs) are centrally collected and analyzed by the Federal Institute for Drugs and Medical Devices (BfArM). During routine analysis of ADR reports related to the antiobesity drug sibutramine, we repeatedly observed descriptions of its label*-inconsistent use (*European Summary of Product Characteristics (SmPC)). In order to quantify this observation, we analyzed all sibutramine-related ADR reports received by the BfArM so far. Using the same data source, we further analyzed the effect of a Dear Doctor Letter (DDL) which was distributed in 2002 in order to reinforce the label-consistent use of sibutramine. Out of a total of 170 identified reports, 104 were considered as suitable for further analysis. Of these, applying a catalogue of 24 SmPC-derived criteria, 34% (35 reports) contained information indicative of label-inconsistent use. The individual SmPC-criteria most often violated were (% of total analyzed reports): the recommended starting dose of 10 mg/day (9%), the body mass index (BMI)-related threshold permitting drug therapy (6%), and the contraindicated "history of drug abuse" (6%). The DDL was ineffective. The observed percentage of ADR reports, indicating a label-inconsistent use of sibutramine, is considered a signal for a therapeutic risk. This signal should be addressed in a drug utilization study investigating the use of sibutramine by means of a representative patient sample.

Placing erection in context: the reflexogenic-psychogenic dichotomy reconsidered.

Penile erections are usually classified as arising from "reflexogenic" or "psychogenic" causes. In practice this dichotomy has translated, somewhat circularly, to a distinction between spinal vs. supraspinal mediation, pelvic vs. hypogastric neural mediation, and perineal somesthetic stimulation vs. stimulation of receptors innervated by the cranial nerves. Evidence for differential regulation of erection in different contexts is reviewed. Research ascribing a physiological role to the hypogastric nerves in psychogenic erection, exemplified by classic studies of cats and spinally injured men, is suggestive but not compelling. Somewhat stronger is evidence that erection in some contexts (e.g., nocturnal penile tumescence (NPT) in humans or touch-stimulated erection in rats) is more sensitive to androgen levels than in other contexts (e.g., visual erotic stimuli in men or copulation in rats). However, some of these differences may arise from the relative erectogenic strength of the stimuli, rather than from qualitative differences in androgen sensitivity of different contexts. More compelling is the possibility that conflicting interpretations of the role of dopamine in erection may stem in large part from differences among laboratories in the context in which erection is evoked. In light of the evidence reviewed, it seems unlikely that the conventional reflexogenic-psychogenic dichotomy should be retained, at least in its present form. As a first step, it may be worth considering that reflexive erections may not be limited to somesthetic perineal stimulation, but rather may also include stimuli received via the cranial nerves. Two alternatives to the standard reflexogenic-psychogenic dichotomy are proposed. The first is a minor revision in which two senses of psychogenic erection are distinguished: the weak, commonly used, sense would include erection resulting from any extrinsic nonsomesthetic stimulation, whether visual, auditory, or chemosensory. In this sense, reflexive erections and psychogenic erections may not be mutually exclusive. The strong sense of psychogenic erection would be limited to memory and fantasy. The origins of psychogenic erection in both senses need not be available to consciousness, which may account for apparently spontaneous erections. In the second alternative taxonomy, erectogenic stimuli are classified as contact (somesthetic) or noncontact, and their action in evoking erection is placed on a continuum of reflexivity. Erectile contexts could then be considered as orthogonal to the other two dimensions. Even without a change in taxonomy, the conduct and interpretation of research into erectile function may be expected to benefit from closer attention to differences and similarities between contexts and species, and to context-sensitive differences in the regulation of erection.

Contextual approaches to the physiology and classification of erectile function, erectile dysfunction, and sexual arousal.

This paper offers a reexamination of some long-held beliefs relating to the physiology of erectile function and dysfunction, including the idea that there is a singular physiology of erection. Rather, there appear to be plural neural, neurochemical, and endocrine mechanisms whose participation in erectile function depends on the behavioral context in which erection occurs. The best examples of this context-dependent physiology come from research on rats. For example, the medial amygdala is essential for noncontact erection in response to inaccessible estrous females, but not for erection during copulation. Also, androgen is necessary for touch-based and noncontact erection, but not for erection during copulation. Even the specific dopamine receptors important to erection may differ, depending on the context. If there is not a singular physiology of erection, then it follows that the physiology of erectile dysfunction may also vary from context to context. Thus, some disorders of the central nervous system may not be manifested in sleep-related erection, and therefore may be misinterpreted as "psychogenic" erectile dysfunction. This term belies the axiom that all psychological processes have a somatic basis; therefore, there can be no psychogenic dysfunction that does not involve organic processes which may respond to pharmacotherapy. A revised classification of erectile dysfunction based on this premise is offered. Finally, closer attention to erectile context may also illuminate male "sexual arousal" and its relation to "sexual motivation". The former term has so many meanings in current usage as to impede research, especially into the physiology of sexual arousal, which depends on comparisons between animals and humans. It is proposed that attention be given to two variables: whether or not erection occurs and whether or not the context is sexual. The occurrence of penile erection within a sexual context is viewed as the only case in which sexual arousal may be inferred unambiguously.

Introduction--reproductive behavior: a symposium in honor of Frank A. Beach, 1911-1988.

A symposium honoring the memory of Frank A. Beach (1911-1988) and celebrating his scientific contributions was held on June 12, 1989 during the 21st Conference on Reproductive Behavior (CRB). The papers arising from the symposium are introduced after a very brief history of the CRB and its origins in an annual meeting of West Coast American sex researchers that was organized by Frank Beach and his colleagues.

Psychiatrist-wife-mother: some aspects of role integration.

Throughout her professional life the woman who chooses to combine the roles of psychiatrist, wife, and mother may find them not only compatible but complementary. If she can adopt a philosophy of life that permits her to function in these roles, and if those around her support her activities, she can perform with relative ease and proficiency. Her lifestyle must of necessity differ from that of her male colleagues, but differing lifestyles among members of a profession vitalize the field. A broad perspective is desirable, especially in a profession that deals with the emotional and mental lives of people. Married women and mothers afford such a broadened perspective to the field of psychiatry.