Anhedonia as a transdiagnostic symptom across psychological disorders: a network approach.

BACKGROUND: Anhedonia is apparent in different mental disorders and is suggested to be related to dysfunctions in the reward system and/or affect regulation. It may hence be a common underlying feature associated with symptom severity of mental disorders. METHODS: We constructed a cross-sectional graphical Least Absolute Shrinkage and Selection Operator (LASSO) network and a relative importance network to estimate the relationships between anhedonia severity and the severity of symptom clusters of major depressive disorder (MDD), anxiety sensitivity (AS), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) in a sample of Dutch adult psychiatric patients (N = 557). RESULTS: Both these networks revealed anhedonia severity and depression symptom severity as central to the network. Results suggest that anhedonia severity may be predictive of the severity of symptom clusters of MDD, AS, ADHD, and ASD. MDD symptom severity may be predictive of AS and ADHD symptom severity. CONCLUSIONS: The results suggest that anhedonia may serve as a common underlying transdiagnostic psychopathology feature, predictive of the severity of symptom clusters of depression, AS, ADHD, and ASD. Thus, anhedonia may be associated with the high comorbidity between these symptom clusters and disorders. If our results will be replicated in future studies, it is recommended for clinicians to be more vigilant about screening for anhedonia and/or depression severity in individuals diagnosed with an anxiety disorder, ADHD and/or ASD.

[Extranodal manifestation of classical Hodgkin lymphoma in the head and neck region]. / Extranodale Manifestation klassischer Hodgkin-Lymphome im HNO-Bereich.

BACKGROUND: Extranodal lymphomas occurring in the head and neck region account for 12-15% of all malignant tumors of this locality. Classical Hodgkin lymphoma (cHL) is a rare subtype, representing around 1% of all lymphomas in Waldeyer's ring. Cases diagnosed in the Reference Centre for Lymph Node Pathology at the Pathological Institute of the University of Würzburg were further analyzed in this study. MATERIALS AND METHODS: Histological subtype and EBV association of 21 cases were reviewed in conjunction with clinical data. RESULTS: Data of 12 male and 9 female patients with an average age of 51 years (median 45; 35-72) were reviewed. All samples were taken from the lymphatic tissue of the Waldeyer's ring (nasopharynx n = 15, palatine tonsils n = 5, lingual tonsils n = 1). The most common symptoms leading to a consultation with an otorhinolaryngologist were otalgia, swelling, or impaired nasal breathing. Only four patients showed typical B­symptoms. In 6 cases (29%), an isolated extranodal manifestation was found, 15 patients (71%) showed simultaneous infiltration of cervical lymph nodes during staging, and 6 cases (29%) were EBV positive. CONCLUSION: An exclusively extranodal manifestation of cHL in Waldeyer's ring is rare, whereas infiltration of extranodal tissue in the case of a primary manifestation of lymphoma in cervical nodes can occur more frequently and may often remain undiagnosed. Therefore, a specialized ENT consultation could be a reasonable complementary module in tumor staging to determine the correct tumor extent.

Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo.

STUDY QUESTION: Does ibuprofen use during the first trimester of pregnancy interfere with the development of the human fetal ovary? SUMMARY ANSWER: In human fetuses, ibuprofen exposure is deleterious for ovarian germ cells. WHAT IS KNOWN ALREADY: In utero stages of ovarian development define the future reproductive capacity of a woman. In rodents, analgesics can impair the development of the fetal ovary leading to early onset of fertility failure. Ibuprofen, which is available over-the-counter, has been reported as a frequently consumed medication during pregnancy, especially during the first trimester when the ovarian germ cells undergo crucial steps of proliferation and differentiation. STUDY DESIGN, SIZE, DURATION: Organotypic cultures of human ovaries obtained from 7 to 12 developmental week (DW) fetuses were exposed to ibuprofen at 1-100 µM for 2, 4 or 7 days. For each individual, a control culture (vehicle) was included and compared to its treated counterpart. A total of 185 individual samples were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian explants were analyzed by flow cytometry, immunohistochemistry and quantitative PCR. Endpoints focused on ovarian cell number, cell death, proliferation and germ cell complement. To analyze the possible range of exposure, ibuprofen was measured in the umbilical cord blood from the women exposed or not to ibuprofen prior to termination of pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: Human ovarian explants exposed to 10 and 100 µM ibuprofen showed reduced cell number, less proliferating cells, increased apoptosis and a dramatic loss of germ cell number, regardless of the gestational age of the fetus. Significant effects were observed after 7 days of exposure to 10 µM ibuprofen. At this concentration, apoptosis was observed as early as 2 days of treatment, along with a decrease in M2A-positive germ cell number. These deleterious effects of ibuprofen were not fully rescued after 5 days of drug withdrawal. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This study was performed in an experimental setting of human ovaries explants exposed to the drug in culture, which may not fully recapitulate the complexity of in vivo exposure and organ development. Inter-individual variability is also to be taken into account. WIDER IMPLICATIONS OF THE FINDINGS: Whereas ibuprofen is currently only contra-indicated after 24 weeks of pregnancy, our results points to a deleterious effect of this drug on first trimester fetal ovaries ex vivo. These findings deserve to be considered in light of the present recommendations about ibuprofen consumption pregnancy, and reveal the urgent need for further investigations on the cellular and molecular mechanisms that underlie the effect of ibuprofen on fetal ovary development.

Emerging roles for the FCRL family members in lymphocyte biology and disease.

Members of the extended Fc receptor-like (FCRL) family in humans and mice are preferentially expressed by B cells and possess tyrosine-based immunoregulatory function. Although the majority of these proteins repress B cell receptor-mediated activation, there is an emerging evidence for their bifunctionality and capacity to counter-regulate adaptive and innate signaling pathways. In light of these findings, the recent discovery of ligands for several of these molecules has begun to reveal exciting potential for them in normal lymphocyte biology and is launching a new phase of FCRL investigation. Importantly, these fundamental developments are also setting the stage for defining their altered roles in the pathogenesis of a growing number of immune-mediated diseases. Here we review recent advances in the FCRL field and highlight the significance of these intriguing receptors in normal and perturbed immunobiology.

Selective attention and fear of cancer recurrence in breast cancer survivors.

BACKGROUND: Anxious people show an attentional bias towards threatening information. PURPOSE: It was investigated whether an attentional bias exists for cancer-related stimuli in breast cancer survivors and if different levels of fear of cancer recurrence would lead to different patterns of selective attention. METHODS: Breast cancer survivors with high (n = 35) and low (n = 32) fear of cancer recurrence were compared to 40 healthy female hospital employees. Specificity of attentional biases was investigated using a modified Emotional Stroop Task. Self-report measures were used to assess depression and anxiety, feelings of fatigue, and experienced traumas. RESULTS: Compared to control participants, breast cancer survivors with both high and low levels of fear of cancer recurrence showed increased interference for cancer-related words, but not for other word types. CONCLUSIONS: The findings suggest a specific attentional bias for cancer-related words in breast cancer survivors that is independent of level of fear of cancer recurrence.

[Head and neck hamartomas: 10 years of experience at the Charité--University Medical Center Berlin]. / Hamartome im Kopf-Hals-Bereich: 10 Jahre Erfahrung an der Charité--Universitätsmedizin Berlin.

BACKGROUND: Head and neck tumors are rare entities in neonates. Hamartomas are benign congenital neoplasms. To date, there is a lack of sufficient epidemiological data concerning hamartomas in the field of otorhinolaryngology. MATERIALS AND METHODS: We retrospectively analyzed experiences at the Charité over the past 10 years in an ICD-10-based manner. Our otorhinolaryngology department maintains close cooperation with the level 1 perinatal center on our campus. RESULTS: The authors identified 3 patients suffering from fibrous hamartomas. This corresponds to an incidence of 2-3/30,000 newborns. The clinical aspects and courses are described in detail. Experiences with the management of hamartomas obstructing the upper aerodigestive tract are described. CONCLUSION: Head and neck hamartomas are very rare malformations. They possess the ability to cause otorhinolaryngological emergencies in newborns. Interdisciplinary management and histological assessment are mandatory. Anmerkung.

Concurrent hyperfractionated accelerated radiotherapy with 5-FU and once weekly cisplatin in locally advanced head and neck cancer. The 10-year results of a prospective phase II trial.

PURPOSE: In this study, the acute toxicity and long-term outcome of a hyperfractionated accelerated chemoradiation regimen with cisplatin/5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinomas of head and neck were evaluated. PATIENTS AND METHODS: From 2000-2002, 38 patients with stage III (5.3 %) and stage IV (94.7 %) head and neck cancer were enrolled in a phase II study. Patients received hyperfractionated-accelerated radiotherapy with 72 Gy in 15 fractions of 2 Gy followed by 1.4 Gy twice daily with concurrent, continuous infusion 5-FU of 600 mg/m(2) on days 1-5 and 6 cycles of weekly cisplatin (30 mg/m(2)). Acute toxicities (CTCAEv2.0), locoregional control (LRC), metastases-free (MFS), and overall survival (OS) were analyzed and exploratively compared with the ARO 95-06 trial. RESULTS: Median follow-up was 11.4 years (95 % CI 8.6-14.2) and mean dose 71.6 Gy. Of the patients, 82 % had 6 (n = 15) or 5 (n = 16) cycles of cisplatin, 5 and 2 patients received 4 and 3 cycles, respectively. Grade 3 anemia, leukopenia, and thrombocytopenia were observed in 15.8, 15.8, and 2.6 %, respectively. Grade 3 mucositis in 50 %, grade 3 and 4 dysphagia in 55 and 13 %. The 2-, 5-, and 10-year LRC was 65, 53.6, and 48.2 %, the MFS was 77.5, 66.7, and 57.2 % and the OS 59.6, 29.2, and 15 %, respectively. CONCLUSION: Chemoradiation with 5-FU and cisplatin seems feasible and superior in terms of LRC and OS to the ARO 95-06C-HART arm at 2 years. However, this did not persist at the 5- and 10-year follow-ups.

Treatment of severe autoimmune blistering skin diseases with combination of protein A immunoadsorption and rituximab: a protocol without initial high dose or pulse steroid medication.

BACKGROUND: Skin blistering diseases due to autoantibodies are typically treated with high dose systemic corticosteroids and other conventional immunosuppressants. However, in severe cases, this treatment may not be sufficient to achieve disease control or contraindicated because of comorbidity. METHODS: We describe 15 patients (pts.) with such diseases: 6 pts. with pemphigus vulgaris, 3 pts. with bullous pemphigoid, 3 pts. with mucous membrane pemphigoid (MMP), one being anti-laminin-332-MMP (AL332-MMP), 2 pts. with pemphigus foliaceus and 1 pt. with epidermolysis bullosa acquisita (EBA). Patients were treated with a combination of protein A immunoadsorption (PAIA, 3-21 treatments) and rituximab (3-6 treatments) in addition to low dose conventional immunosuppression. RESULTS: All patients showed rapid clinical improvement starting within the first 4 weeks and decline of circulating autoantibody levels. Complete/partial remission was 88%/12% in pemphigus and 71%/29% in subepidermal blistering diseases. Overall relapse rate was 13% with an average follow-up of 22 months. In the AL332-MMP pt. the PAIA/rituximab treatment was stopped because of an oesophagus cancer considered as the paraneoplastic cause of the skin disease. CONCLUSION: Combined treatment with PAIA and rituximab showed rapid and long-lasting response, thereby allowing substantial reduction of dosage of concomitant immunosuppressive medication. We hereby confirm data from other investigators that PAIA/rituximab treatment is a promising therapeutical modality for pemphigus, pemphigoids and EBA, characterized by a favourable ratio of beneficial efficacy and minimized long-term adverse effects.

A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes.

AIM: This Phase IIb, randomized, double-blind, placebo-controlled trial evaluated the efficacy, safety, tolerability and pharmacokinetics of empagliflozin in patients with type 2 diabetes. METHODS: Four hundred and eight patients (treatment-naïve or after a 4-week wash-out period) were randomized to receive empagliflozin 5, 10 or 25 mg once daily, placebo or open-label metformin for 12 weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) after 12 weeks. RESULTS: After 12 weeks' treatment, empagliflozin showed dose-dependent reductions in HbA1c from baseline [5 mg: -0.4%, 10 mg: -0.5%, 25 mg: -0.6%; all doses p < 0.0001 vs. placebo (+0.09%)]. Fasting plasma glucose (FPG) decreased with empagliflozin [5 mg: -1.29 mmol/l, 10 mg: -1.61 mmol/l, 25 mg: -1.72 mmol/l; all doses p < 0.0001 vs. placebo (+0.04 mmol/l)]. Body weight decreased in all empagliflozin groups (all doses p < 0.001 vs. placebo). The incidence of adverse events (AEs) was similar in the placebo (32.9%) and empagliflozin (29.1%) groups. The most frequently reported AEs on empagliflozin were pollakiuria (3.3% vs. 0% for placebo), thirst (3.3% vs. 0% for placebo) and nasopharyngitis (2.0% vs. 1.2% for placebo). AEs consistent with urinary tract infections (UTIs) were reported in four (1.6%) patients on empagliflozin vs. one (1.2%) on placebo. Genital infections were reported in five (2%) patients on empagliflozin vs. 0% on placebo. No UTIs or genital infections led to premature discontinuation. CONCLUSIONS: In patients with type 2 diabetes, empagliflozin resulted in dose-dependent, clinically meaningful reductions in HbA1c and FPG, and reductions in body weight compared with placebo. Empagliflozin was well-tolerated with a favourable safety profile.

Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes.

AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of empagliflozin in patients with type 2 diabetes following oral administration of 10, 25 or 100 mg doses once daily over 28 days. METHODS: A total of 78 patients were assigned to empagliflozin 10 mg (n = 16), 25 mg (n = 16) or 100 mg (n = 30) or placebo (n = 16) for 28 days. Assessments included adverse events (AEs) and pharmacokinetic and pharmacodynamic endpoints. RESULTS: Empagliflozin exposure increased dose-proportionally over the dose range 10-100 mg and showed linear pharmacokinetics with respect to time. Urinary glucose excretion (UGE) increased from baseline to day 1 by 74, 90 and 81 g with empagliflozin 10, 25 and 100 mg, respectively. The increases in UGE were maintained over 28 days with multiple dosing. Virtually no change in UGE was observed in the placebo group. Significant reductions from baseline in mean daily plasma glucose and fasting plasma glucose were observed with empagliflozin compared with placebo. The incidence of AEs was similar in the empagliflozin and placebo groups (50.0, 56.3 and 66.7% with empagliflozin rising doses and 62.5% with placebo). The most frequently reported AEs were pollakiuria (10.3%), nasopharyngitis (9.0%), constipation (9.0%) and headache (7.7%). CONCLUSIONS: Oral administration of empagliflozin at doses of 10, 25 or 100 mg once daily over 28 days resulted in significant increases in UGE and reductions in blood glucose compared with placebo, and were well tolerated in patients with type 2 diabetes.

Assessing the risk of ships striking large whales in marine spatial planning.

Marine spatial planning provides a comprehensive framework for managing multiple uses of the marine environment and has the potential to minimize environmental impacts and reduce conflicts among users. Spatially explicit assessments of the risks to key marine species from human activities are a requirement of marine spatial planning. We assessed the risk of ships striking humpback (Megaptera novaeangliae), blue (Balaenoptera musculus), and fin (Balaenoptera physalus) whales in alternative shipping routes derived from patterns of shipping traffic off Southern California (U.S.A.). Specifically, we developed whale-habitat models and assumed ship-strike risk for the alternative shipping routes was proportional to the number of whales predicted by the models to occur within each route. This definition of risk assumes all ships travel within a single route. We also calculated risk assuming ships travel via multiple routes. We estimated the potential for conflict between shipping and other uses (military training and fishing) due to overlap with the routes. We also estimated the overlap between shipping routes and protected areas. The route with the lowest risk for humpback whales had the highest risk for fin whales and vice versa. Risk to both species may be ameliorated by creating a new route south of the northern Channel Islands and spreading traffic between this new route and the existing route in the Santa Barbara Channel. Creating a longer route may reduce the overlap between shipping and other uses by concentrating shipping traffic. Blue whales are distributed more evenly across our study area than humpback and fin whales; thus, risk could not be ameliorated by concentrating shipping traffic in any of the routes we considered. Reducing ship-strike risk for blue whales may be necessary because our estimate of the potential number of strikes suggests that they are likely to exceed allowable levels of anthropogenic impacts established under U.S. laws.

Human PEX1 is mutated in complementation group 1 of the peroxisome biogenesis disorders.

Human peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal-recessive disease caused by mutations in PEX genes that encode peroxins, proteins required for peroxisome biogenesis. These lethal diseases include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum's disease (IRD), three phenotypes now thought to represent a continuum of clinical features that are most severe in ZS, milder in NALD and least severe in IRD2. At least eleven PBD complementation groups have been identified by somatic-cell hybridization analysis compared to the eighteen PEX complementation groups that have been found in yeast. We have cloned the human PEX1 gene encoding a 147-kD member of the AAA protein family (ATPases associated with diverse cellular activities), which is the putative orthologue of Saccharomyces cerevisiae Pex1p (ScPex1p). Human PEX1 has been identified by computer-based 'homology probing' using the ScPex1p sequence to screen databases of expressed sequence tags (dbEST) for human cDNA clones. Expression of PEX1 rescued the cells from the biogenesis defect in human fibroblasts of complementation group 1 (CG1), the largest PBD complementation group. We show that PEX1 is mutated in CG1 patients.

Large cell neuroendocrine carcinoma of the floor of mouth and retromolar trigone in association with basaloid squamous cell carcinoma.

Large cell neuroendocrine carcinoma and basaloid squamous cell carcinoma are each rare but aggressive diseases of the head and neck. A case of large cell neuroendocrine carcinoma occurring simultaneously with a basaloid squamous cell carcinoma originating from the oral cavity is described in this report. The diagnosis of these pathologies can be challenging but is important, as staging and treatment recommendations differ from those for oral cavity squamous cell carcinoma.

Dopamine depletion in wistar rats with epilepsy.

The dopamine content in cerebral structures has been related to neuronal excitability and several approaches have been used to study this phenomenon during seizure vulnerability period. In the present work, we describe the effects of dopamine depletion after the administration of 6-hidroxidopamine (6-OHDA) into the substantia nigra pars compacta of male rats submitted to the pilocarpine model of epilepsy. Susceptibility to pilocarpine-induced status epilepticus (SE), as well as spontaneous and recurrent seizures (SRSs) frequency during the chronic period of the model were determined. Since the hippocampus is one of main structures in the development of this experimental model of epilepsy, the dopamine levels in this region were also determined after drug administration. In the first experiment, 62% (15/24) of 6-OHDA pre-treated rats and 45% (11/24) of those receiving ascorbic acid as control solution progressed to motor limbic seizures evolving to SE, after the administration of pilocarpine. Severeness of seizures during the model´s the acute period, was significantly higher in epileptic experimental rats (56.52%), than in controls (4.16%). In the second experiment, the frequency of seizures in the model's chronic phase did not significantly change between groups. Our data show that dopamine may play an important role on seizure severity in the pilo's model acute period, which seems to be due to dopamine inhibitory action on motor expression of seizure.

Early paternal retrieval experience influences the degree of maternal retrieval behavior in adult California mice offspring.

In biparental species like the California mouse (Peromyscus californicus), paternal presence and care contributes to offspring survival with lasting consequences on brain development and social behavior. Paternal retrieval behavior may be particularly important since it protects young from dangers outside of the nest. We have previously shown that paternal retrievals influence social behavior of adult female and male offspring, as well as the expression of hormones associated with parental behavior. In male offspring, paternal retrieval influences future parenting, but whether paternal retrievals affect maternal behavior in adulthood is unclear. Here, we manipulated the experience of paternal retrieval during development and then assessed maternal behavior of adult female offspring. We did not detect group differences in maternal behavior during undisturbed observation or following pup displacement. However, following pup displacement we observed a moderate positive correlation between paternal retrievals experienced in development and maternal retrievals performed in adulthood. Further analysis revealed that the likelihood of females being a high or low retriever is influenced by their developmental experience. These findings suggest that although female California mice engage in similar levels of maternal behavior regardless of paternal care environment, there may be variation in retrieval behavior that is informed by paternal retrieval experience.

Comorbid depression and treatment of anxiety disorders, OCD, and PTSD: Diagnosis versus severity.

BACKGROUND: Although anxiety and depression are highly comorbid disorders, it remains unclear whether and how a concurrent depression affects the outcome of anxiety treatment. METHOD: Using anonymized routine outcome monitoring (ROM) data of 740 patients having received specialized treatment for an anxiety disorder, OCD, or PTSD, this study investigates whether a comorbid diagnosis of depression and/or self-reported depression severity levels relate to the patients' improvement following anxiety treatment. RESULTS: The results show that both the patients with and those without comorbid depression had profited similarly from the anxiety, OCD, or PTSD treatment, regardless of whether depression was merely diagnosed prior to treatment or based on self-reported severity (and assuming a smallest effect size of interest of d = 0.35/r = .2). Importantly, the post-treatment reductions in self-reported depressive symptoms were strongly and positively related to the reductions in self-reported anxiety symptoms and disorder-related disability. LIMITATIONS: Causal inferences cannot be made due to the retrospective cross-sectional design. CONCLUSIONS: The outcomes obtained in a naturalistic patient sample support current treatment guidelines recommending evidence-based treatment for anxiety disorders, OCD, and PTSD in patients with and without a comorbid depression. Future treatment studies are recommended for investigate the (bi)directionality of anxiety and depressive symptoms throughout treatment.

The relationship of the chemotactic behavior of the complement-derived factors, C3a, C5a, and C567, and a bacterial chemotactic factor to their ability to activate the proesterase 1 of rabbit polymorphonuclear leukocytes.

The inhibition profiles obtained when a series of p-nitrophenyl ethyl alkylphosphonates and of p-nitrophenyl ethyl chloroalkylphosphonates were used to interfere with the chemotactic activity of polymorphonuclear leukocytes stimulated by C3a, C5a, and bacterial factor were the same as found previously when C567 was the chemotactic agent. This indicates that as in the chemotactic activity induced by C567, an obligatory step in the chemotaxis caused by C3a, C5a, and bacterial factor is the activation of proesterase 1 of the rabbit polymorphonuclear leukocyte. C5a and C3a activate proesterase 1 of peripheral blood polymophonuclear leukocytes as measured by the increase of acetyl DL-phenylalanine beta-naphthyl esterase activity. Attempts to detect in a like manner the proesterase 1 of the same leukocytes using bacterial factor under varying circumstances have consistently failed. It is concluded that bacterial factor, for unknown reasons, is unable to activate proesterase 1 to the same extent as the complement-derived chemotactic factors. The hypothesis of there being a quantitative difference in the ability of bacterial factor to activate proesterase 1 compared with the complement-derived factors explains the previous observations that bacterial factor can not deactivate to itself or to the complement-derived factors, although these latter factors can deactivate to themselves, to each other, and to the bacterial factor. The quantitative difference in the ability of bacterial factor to activate proesterase 1 compared to the complement-derived factors is also associated with and explains the finding that the maximal chemotactic activity attainable when bacterial factor is the chemotactic agent is distinctly less than that obtained using either C3a, C5a, or C567. These results indicate that the activation of proesterase 1 is a general requirement for the chemotactic activity of rabbit polymorphonuclear leukocytes with known macromolecular chemotactic agents and suggest that under several different circumstances the level of chemotactic activity attained is related to the degree of such activation.

Release of kallikrein from guinea pig lung during anaphylaxis.

An antigen-antibody reaction occurring in the perfused sensitized guinea pig lung, has been demonstrated to release kallikrein, a proteolytic enzyme related to the formation of kinins. This lung kallikrein is similar to plasma kallikrein in all properties studied, including susceptibility to the same inhibitors, electrophoretic mobility, and heterogeneity in molecular size. The release of kallikrein during anaphylaxis in the guinea pig lung occurs in the presence of ethylenediaminetetraacetate. Perfusion of ellagic acid into nonsensitized lungs will also release kallikrein, presumably through activation of Hageman factor. On the basis of these findings the hypothesis is suggested that the kallikrein in perfused lung activated by the antigen-antibody reaction is, in fact, plasma kallikrein. It is further suggested that activation of such kallikrein by the antigen-antibody reaction proceeds through Hageman factor.

Partial biochemical characterization of the activated esterase required in the complement-dependent chemotaxis of rabbit polymorphonuclear leukocytes.

It was shown in the preceding paper that incubation of the rabbit polymorphonuclearleukocyteswith phosphonate esters leads to an irreversible inhibition of the ability of the leukocyte to respond to the chemotactic factor. This "cell-dependent inhibition" was attributed to the inactivation by the phosphonates of an esterase existing in or on the leukocyte in an already activated state. As shown in this paper, incubating the leukocyte with phosphonate in the presence of certain esters prevents this cell-dependent inhibition. The protection is specific; the ester must be an acetate. Ethyl formate, ethyl propionate, ethyl butyrate, glucose 6-phosphate, fructose 1,6-diphosphate, ATP, tosyl arginine methyl ester, or acetyl tyrosine ethyl ester do not protect. The protection is independent of the phosphonate used to inhibit, and the degree of protection depends on the relative concentrations of acetate and phosphonate. Those acetates which protect are also the esters which inhibit chemotaxis when added to the leukocyte in the upper part of the chemotaxis chamber. It is concluded that the activated esterase is an enzyme capable of specifically splitting, or binding acetates, or doing both. Presumably the esterase is some type of acetylesterase or acetylase. The known aliesterase present in the leukocyte is not the activated esterase. Inhibition of the activated esterase by phosphonates has no effect on endogenous or exogenous glycolysis.