The basilar artery international cooperation study (BASICS).

Basilar artery occlusion is a rare cause of stroke with a high case fatality rate and an often poor clinical outcome among survivors. Our limited knowledge on the outcome in patients with basilar artery occlusion comes from small case series of selected patients.STUDY AIM: The main purpose of the registry is to collect preliminary data that will help direct the design of a future clinical treatment trial. The target number of patients included is 500.DESIGN: BASICS is a prospective, observational, multi-center, international registry of consecutive patients presenting with a symptomatic and radiologically confirmed basilar artery occlusion.STUDY OUTCOMES: From November 2002 until December 2006 data have been collected on 400 patients, from 42 centers in 12 countries. Most patients were treated with IA therapy (55%), followed by antithrombotics (29%) and IV thrombolysis (6%). The overall mortality was 45%.

Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells.

Antibody-drug conjugates (ADC) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents a first-in-class ADC directed against CD30(+) malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response. In this study, we demonstrate that the dolastatin family of microtubule inhibitors, from which the cytotoxic component of brentuximab vedotin is derived, comprises potent inducers of phenotypic and functional dendritic cell (DC) maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes. Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells. Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins, the antitumor effect was far less pronounced in immunocompromised mice. We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways. Ultimately, treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients. Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies, such as brentuximab vedotin, with immune-based therapies. Cancer Immunol Res; 2(8); 741-55. ©2014 AACR.

Linee guida della consensus conference dell'ANGP per il monitoraggio plasmatico dei farmaci (TDM) in psichiatria. Aggiornamento 2011 =AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011

Therapeutic drug monitoring (TDM), i.e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i.e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrateand inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

Psychological correlates of childhood obesity.

To enhance the prevention and intervention efforts of childhood obesity, there is a strong need for the early detection of psychological factors contributing to its development and maintenance. Rather than a stable condition, childhood obesity represents a dynamic process, in which behavior, cognition and emotional regulation interact mutually with each other. Family structure and context, that is, parental and familial attitudes, activity, nutritional patterns as well as familial stress, have an important role with respect to the onset and maintenance of overweight and obesity. Behavioral and emotional problems are found in many, though not all, obese children, with a higher prevalence in clinical, treatment-seeking samples. The interrelatedness between obesity and psychological problems seems to be twofold, in that clinically meaningful psychological distress might foster weight gain and obesity may lead to psychosocial problems. The most frequently implicated psychosocial factors are externalizing (impulsivity and attention-deficit hyperactivity disorder) and internalizing (depression and anxiety) behavioral problems and uncontrolled eating behavior. These findings strengthen the need to further explore the interrelatedness between psychological problems and childhood obesity.

The role of C-Jun N-terminal kinase in a mouse model of intracerebral hemorrhage

Background: Intracerebral hemorrhage (ICH) is a subtype of stroke characterized by a haematoma within the brain parenchyma resulting from blood vessel rupture and with a poor outcome. In ICH, the blood entry into the brain triggers toxicity resulting in a substantial loss of neurons and an inflammatory response. At the same time, blood-brain barrier (BBB) disruption increases water content (edema) leading to growing intracranial pressure, which in turn worsens neurological outcome. Although the clinical presentation is similar in ischemic and hemorrhagic stroke, the treatment is different and the stroke type needs to be determined beforehand by imaging which delays the therapy. C-Jun N-terminal kinases (JNKs) are a family of kinases activated in response to stress stimuli and involved in several pathways such as apoptosis. Specific inhibition of JNK by a TAT-coupled peptide (XG-102) mediates strong neuroprotection in several models of ischemic stroke in rodents. Recently, we have observed that the JNK pathway is also activated in a mouse model of ICH, raising the question of the efficacy of XG-102 in this model. Method: ICH was induced in the mouse by intrastriatal injection of bacterial collagenase (0,1 U). Three hours after surgery, animals received an intravenous injection of 100 mg/kg of XG-102. The neurological outcome was assessed everyday until sacrifice using a score (from 0 to 9) based on 3 behavioral tests performed daily until sacrifice. Then, mice were sacrificed at 6 h, 24 h, 48 h, and 5d after ICH and histological studies performed. Results: The first 24 h after surgery are critical in our ICH mice model, and we have observed that XG-102 significantly improves neurological outcome at this time point (mean score: 1,8 + 1.4 for treated group versus 3,4+ 1.8 for control group, P<0.01). Analysis of the lesion volume revealed a significant decrease of the lesion area in the treated group at 48h (29+ 11mm3 in the treated group versus 39+ 5mm3 in the control group, P=0.04). XG-102 mainly inhibits the edema component of the lesion. Indeed, a significant inhibition Journal of Cerebral Blood Flow & Metabolism (2009) 29, S490-S493 & 2009 ISCBFM All rights reserved 0271-678X/09 $32.00 www.jcbfm.com of the brain swelling was observed in treated animals at 48h (14%+ 13% versus 26+ 9% in the control group, P=0.04) and 5d (_0.3%+ 4.5%versus 5.1+ 3.6%in the control group, P=0.01). Conclusions: Inhibition of the JNK pathway by XG- 102 appears to lead to several beneficial effects. We can show here a significant inhibition of the cerebral edema in the ICH model providing a further beneficial effect of the XG-102 treatment, in addition to the neuroprotection previously described in the ischemic model. This result is of interest because currently, clinical treatment for brain edema is limited. Importantly, the beneficial effects observed with XG-102 in models of both stroke types open the possibility to rapidly treat stroke patients before identifying the stroke subtype by imaging. This will save time which is precious for stroke outcome.

Dosage plasmatique des medicaments antidépresseurs [Recommendations for therapeutic monitoring of antidepressants].

Therapeutic drug monitoring (TDM), combined in certain situations with pharmacogenetic tests of metabolism, has proven a valuable tool for psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, nonresponse at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. This article is an adaptation of guidelines recently issued by the AGNP-TDM group (Hiemke et al., www. agnp.de), but its content focuses mainly on the TDM of antidepressants. Finally, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process.

The C-Jun N-Terminal Kinase Inhibition in Intracerebral Hemorrhage

Background: In intracerebral hemorrhage (ICH), a subtype of stroke, the bloodentry into the brain triggers toxicity resulting in a strong loss of neurons andinflammation. Water content is also increases leading to growing intracranial pressure,which worsens neurological outcome. C-Jun N-terminal kinases (JNKs) areactivated in response to stress stimuli. Specific inhibition of JNK by a TAT-coupledpeptide (XG-102) mediates neuroprotection in several models of ischemic stroke.Recently, we have noted that the JNK pathway is also activated in a mouse modelof ICH, raising the question of the efficacy of XG-102 in this model.Method: ICH was induced in the mouse by intrastriatal injection of bacterialcollagenase (0,1U). Three hours later, animals received an i.v. injection of XG-102(100μg/kg). The neuroscore was assessed using a scale (from 0 to 9) based on 3behavioral tests performed daily. Then, mice were sacrificed at 6h, 24h, 48h and 5dafter ICH and histological studies performed.Results: XG-102 significantly improves neurological outcome at 24h (mean score:1,8±1.4 vs 3,4±1.8, p<0.01). Analysis of the lesion volume revealed a significantdecrease of the lesion area in the treated group at 48h (29±11 mm3 vs 39±5 mm3,p = 0.04). XG-102 mainly inhibits the edema component of the lesion. Indeed, asignificant decrease of the brain swelling was observed in treated animals at 48h(14±13% vs 26±9%, p=0.04) and 5d (-0,3±4.5% vs 5,1±3.6%, p=0.01).Conclusions: Inhibition of the JNK pathway by XG-102 appears to lead to asignificant decrease of the cerebral edema in the ICH model providing a furtherbeneficial effect of the XG-102 treatment. This result is of interest becausecurrently, clinical treatment for brain edema is limited. Importantly, the beneficialeffects observed with XG-102 in both stroke models open the possibility to rapidlytreat patients before identifying the stroke subtype by imaging.

Low-dose angiostatic tyrosine kinase inhibitors improve photodynamic therapy for cancer: lack of vascular normalization.

Photodynamic therapy (PDT) is an effective clinical treatment for a number of different cancers. PDT can induce hypoxia and inflammation, pro-angiogenic side effects, which may counteract its angio-occlusive mechanism. The combination of PDT with anti-angiogenic drugs offers a possibility for improved anti-tumour outcome. We used two tumour models to test the effects of the clinically approved angiostatic tyrosine kinase inhibitors sunitinib, sorafenib and axitinib in combination with PDT, and compared these results with the effects of bevacizumab, the anti-VEGF antibody, for the improvement of PDT. Best results were obtained from the combination of PDT and low-dose axitinib or sorafenib. Molecular analysis by PCR revealed that PDT in combination with axitinib suppressed VEGFR-2 expression in tumour vasculature. Treatment with bevacizumab, although effective as monotherapy, did not improve PDT outcome. In order to test for tumour vessel normalization effects, axitinib was also applied prior to PDT. The absence of improved PDT outcome in these experiments, as well as the lack of increased oxygenation in axitinib-treated tumours, suggests that vascular normalization did not occur. The current data imply that there is a future for certain anti-angiogenic agents to further improve the efficacy of photodynamic anti-cancer therapy.

Brain energy consumption induced by electrical stimulation promotes systemic glucose uptake.

BACKGROUND: Controlled transcranial stimulation of the brain is part of clinical treatment strategies in neuropsychiatric diseases such as depression, stroke, or Parkinson's disease. Manipulating brain activity by transcranial stimulation, however, inevitably influences other control centers of various neuronal and neurohormonal feedback loops and therefore may concomitantly affect systemic metabolic regulation. Because hypothalamic adenosine triphosphate-sensitive potassium channels, which function as local energy sensors, are centrally involved in the regulation of glucose homeostasis, we tested whether transcranial direct current stimulation (tDCS) causes an excitation-induced transient neuronal energy depletion and thus influences systemic glucose homeostasis and related neuroendocrine mediators.METHODS: In a crossover design testing 15 healthy male volunteers, we increased neuronal excitation by anodal tDCS versus sham and examined cerebral energy consumption with (31)phosphorus magnetic resonance spectroscopy. Systemic glucose uptake was determined by euglycemic-hyperinsulinemic glucose clamp, and neurohormonal measurements comprised the parameters of the stress systems.RESULTS: We found that anodic tDCS-induced neuronal excitation causes an energetic depletion, as quantified by (31)phosphorus magnetic resonance spectroscopy. Moreover, tDCS-induced cerebral energy consumption promotes systemic glucose tolerance in a standardized euglycemic-hyperinsulinemic glucose clamp procedure and reduces neurohormonal stress axes activity.CONCLUSIONS: Our data demonstrate that transcranial brain stimulation not only evokes alterations in local neuronal processes but also clearly influences downstream metabolic systems regulated by the brain. The beneficial effects of tDCS on metabolic features may thus qualify brain stimulation as a promising nonpharmacologic therapy option for drug-induced or comorbid metabolic disturbances in various neuropsychiatric diseases.

Resistance of Candida spp. to antifungal drugs in the ICU: where are we now?

Current increases in antifungal drug resistance in Candida spp. and clinical treatment failures are of concern, as invasive candidiasis is a significant cause of mortality in intensive care units (ICUs). This trend reflects the large and expanding use of newer broad-spectrum antifungal agents, such as triazoles and echinocandins. In this review, we firstly present an overview of the mechanisms of action of the drugs and of resistance in pathogenic yeasts, subsequently focusing on recent changes in the epidemiology of antifungal resistance in ICU. Then, we emphasize the clinical impacts of these current trends. The emergence of clinical treatment failures due to resistant isolates is described. We also consider the clinical usefulness of recent advances in the interpretation of antifungal susceptibility testing and in molecular detection of the mutations underlying acquired resistance. We pay particular attention to practical issues relating to ICU patient management, taking into account the growing threat of antifungal drug resistance.

AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint eff ort.

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors.

Angio-oedema (AE) is a known adverse effect of angiotensin converting enzyme inhibitor (ACE-I) therapy. Over the past several decades, evidence of failure to diagnose this important and potentially fatal reaction is commonly found in the literature. Because this reaction is often seen first in the primary care setting, a review was undertaken to analyse and document the keys to both diagnostic criteria as well as to investigate potential risk factors for ACE-I AE occurrence. A general review of published literature was conducted through Medline, EMBASE, and the Cochrane Database, targeting ACE-I-related AE pathomechanism, diagnosis, epidemiology, risk factors, and clinical decision making and treatment. The incidence and severity of AE appears to be on the rise and there is evidence of considerable delay in diagnosis contributing to significant morbidity and mortality for patients. The mechanism of AE due to ACE-I drugs is not fully understood, but some genomic and metabolomic information has been correlated. Additional epidemiologic data and clinical treatment outcome predictors have been evaluated, creating a basis for future work on the development of clinical prediction tools to aid in risk identification and diagnostic differentiation. Accurate recognition of AE by the primary care provider is essential to limit the rising morbidity associated with ACE-I treatment-related AE. Research findings on the phenotypic indicators relevant to this group of patients as well as basic research into the pathomechanism of AE are available, and should be used in the construction of better risk analysis and clinical diagnostic tools for ACE-I AE.

Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fat.

New approaches to the clinical treatment of traumatic nerve injuries may one day utilize stem cells to enhance nerve regeneration. Adipose-derived stem cells (ASC) are found in abundant quantities and can be harvested by minimally invasive procedures that should facilitate their use in such regenerative applications. We have analyzed the properties of human ASC isolated from the deep and superficial layers of abdominal fat tissue obtained during abdominoplasty procedures. Cells from the superficial layer proliferate significantly faster than those from the deep layer. In both the deep and superficial layers, ASC express the pluripotent stem cell markers oct4 and nanog and also the stro-1 cell surface antigen. Superficial layer ASC induce the significantly enhanced outgrowth of neurite-like processes from neuronal cell lines when compared with that of deep layer cells. However, analysis by reverse transcription with the polymerase chain reaction and by enzyme-linked immunosorbent assay has revealed that ASC isolated from both layers express similar levels of the following neurotrophic factors: nerve growth factor, brain-derived neurotrophic factor and glial-derived neurotrophic factor. Thus, human ASC show promising potential for the treatment of traumatic nerve injuries. In particular, superficial layer ASC warrant further analysis of their neurotrophic molecules.

Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response.

Cysteine cathepsin protease activity is frequently dysregulated in the context of neoplastic transformation. Increased activity and aberrant localization of proteases within the tumour microenvironment have a potent role in driving cancer progression, proliferation, invasion and metastasis. Recent studies have also uncovered functions for cathepsins in the suppression of the response to therapeutic intervention in various malignancies. However, cathepsins can be either tumour promoting or tumour suppressive depending on the context, which emphasizes the importance of rigorous in vivo analyses to ascertain function. Here, we review the basic research and clinical findings that underlie the roles of cathepsins in cancer, and provide a roadmap for the rational integration of cathepsin-targeting agents into clinical treatment.