Interferons beta have vasoconstrictive and procoagulant effects: A woman who developed livedo reticularis and Raynaud phenomenon in association with interferon beta treatment for multiple sclerosis

A 31-year-old woman with MS developed livedo reticularis and secondary Raynaud phenomenon 2.5 years after introduction of interferon beta-1b. The symptoms disappeared after withdrawal of the drug. Livedo reticularis and Raynaud phenomenon as well as pulmonary arterial hypertension, venous sinus thrombosis, pulmonary embolism and renal thrombotic microangiopathy have all been described in association with interferon beta therapy. These complications strongly suggest that type I interferons have vasoconstrictive and procoagulant effects with potentially serious systemic complications.     

The ovipositor actuation mechanism of a parasitic wasp and its functional implications

Parasitic wasps use specialized needle-like structures, ovipositors, to drill into substrates to reach hidden hosts. The external ovipositor (terebra) consists of three interconnected, sliding elements (valvulae), which are moved reciprocally during insertion. This presumably reduces the required pushing force on the terebra and limits the risk of damage whilst probing. Although this is an important mechanism, it is still not completely understood how the actuation of the valvulae is achieved, and it has only been studied with the ovipositor in rest position. Additionally, very little is known about the magnitude of the forces generated during probing. We used synchrotron X-ray microtomography to reconstruct the actuation mechanism of the parasitic wasp Diachasmimorpha longicaudata (Braconidae) in four distinct phases of the probing cycle. We show that only the paired first valvulae of the terebra move independently, while the second valvula moves with the metasoma (‘abdomen’). The first valvula movements are initiated by rotation of one chitin plate (first valvifer) with respect to another such plate (second valvifer). This is achieved indirectly by muscles connecting the non-rotating second valvifer and the abdominal ninth tergite. Contrary to previous reports, we found muscle fibres running inside the terebra, although their function remains unclear. The estimated maximal forces that can be exerted by the first valvulae are small (protraction 1.19 mN and retraction 0.874 mN), which reduces the risk of buckling, but are sufficient for successful probing. The small net forces of the valvulae on the substrate may still lead to buckling of the terebra; we show that the sheaths surrounding the valvulae prevent this by effectively increasing the diameter and second moment of area of the terebra. Our findings improve the comprehension of hymenopteran probing mechanisms, the function of the associated muscles, and the forces and damage-limiting mechanism that are involved in drilling a slender terebra into a substrate.     

Generation of life events in bipolar spectrum disorders: A re‐examination and extension of the stress generation theory

The extent to which stress generation occurs in bipolar spectrum disorders (BSD) is not well understood. The present study examined whether 75 BSD participants experienced elevated rates of behavior‐dependent life events, as compared with 38 normal control participants. Within the BSD group, we also examined whether depressive or hypomanic symptoms prospectively predicted increases in various types of negative and positive life events. Results indicated that BSD participants experienced overall increases in behavior‐dependent events over the follow‐up, as compared with normal controls. At the symptom level, the event generation process occurred in more specific event domains. Results suggest that the stress generation theory of unipolar depression can be extended to BSD and that the type of generated events may be polarity‐specific. © 2010 Wiley Periodicals, Inc. J Clin Psychol: 66: 1–20, 2010.     

Mixed desmoplastic primitive neuroepithelial tumor of infancy: a light microscopic,immunocytochemical, ultrastructural and genetic study

We describe a case of a desmoplastic brain tumor which was initially resected from the right fronto-temporal region in a 2 year-old boy. This nodular, calcified tumor was vascularized by the internal carotid artery and the middle meningeal artery branches. Grossly, it contained several mucoid cysts. Light microscopy showed cords or nests of small cuboidal cells surrounded by a loose connective tissue and desmoplasic areas containing fibers and spindle cells. The cuboidal cells expressed epithelial, neuronal and neuroendocrine markers. Some foci of spindle cells showed glial differentiation. The tumor recurred 16 months later and displayed some characteristics of the small cell neuroepithelial component, mitoses being conspicuous. Electron microscopy revealed undifferentiated clear cells, some containing neurosecretory granules. Karyotyping demonstrated the following formula: < 15 > 46, t(8;11) (a13; q11). The chromosome 11 breakpoint was different from that described in Ewing's sarcoma. This isolated translocation has not been previously reported to our knowledge. These unusual features lead us to report this case and to discuss its pathogenesis.     

Das Schlafverhalten der Epileptiker

Zusammenfassung Nachdem Schlafdauer, Schlaftiefe und Besonderheiten der Schlafperiodik der Epileptiker in einer früheren Mitteilung [45] dargestellt worden sind, werden hier Graphoelemente des Elektrencephalogramms, Herzfrequenz, Schwankungen des galvanischen Hautreflexes, die Motorik sowie die Kontrolle des Schlafverlaufes durch meßbare akustische Weckreize beschrieben. Es wurden sowohl die Elemente des Wach- als auch des Schlaf-EEG ausgewertet.1. Bei Aufwachepileptikern war im Wach-EEG eine Dysrhythmie mit vorwiegend bilateral-symmetrischen Krampfelementen (KE) nachweisbar. Die Schlaf-EEG boten nur eine geringe Zuwachsrate der KE. Dagegen waren die Wach-EEG bei Schlafepileptikern vorwiegend normal, während die Zuwachsrate der krampfspezifischen Elemente im Schlaf-EEG acht bis zehn betrug. Die KE traten vorwiegend lokalisiert, und zwar vornehmlich temporal oder generalisiert mit temporaler Betonung auf.2. Die Herzfrequenz war bei Aufwachepileptikern initial vorwiegend tachykard, bei Schlafepileptikern bradykard. Während des Schlafes ließen sich zwei Senkungen der Herzfrequenz nachweisen. Eine leichtere lag unmittelbar nach dem Einschlafen und eine tiefere, sehr bradykarde kam 7 Std nach dem Einschlafen vor. Diese bradykarde Phase ist besonders bei Schlafepileptikern deutlich ausgeprägt, während die Aufwachepileptiker unregelmäßigere Änderungen der Herzfrequenz aufwiesen.3. Die Änderungen des Hautwiderstandes (Änderungen der Schweißdrüsensekretion) im Schlaf unterschieden sich bei Schlafepileptikern wesentlich von denen der Aufwachepileptiker. Der Hautwiderstand erhöhte sich bei Schlafepileptikern gleich nach dem Einschlafen erheblich, bei Aufwachepileptikern aber erst nach 4 Std.4. Die Motorik war bei Schlafepileptikern deutlich geringer als bei Aufwachepileptikern mit ihrem unruhigen Schlaf.5. Auch die Kontrolle der Schlaftiefe durch akustische Weckreize zeigte einen langen tiefen Schlaf bei Schlafepileptikern an. Aufwachepileptiker schliefen auch laut Reaktionen auf akustische Reize oberflächlich mit einer morgendlichen Schlafvertiefungstendenz.6. Das Schlafverhalten des Petit mal (PM) ähnelte dem der Aufwachepileptiker und bei Kranken mit psychomotorischer Epilepsie (PE) dem der Schlafepileptiker. Diffuse Epileptiker schlafen individuell verschieden.7. Auf Grund dieser ergänzenden Befunde ließen sich in Bestätigung früherer Theorien drei Epilepsieformenkreise unterscheiden: A. Zentrencephaler oder diencephalo-corticaler Epilepsieformenkreis, der Aufwach- und Petit mal-Epileptiker umfaßt; B. Temporocephaler oder rhombencephalocorticaler (= rhombencephalo-rhinencephaler) Epilepsieformenkreis (Schlaf- und psychomotorische Epileptiker); C. Kombinierter oder rhombencephal-diencephalo-corticaler Epilepsieformenkreis (diffuse Epilepsie, fokale Anfälle, kombinierte Formen).

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Summary Duration of sleep in epileptics, its depth and its particular features had been considered in an earlier publication [45]. This report is dealing with the EEG-tracings, the heart rate, fluctuations of the galvanic skin conductance, the motor activity, and the control of sleep by acoustic stimuli.The EEG during wakefulness disclosed dysrhythmia with bilateral symmetrical convulsive elements (KE) in matutinal epileptics. The EEG during sleep showed only a slight increase of the KE-rate. On the other hand, the EEG during wakefulness was normal in most cases of nocturnal epileptics, while the rate increase of the more temporally localized KE amounted to 8–10 in the EEG during sleep.Epileptics on awakening showed initially a tachycardic heart rate, nocturnal epileptics were bradycardic. After onset of sleep, the heart rate dropped in both groups. A very marked bradycardic heart rate was registered, though not until 7 hours following the beginning of sleep, a phenomenon which was less apparent in matutinal epileptics.The galvanic skin resistance in nocturnal epileptics increased directly after their falling asleep, and 4–5 hours later in epileptics with attacks during wakefulness. The motor activity was definitely less in the former category than in the latter.Control of sleep by acoustic stimuli showed long, deep sleep in nocturnal epileptics and light sleep in epileptics with attacks on awakening. The deep sleep in sleep epilepsy occurs in the evening, in matutinal epileptics in the morning. The sleep pattern in Petit-Mal resembles that of epileptics on awakening, whereas the sleep of those afflicted with psychomotor epilepsy was similar to that of patients with sleep epilepsy. The sleep of diffuse epileptics differed from individual to individual. In the discussion 3 epilepsy patterns were elaborated: A) A centrencephalic epileptic pattern (awakening epilepsy and petit-mal); B) A temporocephalic epileptic pattern (sleep and psychomotor epilepsy), and C) a combined epileptic pattern (diffuse epilepsy, focal fits and combined forms).

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Herrn Professor Dr. H. J. Bauer, Herrn Professor Dr. F. Duensing, Herrn Professor Dr. J. E. Meyer, Herrn Professor Dr. H. Orthner, Herrn wiss. Ass. Dr. W. Firnhaber, meinen Kolleginnen und Kollegen der Neurologischen und Psychiatrischen Klinik der Universität Göttingen bin ich für ihre direkte und indirekte Hilfe bei der Durchführung dieser Untersuchungen sowie für die Überlassung des Krankenmaterials sehr dankbar.     

Effects of Exposing Two Non-Target Crustacean Species, Asellus aquaticus L., and Gammarus fossarum Koch., to Atrazine and Imidacloprid

The physiological responses of two freshwater crustaceans, Asellus aquaticus L. and Gammarus fossarum Koch., following in vitro exposure to two pesticides were measured. Both species responded to short-term exposure with elevated levels of Respiration (R) and/or lower levels of Electron Transport System (ETS) activity. 1 h exposure to concentrations of up to 10 mg L⁻¹ showed an effect in both test species. Laboratory tests confirmed that G. fossarum is more sensitive to short-term pesticide exposure than A. aquaticus. ETS/R ratio may be used as a quick predictor of effects on organisms exposed to pesticides.     

In Vitro Activity of LK-157, a Novel Tricyclic Carbapenem As Broad-Spectrum β-Lactamase Inhibitor

LK-157 is a novel tricyclic carbapenem with potent activity against class A and class C β-lactamases. When tested against the purified TEM-1 and SHV-1 enzymes, LK-157 exhibited 50% inhibitory concentrations (IC₅₀s) in the ranges of the clavulanic acid and tazobactam IC₅₀s (55 nM and 151 nM, respectively). Moreover, LK-157 significantly inhibited AmpC β-lactamase (IC₅₀, 62 nM), as LK-157 was >2,000-fold more potent than clavulanic acid and approximately 28-fold more active than tazobactam. The in vitro activities of LK-157 in combination with amoxicillin, piperacillin, ceftazidime, cefotaxime, ceftriaxone, cefepime, cefpirome, and aztreonam against an array of Ambler class A (TEM-, SHV-, CTX-M-, KPC-, PER-, BRO-, and PC-type)- and class C-producing bacterial strains derived from clinical settings were evaluated in synergism experiments and compared with those of clavulanic acid, tazobactam, and sulbactam. In vitro MICs against ESBL-producing strains (except CTX-M-containing strains) were reduced 2- to >256-fold, and those against AmpC-producing strains were reduced even up to >32-fold. The lowest MICs (≤0.025 to 1.6 μg/ml) were observed for the combination of cefepime and cefpirome with a constant LK-157 concentration of 4 μg/ml, thus raising an interest for further development. LK-157 proved to be a potent β-lactamase inhibitor, combining activity against class A and class C β-lactamases, which is an absolute necessity for use in the clinical setting due to the worldwide increasing prevalence of bacterial strains resistant to β-lactam antibiotics.Antibiotics have drastically reduced illness and death due to infectious diseases. However, bacteria have exhibited a remarkable capacity to quickly become resistant to one or several classes of antibiotics, which is widely considered to be one of the major problems in human medicine today (1, 19). The dramatic increase in antibacterial resistance is now a global threat, both for nosocomial and for community-acquired infections.Although bacteria have developed several strategies for escaping the lethal action of β-lactam antibiotics, the most common and clinically important mechanism is the synthesis of β-lactamases, leading to hydrolysis of the antibiotic. Currently, the β-lactamase superfamily has more than 700 members, many of which differ only by a single amino acid (K. Bush and G. A. Jacoby, personal communication).Class A enzymes TEM-1 and SHV-1 (functional group 2b) are the most widely disseminated. The mutated β-lactamases either have broader substrate specificities, including extended-spectrum cephalosporins (extended-spectrum β-lactamases [ESBLs]; functional group 2be), or exhibit decreased sensitivities to β-lactamase inhibitors (inhibitor-resistant TEMs; functional group 2br) (4).Among the cephalosporin-resistant organisms causing concern were mutants of Enterobacter spp., Citrobacter freundii, Serratia spp., Morganella morganii, Providencia spp., and Pseudomonas aeruginosa, where high- or low-level constitutive expression of class C β-lactamases may be induced by exposure to certain β-lactams. Chromosomal or plasmid-encoded AmpC cephalosporinases (functional group 1) may be hyperproduced through reversible induction or stable derepression and typically confer resistance to most cephalosporins and monobactams.Commercially available inhibitors, such as potassium clavulanate, sulbactam, and tazobactam, have been successfully used against bacteria producing the ubiquitous and prevalent class A and some class D β-lactamases, but activity against class C types is poor in general (13). In recent years, several quite potent inhibitors, such as alkylidene penems, 2β-substituted penam sulfones, oxapenems, cephalosporin-derived compounds, and cyclic acyl phosphonates, which exhibit antibacterial synergistic activity against both class A and class C β-lactamases, have been developed, but none has been approved by the FDA yet (3, 5, 9, 10, 12, 14, 21). In addition, bacterial susceptibility to such combinations has recently been challenged by the spontaneous appearance of new β-lactamases of the TEM family, which are resistant to the mechanism-based inhibitors on the market (inhibitor-resistant TEM β-lactamases [www.lahey.org/Studies]). Given the current situation, it is vital to develop new, effective agents and to sustain the clinical utility of these and existing therapies.Recently, following a rational structure-based drug design approach, novel tricyclic carbapenem compounds (trinems) with potent inhibitory activity against serine β-lactamases have been synthesized by Lek Pharmaceuticals, d.d. (Fig. ​(Fig.1).1). Lead LK-157 was identified as a promising β-lactamase inhibitor to be coadministered with a selected cephalosporin antibiotic in bacterial infections caused by β-lactam-resistant bacteria (7, 8, 11, 15-17, 20). LK-157 is a close structural analogue of a broad-spectrum antibiotic, sanfetrinem, whose development was stopped in phase II clinical trials (2, 18).Open in a separate windowFIG. 1.Structural formula of tricyclic carbapenem LK-157.The main objective of the present study was to evaluate the activity of LK-157 by in vitro synergism experiments with various β-lactam antibiotics against a wide range of clinically relevant bacteria expressing class A and class C β-lactamases (4). We also present the 50% inhibitory concentrations (IC₅₀s) of LK-157 against purified TEM-1, SHV-1, and AmpC enzymes.     

Multi-locus genetic risk score predicts risk for Crohn's disease in Slovenian population

AIM: To develop a risk model for Crohn's disease(CD) based on homogeneous population.METHODS: In our study were included 160 CD patients and 209 healthy individuals from Slovenia. The association study was performed for 112 single nucleotide polymorphisms(SNPs). We generated genetic risk scores(GRS) based on the number of risk alleles using weighted additive model. Discriminatory accuracy was measured by area under ROC curve(AUC). For risk evaluation, we divided individuals according to positive and negative likelihood ratios(LR) of a test, with LR 5 for high risk group and LR 0.20 for low risk group.RESULTS: The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively. Individuals with the highest risk(GRS 5.54) showed significantly increased odds of developing CD(OR = 26.65, 95%CI: 11.25-63.15) compared to the individuals with the lowest risk(GRS 4.57) which is a considerably greater risk captured than in one SNP with the highest effect size(OR = 3.24). When more than 33 SNPs were included in GRS, discriminatory ability was not improved significantly; AUC of all 74 SNPs was 0.76.CONCLUSION: The authors proved the possibility of building accurate genetic risk score based on 33 risk variants on Slovenian CD patients which may serve as a screening tool in the targeted population.