Impact of Transient and Persistent Donor-Specific Antibodies in Lung Transplantation.

Lung transplantation (LuTx) is an established treatment for patients with end-stage lung diseases, however, outcomes are limited by acute and chronic rejection. One aspect that has received increasing attention is the role of the host's humoral alloresponse, particularly the formation of de novo donor-specific antibodies (dnDSAs). The aim of this study was to investigate the clinical significance of transient and persistent dnDSAs and to understand their impact on outcomes after LuTx. A retrospective analysis was conducted using DSA screening data from LuTx recipients obtained at the Medical University of Vienna between February 2016 and March 2021. Of the 405 LuTx recipients analyzed, 205 patients developed dnDSA during the follow-up period. Among these, 167 (81%) had transient dnDSA and 38 (19%) persistent dnDSA. Persistent but not transient dnDSAs were associated with chronic lung allograft dysfunction (CLAD) and antibody-mediated rejection (AMR) (p < 0.001 and p = 0.006, respectively). CLAD-free survival rates for persistent dnDSAs at 1-, 3-, and 5-year post-transplantation were significantly lower than for transient dnDSAs (89%, 59%, 56% vs. 91%, 79%, 77%; p = 0.004). Temporal dynamics of dnDSAs after LuTx have a substantial effect on patient outcomes. This study underlines that the persistence of dnDSAs poses a significant risk to graft and patient survival.

[Congenital Pulmonary Artery Stenoses as a Rare Cause of Pulmonary Hypertension]. / Kongenitale Pulmonalarterienstenosen als seltene Ursache einer pulmonalen Hypertonie.

Kongenitale Pulmonalarterienstenosen sind eine seltene Ursache der pulmonalen Hypertonie (PH). Die Erkrankung wird in ihrer Häufigkeit vermutlich unterschätzt, und sie sollte in der Abklärung einer PH bedacht werden.Die Vorstellung einer 43-jährigen Patientin erfolgte zur Therapieoptimierung und Evaluation einer möglichen Lungentransplantation mit der Arbeitsdiagnose kongenitale Pulmonalarterienstenosen.Die Patientin beklagte eine seit der frühen Kindheit bestehende Belastungsdyspnoe aktuell entsprechend WHO-FC-Klasse II-III.Die Krankengeschichte zeigte die Erstdiagnose einer primären pulmonalarteriellen Hypertonie (IPAH) vor 17 Jahren. Es erfolgte eine PH-spezifische Medikation in wechselnden Kombinationen. Im Rahmen eines Zentrumswechsels erfolgte eine Reevaluation, und bei Nachweis eines typischen Mismatch mit normaler Ventilation, jedoch keilförmig gestörter Perfusion in der Lungenszintigrafie wurde eine chronisch thromboembolische pulmonale Hypertonie (CTEPH) vermutet. Die Pulmonalis-Angiografie zeigte ausschließlich subsegmental gelegene Stenosierungen sowie Gefäßabbrüche mit korrespondierenden Minderperfusionen, passend zu einer CTEPH. Im Rahmen der ersten Intervention erfolgte aufgrund der ungewöhnlichen Morphologie der pulmonalarteriellen Läsionen eine Erweiterung der Diagnostik mittels optischer Kohärenztomografie (OCT). Bei der Patientin fand sich kein endoluminales Material, jedoch eine kräftige Gefäßwand. Damit wurde die Diagnose einer pumonalen Hypertonie bei kongenitalen Pulmonalarterienstenosen mit In-situ-Thrombosierung gestellt.

Left ventricular apical rotation is associated with mitral annular function in healthy subjects. Results from the three-dimensional speckle-tracking echocardiographic MAGYAR-Healthy Study.

INTRODUCTION: Left ventricular (LV) twist is considered an essential part of LV function due to oppositely directed LV basal and apical rotations. Several factors could play a role in determining LV rotational mechanics in normal circumstances. This study aimed to investigate the relationship between LV rotational mechanics and mitral annular (MA) size and function in healthy subjects. METHODS: The study comprised 118 healthy adult volunteers (mean age: 31.5 ± 11.8 years, 50 males). All subjects had undergone complete two-dimensional (2D) Doppler echocardiography and three-dimensional speckle-tracking echocardiography (3DSTE) at the same time by the same echocardiography equipment. RESULTS: The normal mean LV apical and basal rotations proved to be 9.57 ± 3.33 and -3.75 ± 1.98°, respectively. LV apical rotation correlated with end-systolic MA diameter, area, perimeter, fractional area change, and fractional shortening, but did not correlate with any end-diastolic mitral annular morphologic parameters. The logistic regression model identified MA fractional area change as an independent predictor of ≤6° left ventricular apical rotation (P < 0.003). CONCLUSIONS: Correlations could be detected between apical LV rotation and end-systolic MA size and function, suggesting relationships between MA dimensions and function and LV rotational mechanics.

Utilization of Analytical Omics Tools in the Molecular Diagnostics of Multiple Myeloma.

Multiple myeloma (MM) is characterized by the clonal proliferation of malignant plasma B-lymphocytes and even as of today, it is an incurable disease. MM accounts for approximately 10% of all hematologic cancers. Its molecular pathogenesis is poorly understood, but the bone marrow microenvironment of tumor cells and genetic factors have apparent roles in the process. Accurate diagnosis is important to properly identify and stratify the disease, however, MM identification steps are time-consuming and expensive. Thus, development of early molecular diagnostic methods is of high importance in order to start proper therapies as early in the disease progression as possible, given the nature of the poor survival rates/remission periods. Molecular diagnostics via analytical omics represents one of the promising toolsets to speed up the diagnostic process. In this paper, we critically review the utilization of state of the art, high sensitivity analytical omics approaches (genomics, proteomics, metabolomics, lipidomics and glycomics) in MM diagnostics at the molecular level.

Concurrent spectrometry of annihilation radiation and characteristic gamma-rays for activity assessment of selected positron emitters.

A method is described to determine the activity of non-pure positron emitters in a radionuclide production environment by assessing the 511keV annihilation radiation concurrently with selected γ-lines, using a single High-Purity Germanium (HPGe) detector. Liquid sources of 22Na, 52Fe, 52mMn, 61Cu, 64Cu, 65Zn, 66Ga, 68Ga, 82Rb, 88Y, 89Zr and 132Cs were prepared specifically for this study. Acrylic absorbers surrounding the sources ensured that the emitted ß+-particles could not escape and annihilate away from the source region. The absorber thickness was matched to the maximum ß+ energy for each radionuclide. The effect on the 511keV detection efficiency by the non-homogeneous distribution of annihilation sites inside the source and absorber materials was investigated by means of Monte Carlo simulations. It was found that no self-absorption corrections other than those implicit to the detector calibration procedure needed to be applied. The medically important radionuclide, 64Cu, is of particular interest as its strongest characteristic γ-ray has an intensity of less than 0.5%. In spite of the weakness of its emission intensity, the 1346keV γ-line is shown to be suitable for quantifying the 64Cu production yield after chemical separation from the target matrix has been performed.

Risk of psychiatric disorders, self-harm behaviour and service use associated with bariatric surgery.

OBJECTIVE: To investigate psychiatric outcomes after bariatric surgery, including suicide, self-harm, psychiatric service use and substance misuse. METHOD: Retrospective study on a Danish nationwide register-based cohort of 22 451 patients followed for 1 029 736 person-years. Data were analysed utilizing single- and multi-event Cox regression with non-operated controls with obesity and mirror-image analyses with the operated patient serving as their own controls. RESULTS: We showed an increased ratio of self-harm (hazard ratio [HR] 3.23, P < 0.001; incidence rate ratio [IRR] 1.71, P < 0.001), psychiatric service use (admissions IRR 1.52, P < 0.001; emergency room visits IRR 1.70, P < 0.001), psychiatric diagnosis (organic psychiatric disorders HR 1.78, P < 0.001; substance use HR 2.06, P < 0.001; mood disorders HR 2.66, P < 0.001; neurotic, stress-related and somatoform disorders HR 2.48, P < 0.001; behavioural syndromes HR 3.15, P < 0.001; disorders of personality HR 2.68, P < 0.001; behavioural and emotional disorders HR 6.43, P < 0.001), as well as substance misuse utilizing Cox regression as well as mirror-image analyses, as compared to non-operated. We did not find an increased suicide rate (HR 1.35, P = 0.658) among operated as compared to non-operated. CONCLUSION: Our study shows that undergoing bariatric surgery is associated with increases in self-harm, psychiatric service use and occurrence of mental disorders.

Production cross sections of radioisotopes from 3He-particle induced nuclear reactions on natural titanium.

Excitation functions were measured using the stacked-foil method for the natTi(3He,x)44mSc, 46m+gSc, 47Sc, 48Sc, 48V and 48Cr nuclear processes up to 68MeV. Our new cross-section data were compared with the earlier reported values as well as the evaluated theoretical predictions by means of the TALYS 1.6 code as compiled in the TENDL-2015 library. The new data show acceptable agreement with the previous experimental values in the overlapping energy regions, however only a partial agreement was found in the case of the results of the nuclear reaction model code. The present work not only strengthens the experimental datasets of the above processes but also provides new cross-section values above 36MeV where only one dataset is available for each reaction.

Absence epileptic activity changing effects of non-adenosine nucleoside inosine, guanosine and uridine in Wistar Albino Glaxo Rijswijk rats.

Adenosine (Ado) and non-adenosine (non-Ado) nucleosides such as inosine (Ino), guanosine (Guo) and uridine (Urd) may have regionally different roles in the regulation of physiological and pathophysiological processes in the central nervous system (CNS) such as epilepsy. It was demonstrated previously that Ino and Guo decreased quinolinic acid (QA)-induced seizures and Urd reduced penicillin-, bicuculline- and pentylenetetrazole (PTZ)-induced seizures. It has also been demonstrated that Ino and Urd may exert their effects through GABAergic system by altering the function of GABA(A) type of gamma-aminobutyric acid receptors (GABAA receptors) whereas Guo decreases glutamate-induced excitability through glutamatergic system, which systems (GABAergic and glutamatergic) are involved in pathomechanisms of absence epilepsy. Thus, we hypothesized that Ino and Guo, similarly to the previously described effect of Urd, might also decrease absence epileptic activity. We investigated in the present study whether intraperitoneal (i.p.) application of Ino (500 and 1000mg/kg), Guo (20 and 50mg/kg), Urd (500 and 1000mg/kg), GABA(A) receptor agonist muscimol (1 and 3mg/kg), GABA(A) receptor antagonist bicuculline (2 and 4mg/kg), non-selective Ado receptor antagonist theophylline (5 and 10mg/kg) and non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine maleate (MK-801, 0.0625 and 0.1250mg/kg) alone and in combination have modulatory effects on absence epileptic activity in Wistar Albino Glaxo Rijswijk (WAG/Rij) rats. We found that Guo decreased the number of spike-wave discharges (SWDs) whereas Ino increased it dose-dependently. We strengthened that Urd can decrease absence epileptic activity. Our results suggest that Guo, Urd and their analogs could be potentially effective drugs for treatment of human absence epilepsy.

Aquagrams of raw milk for oestrus detection in dairy cows.

The purpose of this research was to develop rapid and cost-effective method for oestrus detection in dairy cows by means of near infrared spectroscopy and aquaphotomics, using raw milk from individual cows. We found that aquaphotomics approach showed consistent specific water spectral pattern of milk at the oestrus periods of the investigated Holstein cows. Characteristic changes were detected especially in foremilk collected at morning milking. They were reflected in calculated aquagrams of milk spectra where distinctive spectral pattern of oestrus showed increased light absorbance of strongly hydrogen-bonded water. Results showed that monitoring of raw milk near infrared spectra provides an opportunity for analysing hormone levels indirectly, through the changes of water spectral pattern caused by complex physiological changes related to fertile periods.

The antiepileptic potential of nucleosides.

Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

Receptors of peptides as therapeutic targets in epilepsy research.

Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre- and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have receptors implicated in epilepsy and many of them are considered to participate in endogenous neuroprotective actions. Neuropeptide receptors, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic targets. Receptors of hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and receptors of some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin- releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Activation and inhibition of receptors by oral application of peptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration of peptides through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of agonists and antagonists within the central nervous system will also be discussed.

Genistein induces phosphorylation of cAMP response element-binding protein in neonatal hypothalamus in vivo.

We investigated the effect of the phytoestrogen, genistein and 17beta-oestradiol on cAMP response element-binding protein (CREB) phosphorylation in the neonatal female rat hypothalamus in vivo using western blot analysis and immunohistochemistry. Although CREB expression was insensitive to the compounds we tested, administration of genistein and 17beta-oestradiol induced rapid CREB phosphorylation (< 15 min) in the hypothalamus and its level remained elevated at 4 h. Quantitative immunohistochemical analysis showed that genistein and 17beta-oestradiol had no effect on CREB phosphorylation in the magnocellular subdivision of paraventricular nucleus. By contrast, genistein induced a dose-dependent increase in CREB phosphorylation in the medial preoptic area (mPOA) and anteroventral periventricular nucleus (AVPV). Administration of 17beta-oestradiol also caused a rapid, dose-dependent increase in CREB phosphorylation in the hypothalamus, mPOA and AVPV. These results demonstrate that genistein induces oestrogen-like rapid action on CREB phosphorylation in the neonatal central nervous system in vivo.

The production of (88)Y in the proton bombardment of (nat)Sr: New excitation and separation studies.

The cyclotron production of (88)Y at iThemba LABS is performed via the reaction (88)Sr(p,n)(88)Y. The yields obtained were inconsistent with nuclear data obtained from the literature and the excitation function of the nuclear reaction was re-measured, using a differentiation of thick-target production rate measurements. Ion exchange chromatographic methods are described to separate (88)Y from (nat)Sr target material using AG MP-1 resin and AG 50W-X4 resins, respectively.

Direct neuronal projection from a brainstem thermosensitive cell group to the preoptic thermoregulatory center.

The preoptic area orchestrates thermoregulatory responses in homeotherm animals and humans. This thermoregulatory center receives thermal information about core body and skin temperatures, and in turn, it induces thermogenic responses. The physiology of effector mechanisms has been described in detail outlining the brain areas participating in the execution of thermal responses. Previous studies have presented evidence of peripheral thermosensation, existence of skin thermoreceptors, participation of spinal and brainstem sensory neurons in thermal stress, but only recently has been identified the first evidence of an ascending neuronal pathway transmitting thermal signal to the preoptic thermoregulatory center. Nevertheless, a few brainstem areas have not been linked to an afferent or efferent thermal pathway and the neuronal network of thermoafferent signals has only partially been identified. In the present study, we identified a distinct ascending neuronal projection that originates from the thermoreactive cells of the peritrigeminal nucleus in the medulla oblongata, and projects to the thermoreactive cells of the medial preoptic area in the hypothalamus of rats. First, we have demonstrated retrogradely labeled thermoreactive neurons in the parabrachial, pontine and peritrigeminal cells following the injection of pseudorabies virus, a retrograde multi-synaptic tract tracer, into the ventrolateral subdivision of the medial preoptic area. Confirming the existence of a direct neuronal connection, we detected biotinylated dextran amine (BDA) containing axonal fibers and boutons around thermoreactive cells of the ventrolateral subdivision of the medial preoptic area after BDA injection into the peritrigeminal nucleus that is known to respond the temperature changes. Our findings indicate the existence of a so far unrecognized ascending direct neuronal pathway that transmits thermal signal from the lower brainstem to the thermoregulatory preoptic center.

Regional distribution and effects of postmortal delay on endocannabinoid content of the human brain.

Tissue levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have been determined in 16 regions and nuclei from human brains, using liquid chromatography/in-line mass spectrometry. Measurements in brain samples stored at -80 degrees C for 2 months to 13 years indicated that endocannabinoids were stable under such conditions. In contrast, the postmortal delay had a strong effect on brain endocannabinoid levels, as documented in brain samples microdissected and frozen 1-6 h postmortem, and in neurosurgical samples 0, 5, 30, 60, 180 and 360 min after their removal from the brain. The tissue levels of AEA increased continuously and in a region-dependent manner from 1 h after death, increasing about sevenfold by 6 h postmortem. In contrast, concentrations of 2-AG, which were 10-100 times higher in human brain regions than those of AEA, rapidly declined: within the first hour, 2-AG levels dropped to 25-35% of the initial ('0 min') value, thereafter they remained relatively stable. As analyzed in samples removed 1-1.5 h postmortem, AEA levels ranged from a high of 96.3 fmol/mg tissue in the nucleus accumbens to a low of 25.0 fmol/mg in the cerebellum. 2-AG levels varied eightfold, from 8.6 pmol/mg in the lateral hypothalamus to 1.1 pmol/mg in the nucleus accumbens. Relative levels of AEA and 2-AG varied from region to region, with the 2-AG:AEA ratio being high in the sensory spinal trigeminal nucleus (140:1), the spinal dorsal horn (136:1) and the lateral hypothalamus (98:1) and low in the nucleus accumbens (16:1) and the striatum (31:1). The results highlight the pitfall of analyzing endocannabinoid content in brain samples of variable postmortal delay, and document differential distribution of the two main endocannabinoids in the human brain.

Site-specific acid-base properties of pholcodine and related compounds.

The acid-base properties of pholcodine, a cough-depressant agent, and related compounds including metabolites were studied by 1H NMR-pH titrations, and are characterised in terms of macroscopic and microscopic protonation constants. New N-methylated derivatives were also synthesized in order to quantitate site- and nucleus-specific protonation shifts and to unravel microscopic acid-base equilibria. The piperidine nitrogen was found to be 38 and 400 times more basic than its morpholine counterpart in pholcodine and norpholcodine, respectively. The protonation data show that the molecule of pholcodine bears an average of positive charge of 1.07 at physiological pH, preventing it from entering the central nervous system, a plausible reason for its lack of analgesic or addictive properties. The protonation constants of pholcodine and its derivatives are interpreted by comparing with related molecules of pharmaceutical interest. The pH-dependent relative concentrations of the variously protonated forms of pholcodine and morphine are depicted in distribution diagrams.

Facilitation of spike-wave discharge activity by lipopolysaccharides in Wistar Albino Glaxo/Rijswijk rats.

In normal rats the proinflammatory cytokines like interleukin-1beta, interleukin-6, which are induced by bacterial lipopolysaccharides, are able to control thalamo-cortical excitability by exerting strong effects on physiological synchronization such as sleep and on pathological synchronization like that in epileptic discharges. To investigate whether proinflammatory cytokines or lipopolysaccharides could modulate absence seizures resulting from a very different generator mechanism than the already investigated bicuculline-, kindling- and kainate-induced seizures, we used a genetically epileptic Wistar Albino Glaxo/Rijswijk rat strain, which is spontaneously generating high voltage spike-wave discharges. Wistar Albino Glaxo/Rijswijk rats responded with an increase of the number of spike-wave discharges to lipopolysaccharide injection (from 10 microg/kg to 350 microg/kg). Repetitive administration of 350 microg/kg lipopolysaccharides daily for 5 days increased the number of spike-wave discharges on the first, second and third days but the number of spike-wave discharges returned to the control value on day 5, at the 5th injection of lipopolysaccharides, showing a tolerance to lipopolysaccharides. The lipopolysaccharide-induced increase in spike-wave discharges was not directly correlated with the elevation of the core body temperature, as it is in febrile seizures, although lipopolysaccharide induced prostaglandin and is clearly pyrogenic at the doses used. Indomethacin, the prostaglandin synthesis inhibitor, efficiently blocked lipopolysaccharide-induced enhancement of spike-wave discharge genesis suggesting that the spike-wave discharge facilitating effect of lipopolysaccharides involves induction of cyclooxygenase 2 and subsequent synthesis and actions of prostaglandin E2. Low dose (40 mg/kg, i.p.) of competitive N-methyl-d-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid, and low dose of lipopolysaccharide (20 microg/kg) showed a synergistic interaction to increase the number of spike-wave discharges, whereas at supramaximal doses of lipopolysaccharide and the N-methyl-D-aspartate antagonist no synergy was present. The data reveal a functional connection between absence epileptic activity and lipopolysaccharide induction of prostaglandin synthesis and prostaglandin action and suggest some common cellular targets in epilepsy and lipopolysaccharide-induced inflammation.

Comments on the feasibility of 61Cu production by proton irradiation of (nat)Zn on a medical cyclotron.

Feasibility of 61Cu production in high radionuclidic purity form via (nat)Zn(p,x) 61Cu nuclear process is discussed. Based on the experimentally available cross-sections of the (nat)Zn(p,x) 61Cu, (nat)Zn(p,x) 60Cu and (nat)Zn(p,x) 64Cu nuclear processes the usefulness of the (nat)Zn(p,x) 61Cu process for high-scale production is questionable in the 22 --> 12 MeV energy range.

Fluctuation formula in the Nosé-Hoover thermostated Lorentz gas.

In this paper we examine numerically the Gallavotti-Cohen fluctuation formula for phase-space contraction rate and entropy production rate fluctuations in the Nosé-Hoover thermostated periodic Lorentz gas. Our results indicate that while the phase-space contraction rate fluctuations violate the fluctuation formula near equilibrium states, the entropy production rate fluctuations obey this formula near and far from equilibrium states as well.