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Background:
Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning.
Methods
Thirteen adolescent male patients (9–16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-β-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH.
Results
On-MPH status was associated with a highly significant change (−29.9%) of striatal DAT BP as compared to off-MPH (t = −4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04).
Conclusion
Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity.
Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b-1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways.
Patients with refractory or relapsed and refractory multiple myeloma who no longer receive benefit from novel agents have limited treatment options and short expected survival. del(17p) and t(4;14) are correlated with shortened survival. The phase 3 MM-003 trial demonstrated significant progression-free and overall survival benefits from treatment with pomalidomide plus low-dose dexamethasone compared to high-dose dexamethasone among patients in whom bortezomib and lenalidomide treatment had failed. At an updated median follow-up of 15.4 months, the progression-free survival was 4.0 versus 1.9 months (HR, 0.50; P<0.001), and median overall survival was 13.1 versus 8.1 months (HR, 0.72; P=0.009). Pomalidomide plus low-dose dexamethasone, compared with high-dose dexamethasone, improved progression-free survival in patients with del(17p) (4.6 versus 1.1 months; HR, 0.34; P < 0.001), t(4;14) (2.8 versus 1.9 months; HR, 0.49; P=0.028), and in standard-risk patients (4.2 versus 2.3 months; HR, 0.55; P<0.001). Although the majority of patients treated with high-dose dexamethasone took pomalidomide after discontinuation, the overall survival of patients treated with pomalidomide plus low-dose dexamethasone or highdose dexamethasone was 12.6 versus 7.7 months (HR, 0.45; P=0.008) in patients with del(17p), 7.5 versus 4.9 months (HR, 1.12; P=0.761) in those with t(4;14), and 14.0 versus 9.0 months (HR, 0.85; P=0.380) in standard-risk subjects. The overall response rate was higher in patients treated with pomalidomide plus low-dose dexamethasone than in those treated with high-dose dexamethasone both among standard-risk patients (35.2% versus 9.7%) and those with del(17p) (31.8% versus 4.3%), whereas it was similar in patients with t(4; 14) (15.9% versus 13.3%). The safety of pomalidomide plus low-dose dexamethasone was consistent with initial reports. In conclusion, pomalidomide plus low-dose dexamethasone is efficacious in patients with relapsed/refractory multiple myeloma and del(17p) and/or t(4;14).
Objective:
Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.
Methods:
We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.
Results:
Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.
Interpretation:
The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.
Background
The vascular type represents a very rare, yet the clinically most fatal entity of Ehlers-Danlos syndrome (EDS). Patients are often admitted due to arterial bleedings and the friable tissue and the altered coagulation contribute to the challenge in treatment strategies. Until now there is little information about clotting characteristics that might influence hemostasis decisively and eventually worsen emergency situations.
Results
22 vascular type EDS patients were studied for hemoglobin, platelet volume and count, Quick and activated partial thromboplastin time, fibrinogen, factor XIII, von Willebrand disease, vitamin D and platelet aggregation by modern standard laboratory methods. Results show a high prevalence of over 50 % for platelet aggregation disorders in vascular type EDS patients, especially for collagen and epinephrine induced tests, whereas the plasmatic cascade did not show any alterations. Additionally, more than half of the tested subjects showed low vitamin D serum levels, which might additionally affect vascular wall integrity.
Conclusion
The presented data underline the importance of detailed laboratory screening methods in vascular type EDS patients in order to allow for targeted application of platelet-interacting substances that might be of decisive benefit in the emergency setting.
Background
Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry.
Methods
A weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [\(^{18}\)F]DPA-714 was performed on day 1, 7, and 16 and [\(^{18}\)F]FDG-μPET imaging for energy metabolism on days 2–5 after trauma using freshly synthesized radiotracers. Immediately after [\(^{18}\)F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [\(^{18}\)F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1.
Results
Functional outcome correlated with focal brain lesions, gliosis, and axonal injury. [\(^{18}\)F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [\(^{18}\)F]FDG uptake on days 2–5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [\(^{18}\)F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [\(^{18}\)F]DPA-714 was not increased in autoradiography or in μPET imaging.
Conclusions
[\(^{18}\)F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI.
Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.
The two bradykinin receptors B1R and B2R are central components of the kallikrein–kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.
Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite improvements in acute intensive care, there are currently no specific therapies to ameliorate the effects of TBI. Successful therapeutic strategies for TBI should target multiple pathophysiologic mechanisms that occur at different stages of brain injury. The kallikrein-kinin system is a promising therapeutic target for TBI as it mediates key pathologic events of traumatic brain damage, such as edema formation, inflammation, and thrombosis. Selective and specific kinin receptor antagonists and inhibitors of plasma kallikrein and coagulation factor XII have been developed, and have already shown therapeutic efficacy in animal models of stroke and TBI. However, conflicting preclinical evaluation, as well as limited and inconclusive data from clinical trials in TBI, suggests that caution should be taken before transferring observations made in animals to humans. This review summarizes current evidence on the pathologic significance of the kallikrein-kinin system during TBI in animal models and, where available, the experimental findings are compared with human data.
Das Ausmaß der Proteinbindung eines Arzneistoffs wirkt sich auf viele unterschiedliche pharmakokinetische Parameter aus. So wird beispielsweise das Verteilungsvolumen, die Metabolisierung oder die Elimination des entsprechenden Stoffes durch die Höhe seiner Proteinbindung beeinflusst. Da nur der im Plasma frei vorliegende Anteil eines Arzneistoffs in der Lage ist biologische Membranen zu überwinden, können auch nur die freien Arzneistoffmoleküle eine pharmakologische Wirkung an Rezeptoren oder Enzymen auslösen. Dementsprechend ist auch die Intensität der hervorgerufenen Wirkung von der Größe des ungebundenen Anteils eines Arzneistoffs abhängig. Aufgrund dieser Zusammenhänge ist klar, dass die Proteinbindung eines Arzneistoffes letztendlich Einfluss auf die Dosisfindung hat. Zur Ermittlung der Proteinbindung stehen viele unterschiedliche Methoden, wie beispielsweise die HPLC, Kapillarelektrophorese, Ultrazentrifugation, Gleichgewichtsdialyse und Ultrafiltration zur Verfügung. In der vorliegenden Arbeit wurde die kontinuierliche Ultrafiltration zur Ermittlung der Proteinbindung von Arzneistoffen angewendet. Hier wird die Proteinbindung nicht nur anhand einer bestimmten Arzneistoff- bzw. Albuminkonzentration gemessen, sondern über einen weiteren Bereich von Wirkstoff-Protein-Verhältnissen beobachtet. Des Weiteren ist der apparative Aufwand im Vergleich zu vielen anderen Methoden als geringer einzustufen. Im Rahmen dieser Arbeit wurde, die auf der von Heinze[122] entwickelte Messanlage weiter optimiert und eine zweite Anlage mit einem Diodenarraydetektor aufgebaut. Für letztere musste eine Software-Anpassung vorgenommen werden. Folgende Projekte wurden durchgeführt: 1) Um den In-vivo-Bedingungen nahe zu kommen, wurde bei der Bestimmung der Proteinbindung der Sartane nicht nur BSA und HSA verwendet, sondern erstmals auch humanes Plasma. Die Plasmamessungen der Sartane verliefen insgesamt problemlos, allerdings ist eine erfolgreiche Messung stark von der Qualität des eingesetzten Plasmas abhängig, wie Messungen der Naphthylisochinoline gezeigt haben. Im Vergleich mit HSA und Plasma ergaben die Messungen der Sartane mit bovinem Serumalbumin geringfügig erniedrigte Proteinbindungswerte. Insgesamt sind alle Ergebnisse sehr gut mit den Literaturwerten vergleichbar. 2) Das Ausmaß der Proteinbindung von Naphthylisochinolinen war bislang unbekannt und lag im Bereich von ca. 30-70%. Erneut waren die Resultate aus den Messungen von BSA und HSA nahezu gleich. 3) Am Beispiel der Interaktion zwischen Phenprocoumon und Phenylbutazon wurden zwei unterschiedliche Ansätze getestet, um die Verdrängung aus der Proteinbindung zu simulieren. Die erste Methode entsprach hierbei einer Konkurrenz der beiden interagierenden Stoffe um die Proteinbindungsstellen. Durch den Einfluss des Phenylbutazon verringerte sich die Proteinbindung des Phenprocoumon um 1%, was allerdings als statistisch nicht signifikant betrachtet werden kann. Im zweiten Ansatz, der eine direktere Verdrängung aus der Proteinbindung simulieren sollte, fiel die Proteinbindung des Phenprocoumon gegenüber den Einzelmessungen um 2,5% ab. Unter physiologischen Konzentrationsverhältnissen sank sich die Proteinbindung des Phenprocoumon auf 93,3%. Der freie Anteil erhöhte sich dementsprechend von 1% auf 6,7%. Somit konnte der Einfluss des Phenylbutazon auf die Proteinbindung des Phenprocoumon erfolgreich nachgewiesen werden. Die unveränderte Proteinbindung des Phenylbutazon im inversen Ansatz und die ermittelten pK-Werte bestätigen diese Interaktion. Grundsätzlich ist es also möglich mit der kontinuierlichen Ultrafiltration solche Interaktionen zu simulieren. 4) Zuletzt sollte der Frage nachgegangen werden, ob es mit der kontinuierlichen Ultrafiltration auch möglich ist die Proteinbindung von wasserunlöslichen Stoffen, nämlich den Aziridinen, in Gegenwart steigender Mengen DMSO, zu bestimmen. Die erhaltenen Ergebnisse wurden mit Literaturwerten ohne DMSO-Zusatz verglichen. Abgesehen von Candesartan, das eine lineare Korrelation zwischen DMSO-Gehalt der Wirkstofflösung und Absinken der Proteinbindung zeigte, konnte kein Zusammenhang zwischen der DMSO-Konzentration und der gemessenen Proteinbindung festgestellt werden. Die Mittelwerte lagen im Bereich der Literaturwerte. Insgesamt zeigten alle Versuchsreihen, dass die kontinuierliche Ultrafiltration eine ausgezeichnete, schnelle und robuste Screeningmethode zur Bestimmung des Ausmaßes der Proteinbindung bekannter und neuer Wirkstoffe darstellt.