An explorative metabolomic analysis of the endothelium in pulmonary hypertension.

Pulmonary hypertension (PH) is classified into five clinical diagnostic groups, including group 1 [idiopathic pulmonary arterial hypertension (IPAH) and connective tissue disease-associated PAH (CTD-aPAH)] and group 4 (chronic thromboembolic pulmonary hypertension (CTEPH)). PH is a progressive, life-threatening, incurable disease. The pathological mechanisms underlying PH remain elusive; recent evidence has revealed that abnormal metabolic activities in the endothelium may play a crucial role. This research introduces a novel approach for studying PH endothelial function, building on the genome-scale metabolic reconstruction of the endothelial cell (EC) to investigate intracellular metabolism. We demonstrate that the intracellular metabolic activities of ECs in PH patients cluster into four phenotypes independent of the PH diagnosis. Notably, the disease severity differs significantly between the metabolic phenotypes, suggesting their clinical relevance. The significant metabolic differences between the PH phenotypes indicate that they may require different therapeutic interventions. In addition, diagnostic capabilities enabling their identification is warranted to investigate whether this opens a novel avenue of precision medicine.

Can Shunt Response in Patients with Idiopathic Normal Pressure Hydrocephalus Be Predicted from Preoperative Brain Imaging? A Retrospective Study of the Diagnostic Use of the Normal Pressure Hydrocephalus Radscale in 119 Patients.

BACKGROUND AND PURPOSE: The Normal Pressure Hydrocephalus Radscale is a combined scoring of 7 different structural imaging markers on preoperative brain CT or MR imaging in patients with idiopathic normal pressure hydrocephalus: callosal angle, Evans Index, Sylvian fissure dilation, apical sulcal narrowing, mean temporal horn diameter, periventricular WM lesions, and focal sulcal dilation. The purpose of this retrospective study was to assess the performance of the Normal Pressure Hydrocephalus Radscale in distinguishing idiopathic normal pressure hydrocephalus shunt responders from nonresponders. MATERIALS AND METHODS: The preoperative MR imaging and CT scans of 119 patients with idiopathic normal pressure hydrocephalus were scored using the Normal Pressure Hydrocephalus Radscale. A summary shunt-response score assessed within 6 months from ventriculoperitoneal shunt surgery, combining the effect on cognition, gait, and urinary incontinence, was used as a reference. The difference between the mean Normal Pressure Hydrocephalus Radscale for responders and nonresponders was tested using the Student t test. The area under the curve was calculated for the Normal Pressure Hydrocephalus Radscale to assess shunt response. To ascertain reproducibility, we assessed the interobserver agreement between the 2 independent observers as intraclass correlation coefficients for the Normal Pressure Hydrocephalus Radscale for 74 MR imaging scans and 19 CT scans. RESULTS: Ninety-four (79%) of 119 patients were shunt responders. The mean Normal Pressure Hydrocephalus Radscale score for shunt responders was 8.35 (SD, 1.53), and for nonresponders, 7.48 (SD, 1.53) (P = .02). The area under the curve for the Normal Pressure Hydrocephalus Radscale was 0.66 (range, 0.54-0.78). The intraclass correlation coefficient for the Normal Pressure Hydrocephalus Radscale was 0.86 for MR imaging and 0.82 for CT. CONCLUSIONS: The Normal Pressure Hydrocephalus Radscale showed moderate discrimination for shunt response but cannot, on its own, be used for selecting patients with idiopathic normal pressure hydrocephalus for shunt surgery.

Cortical thickness following electroconvulsive therapy in patients with depression: a longitudinal MRI study.

OBJECTIVE: Several studies have found an increase in hippocampal volume following electroconvulsive therapy (ECT), but the effect on cortical thickness has been less investigated. We aimed to examine the effects of ECT on cortical thickness and their associations with clinical outcome. METHOD: Using 3 Tesla MRI scanner, we obtained T1-weighted brain images of 18 severely depressed patients at three time points: before, right after and 6 months after a series of ECT. The thickness of 68 cortical regions was extracted using Free Surfer, and Linear Mixed Model was used to analyze the longitudinal changes. RESULTS: We found significant increases in cortical thickness of 26 regions right after a series of ECT, mainly within the frontal, temporal and insular cortex. The thickness returned to the baseline values at 6-month follow-up. We detected no significant decreases in cortical thickness. The increase in the thickness of the right lateral orbitofrontal cortex was associated with a greater antidepressant effect, r = 0.75, P = 0.0005. None of the cortical regions showed any associations with cognitive side effects. CONCLUSION: The increases in cortical thickness induced by ECT are transient. Further multimodal MRI studies should examine the neural correlates of these increases and their relationship with the antidepressant effect.

Donor Smoking and Older Age Increases Morbidity and Mortality After Lung Transplantation.

BACKGROUND: The lack of lung transplant donors has necessitated the use of donors with a smoking history and donors of older age. We have evaluated the effects of donor smoking history and age on recipient morbidity and mortality with baseline values of pulmonary function and survival free of chronic lung allograft dysfunction (CLAD) as morbidity variables. METHODS: This is a retrospective analysis of 588 consecutive lung transplant recipients and their corresponding 454 donors. Donors were divided into three groups: group 1 included smokers, group 2 nonsmokers, and group 3 had unknown smoking status; these were further divided into three age groups: group A: 0 to 39 years; group B: 40 to 54 years; and group C: ≥55 years. RESULTS: One hundred fifty-one donors were former or actual smokers, 175 were nonsmokers, and 128 had unknown smoking histories. Baseline forced expiratory volume in 1 second, forced vital capacity, and diffusion capacity of carbon monoxide were lowest in the groups who received lungs from a smoking donor. CLAD-free survival was identical in all smoking groups, and overall survival was better both for lungs from nonsmoking donors and donors with unknown smoking status compared to lungs from smoking donors. One hundred sixty-nine donors were in age group A, 203 in B, and 82 in C. Baseline forced expiratory volume in 1 second, forced vital capacity, and diffusion capacity of carbon monoxide were lowest in the groups who received lungs from donors older than 55 years. Overall survival as well as CLAD-free survival was significantly lower with donors ≥55 years. CONCLUSIONS: Donor smoking history and older donor age impact lung function, mortality, and CLAD-free survival after transplantation. Because of a shortage of organs, extended donor criteria may be considered while taking waiting list mortality into account.

Ultrasound Vascular Elastography as a Tool for Assessing Atherosclerotic Plaques - A Systematic Literature Review.

Atherosclerosis is a widespread disease that accounts for nearly 3-quarters of deaths due to cardiovascular disease. Ultrasound elastography might be able to reliably identify characteristics associated with vulnerable plaques. There is a need for the evaluation of elastography and its ability to distinguish between vulnerable and stable plaques. The aim of this paper is to provide an overview of the literature on vascular elastography. A systematic search of the available literature for studies using elastography for assessing atherosclerotic plaques was conducted using the MEDLINE, Embase, Cochrane Library and Web of Science databases. A standardized template was used to extract relevant data following the PRISMA 2009 checklist. 20 articles were included in this paper. The studies were heterogeneous. All studies reported that elastography was a feasible technique and provided additional information compared to B-mode ultrasound alone. Most studies reported higher strain values for vulnerable plaques. Ultrasound elastography has potential as a clinical tool in the assessment of atherosclerotic plaques. Elastography is able to distinguish between different plaque types, but there is considerable methodological variation between studies. There is a need for larger studies in a clinical setting to determine the full potential of elastography.

Ultrasound Elastography in Breast Cancer Diagnosis.

Ultrasound elastography is an established method for characterization of focal lesions in the breast. Different techniques and analyses of the images may be used for the characterization. This article addresses the use of ultrasound elastography in breast cancer diagnosis. In the first part of the article the techniques behind both strain- and shear-wave-elastography are explained and followed by a section on how to obtain adequate elastography images and measurements. In the second part of the article the application of elastography as an adjunct to B-mode ultrasound in clinical practice is described, and the potential diagnostic gains and limitations of elastography are discussed.

Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment.

In a positron-emission tomography (PET) study with the ß-amyloid (Aß) tracer [(18)F]-florbetaben, we previously showed that Aß deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aß42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aß-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aß-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aß were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aß42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aß-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.

Strain Elastography for Prediction of Malignancy in Soft Tissue Tumours--Preliminary Results.

PURPOSE: To evaluate the ability of strain elastography to predict malignancy in patients with soft tissue tumors, and to compare three evaluation methods of strain elastography: strain ratios, strain histograms and visual scoring. MATERIALS AND METHODS: 60 patients with 61 tumors were analyzed in the study. All patients were referred due to suspicion of malignant soft tissue tumors after diagnostic imaging (contrast-enhanced MRI, CT or PET-CT). Ultrasound-guided biopsy was preceded by the recording of strain elastography video clips, which were evaluated in consensus between three investigators. Strain ratio, strain histogram analysis and visual scoring using a five-point visual scale were compared with the final pathology from either biopsy or resection of the tumors. RESULTS: The difference between the mean strain ratio for malignant and benign tumors was significant (p = 0.043). The mean strain ratios for malignant and benign tumors were 1.94 (95% CI [0.37; 10.21]) and 1.35 (95% CI [0.32; 5.63]), respectively. There were no significant differences for strain histograms or visual scoring. Liposarcomas had lower mean strain ratio, strain histogram values, and visual scoring than other malignant tumors. When analyzing a subgroup of patients without fat-containing tumors (n = 46), based on appearance on MRI or CT, the difference between the mean strain ratios for malignant and benign tumors increased (p = 0.014). CONCLUSION: The mean strain ratios of malignant tumors were significantly higher than the mean strain ratios of benign tumors. There was no significant difference for strain histograms and visual scoring. Strain ratios may be used as an adjunct in soft tissue tumor diagnosis, possibly minimizing the number of biopsies.

Recurrence of sarcoid granulomas in lung transplant recipients is common and does not affect overall survival.

BACKGROUND: Sarcoidosis represents 2,5% of all indications for lung transplantation and criteria are generally assumed to be the same as for pulmonary fibrosis. Recurrence of granulomas in transplanted lungs has earlier been proved to derive from recipient immune cells, but its role in relation to lung function and overall survival after lung transplantation remains uncertain. OBJECTIVE: To identify recurrent granuloma in transbronchial biopsies in patients receiving lung transplant because of sarcoidosis, and relate the findings to overall survival and lung function. DESIGN: A total of 620 patients were transplanted at this centre from 1992 until august 2012. This study comprised all patients (n=25) transplanted due to pulmonary sarcoidosis. Lung functions, trans-bronchial biopsies, and survival were compared in patients with and without recurrence of granulomas. Granulomas were defined as non-necrotizing epitheloid granulomas with multinucleated giant cells according to standard criteria (formation of epitheloid giant cells) without presence of infection. CONCLUSIONS: Approximately 30% of lung transplant recipients due to sarcoidosis have recurrence of sarcoid granulomas. Recurrence of granulomas does not affect overall survival or lung function.

Acute administration of the small-molecule p75(NTR) ligand does not prevent hippocampal neuron loss or development of spontaneous seizures after pilocarpine-induced status epilepticus.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are initially expressed in a precursor form (e.g., pro-BDNF) and cleaved to form mature BDNF (mBDNF). After pilocarpine-induced status epilepticus (SE), increases in neurotrophins regulate a wide variety of cell-signaling pathways, including prosurvival and cell-death machinery in a receptor-specific manner. Pro-BDNF preferentially binds to the p75 neurotrophin receptor (p75(NTR) ), whereas mBDNF is the major ligand of the tropomyosin-related kinase receptor. To elucidate a potential role for p75(NTR) in acute stages of epileptogenesis, rats were injected prior to and at onset of SE with LM11A-31, a small-molecule ligand that binds to p75(NTR) to promote survival signaling and inhibit neuronal cell death. Modulation of early p75(NTR) signaling and its effects on electrographic SE, SE-induced neurodegeneration, and subsequent spontaneous seizures were examined after LM11A-31 administration. Despite an established neuroprotective effect of LM11A-31 in several animal models of neurodegenerative disorders (e.g., Alzheimer's disease, traumatic brain injury, and spinal cord injury), high-dose LM11A-31 administration prior to and at onset of SE did not reduce the intensity of electrographic SE, prevent SE-induced neuronal cell injury, or inhibit the progression of epileptogenesis. Further studies are required to understand the role of p75(NTR) activation during epileptogenesis and in seizure-induced cell injury in the hippocampus, among other potential cellular pathologies contributing to the onset of spontaneous seizures. Additional studies utilizing more prolonged treatment with LM11A-31 are required to reach a definite conclusion on its potential neuroprotective role in epilepsy.

The hydrostatic pressure indifference point underestimates orthostatic redistribution of blood in humans.

The hydrostatic indifference point (HIP; where venous pressure is unaffected by posture) is located at the level of the diaphragm and is believed to indicate the orthostatic redistribution of blood, but it remains unknown whether HIP coincides with the indifference point for blood volume (VIP). During graded (± 20°) head-up (HUT) and head-down tilt (HDT) in 12 male volunteers, we determined HIP from central venous pressure and VIP from redistribution of both blood, using ultrasound imaging of the inferior caval vein (VIPui), and fluid volume, by regional electrical admittance (VIPadm). Furthermore, we evaluated whether inflation of medical antishock trousers (to 70 mmHg) affected HIP and VIP. Leaving cardiovascular variables unaffected by tilt, HIP was located 7 ± 4 cm (mean ± SD) below the 4th intercostal space (IC-4) during HUT and was similar (7 ± 3 cm) during HDT and higher (P < 0.0001) than both VIPui (HUT: 22 ± 16 cm; HDT: 13 ± 7 cm) and VIPadm (HUT: 29 ± 9 cm; HDT: 20 ± 9 cm below IC-4). During HUT antishock trousers elevated both HIP and VIPui [to 3 ± 5 cm (P = 0.028) and 17 ± 7 cm below IC-4 (P = 0.051), respectively], while VIPadm remained unaffected. By simultaneous recording of pressure and filling of the inferior caval vein as well as fluid distribution, we found HIP located corresponding to the diaphragm while VIP was placed low in the abdomen, and that medical antishock trousers elevated both HIP and VIP. The low indifference point for volume shows that the gravitational influence on distribution of blood is more profound than indicated by the indifference point for venous pressure.

The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy.

Pilocarpine-induced status epilepticus (SE), which results in temporal lobe epilepsy (TLE) in rodents, activates the JAK/STAT pathway. In the current study, we evaluate whether brief exposure to a selective inhibitor of the JAK/STAT pathway (WP1066) early after the onset of SE affects the severity of SE or reduces later spontaneous seizure frequency via inhibition of STAT3-regulated gene transcription. Rats that received systemic WP1066 or vehicle at the onset of SE were continuously video-EEG monitored during SE and for one month to assess seizure frequency over time. Protein and/or mRNA levels for pSTAT3, and STAT3-regulated genes including: ICER, Gabra1, c-myc, mcl-1, cyclin D1, and bcl-xl were evaluated in WP1066 and vehicle-treated rats during stages of epileptogenesis to determine the acute effects of WP1066 administration on SE and chronic epilepsy. WP1066 (two 50mg/kg doses) administered within the first hour after onset of SE results in transient inhibition of pSTAT3 and long-term reduction in spontaneous seizure frequency. WP1066 alters the severity of chronic epilepsy without affecting SE or cell death. Early WP1066 administration reduces known downstream targets of STAT3 transcription 24h after SE including cyclin D1 and mcl-1 levels, known for their roles in cell-cycle progression and cell survival, respectively. These findings uncover a potential effect of the JAK/STAT pathway after brain injury that is physiologically important and may provide a new therapeutic target that can be harnessed for the prevention of epilepsy development and/or progression.

Paraplegia due to drop metastases from anaplastic oligodendroglioma.

In this article, we report on a rare case of spinal seeding from a cerebral anaplastic oligodendroglioma presenting with signs of medullar compression. We discuss the prevalence, mechanisms and imaging findings of spinal seeding in various gliomas. A suitable clinical treatment and follow up for these patients is suggested.

Treatment of intractable interstitial lung injury with alemtuzumab after lung transplantation.

A 44-year-old woman underwent left single-lung transplantation for end-stage emphysema due to α1-antitrypsin deficiency in January 2010. Cyclosporine, azathioprine, and prednisolone were administered for immunosuppression and antithymocyte globulin for induction therapy at the time of transplantation. Routine examination of a lung biopsy, 4 months after transplantation, showed nonspecific, diffuse interstitial inflammation with alveolar septal fibrosis. The patient's clinical status and imaging studies, consistent with nonspecific interstitial pneumonitis, which was considered as signs of acute rejection, worsened within 2 weeks, despite high-dose steroids, change of calcineurin inhibitor, and plasmapheresis. Within a few days after a single, 10-mg, intravenous dose of alemtuzumab, the patient's health improved markedly. She has remained stable for 4 months on a standard, ambulatory, posttransplant antirejection drug regimen. We have since successfully treated with alemtuzumab three additional patients who developed interstitial lung injury after lung transplantation, who are also summarized in this report.

An instrument for person-of-the-therapist supervision.

This article introduces a tool that serves as a guide for building an effective bridge between the personal and technical aspects of therapy in supervision. The instrument is based on a model of clinical supervision that emphasizes the purposeful utilization of self-in the moment, with both flaws and strengths-in the therapeutic relationship in combination with the technical interventions with clients. The article also offers some aid to promote a personal integration of the philosophy underlying this supervisory model into a therapist's clinical thinking and practice.

Rapid decline in 51Cr-EDTA measured renal function during the first weeks following lung transplantation.

We previously described a 54% decline in renal function at 6 months after lung transplantation (LTx). We hypothesized that this decline is a very early event following LTx. Thirty-one consecutive patients (16 females/15 males), mean age 49 (+/-13) years, with emphysema, cystic fibrosis/bronchiectasis or idiopathic pulmonary fibrosis were included in an analysis of renal function before and after LTx. The glomerular filtration rate (GFR) was measured using the (51)Cr-ethylenediaminetetra acetic acid plasma clearance single injection technique (mGFR) at baseline before transplantation and at 1, 2, 3 and 12 weeks postoperatively. Mean mGFR declined from 103 +/- 18 to 65 +/- 22, 53 +/- 16 and 57 +/- 18 mL/min/1.73m(2) at 1-, 3- and 12-weeks post-LTx (p < 0.0001), respectively. In a time-dependent repeated measures ANOVA, risk factors for a decline in mGFR posttransplant included: time (p < 0.0001), acute renal failure within 2 weeks post-LTx (p = 0.0003), use of heart and lung machine (p = 0.04), and the use of ephedrine (p = 0.048), as well as increasing age, older than 18 years at LTx (p = 0.006). These data demonstrate that renal function, measured with an isotope method, decreases dramatically during the first week after LTx.

Aspergillus infection in lung transplant patients: incidence and prognosis.

Lung transplant recipients experience a particularly high incidence of Aspergillus infection in comparison with other solid-organ transplantations. This study was conducted to determine the incidence of Aspergillus colonisation and invasive aspergillosis, and the impact on long-term survival associated with Aspergillus infection. A retrospective study of 362 consecutive lung transplant patients from a single national centre who were transplanted 1992-2003 were studied. Twenty-seven patients were excluded due to incomplete or missing files. A total of 105/335 (31%) patients had evidence of Aspergillus infection (colonisation or invasion), including 83 (25%) patients with colonisation and 22 (6%) patients with radiographic or histological evidence of invasive disease. Most of the infections occurred within the first 3 months after transplantation. Cystic fibrosis (CF) patients had higher incidences of colonisation and invasive disease [15 (42%) and 4 (11%) of 36 patients] than non-CF patients [68 (23%) and 18 (6%) of 299 patients] (P = 0.01). Invasive aspergillosis was associated with 58% mortality after 2 years, whereas colonisation was not associated with early increased mortality but was associated with increased mortality after 5 years compared to non-infected patients (P < 0.05). An analysis of demographic factors showed that donor age [OR 1.40 per decade (95% CI 1.10-1.80)], ischaemia time [OR 1.17 per hour increase (95% CI 1.01-1.39)], and use of daclizumab versus polyclonal induction [OR 2.05 (95% CI 1.14-3.75)] were independent risk factors for Aspergillus infection. Invasive aspergillosis was associated with early and high mortality in lung transplant patients. Colonisation with Aspergillus was also associated with a significant increase in mortality after 5 years. CF patients have a higher incidence of Aspergillus infection than non-CF patients.

Results of European post-marketing surveillance of bosentan in pulmonary hypertension.

After the approval of bosentan for the treatment of pulmonary arterial hypertension (PAH), European authorities required the introduction of a post-marketing surveillance system (PMS) to obtain further data on its safety profile. A novel, prospective, internet-based PMS was designed, which solicited reports on elevated aminotransferases, medical reasons for bosentan discontinuation and other serious adverse events requiring hospitalisation. Data captured included demographics, PAH aetiology, baseline functional status and concomitant PAH-specific medications. Safety signals captured included death, hospitalisation, serious adverse events, unexpected adverse events and elevated aminotransferases. Within 30 months, 4,994 patients were included, representing 79% of patients receiving bosentan in Europe. In total, 4,623 patients were naïve to treatment; of these, 352 had elevated aminotransferases, corresponding to a crude incidence of 7.6% and an annual rate of 10.1%. Bosentan was discontinued due to elevated aminotransferases in 150 (3.2%) bosentan-naïve patients. Safety results were consistent across subgroups and aetiologies. The novel post-marketing surveillance captured targeted safety data ("potential safety signals") from the majority of patients and confirmed that the incidence and severity of elevated aminotransferase levels in clinical practice was similar to that reported in clinical trials. These data complement those from randomised controlled clinical trials and provide important additional information on the safety profile of bosentan.