Liver regeneration after portal and hepatic vein embolization improves overall survival compared with portal vein embolization alone: mid-term survival analysis of the multicentre DRAGON 0 cohort.

BACKGROUND: The purpose of this study was to compare 3-year overall survival after simultaneous portal (PVE) and hepatic vein (HVE) embolization versus PVE alone in patients undergoing liver resection for primary and secondary cancers of the liver. METHODS: In this multicentre retrospective study, all DRAGON 0 centres provided 3-year follow-up data for all patients who had PVE/HVE or PVE, and were included in DRAGON 0 between 2016 and 2019. Kaplan-Meier analysis was undertaken to assess 3-year overall and recurrence/progression-free survival. Factors affecting survival were evaluated using univariable and multivariable Cox regression analyses. RESULTS: In total, 199 patients were included from 7 centres, of whom 39 underwent PVE/HVE and 160 PVE alone. Groups differed in median age (P = 0.008). As reported previously, PVE/HVE resulted in a significantly higher resection rate than PVE alone (92 versus 68%; P = 0.007). Three-year overall survival was significantly higher in the PVE/HVE group (median survival not reached after 36 months versus 20 months after PVE; P = 0.004). Univariable and multivariable analyses identified PVE/HVE as an independent predictor of survival (univariable HR 0.46, 95% c.i. 0.27 to 0.76; P = 0.003). CONCLUSION: Overall survival after PVE/HVE is substantially longer than that after PVE alone in patients with primary and secondary liver tumours.

Contrast-Enhanced T1-Weighted Head and Neck MRI: Prospective Intraindividual Image Quality Comparison of Spiral GRE, Cartesian GRE, and Cartesian TSE Sequences.

BACKGROUND. Sequences with noncartesian k-space sampling may improve image quality of head and neck MRI. OBJECTIVE. The purpose of this study was to compare intraindividually the image quality of a spiral gradient-recalled echo (GRE) sequence and conventional cartesian GRE and cartesian turbo spin-echo (TSE) sequences for contrast-enhanced T1-weighted head and neck MRI. METHODS. This prospective study included patients referred for contrast-enhanced head and neck MRI from August 2020 to May 2021. Patients underwent 1.5-T MRI including contrast-enhanced spiral GRE (2 minutes 28 seconds), cartesian GRE (4 minutes 27 seconds), and cartesian TSE (3 minutes 41 seconds) sequences, acquired in rotating order across patients. Three radiologists independently assessed image quality measures, including conspicuity of prespecified lesions, using 5-point Likert scales. One reader measured maximal extent of dental material artifact and contrast-to-noise ratio (CNR). RESULTS. Thirty-one patients (13 men, 18 women; mean age, 63.8 years) were enrolled. Nineteen patients had a focal lesion; 22 had dental material. Interreader agreement for image quality measures was substantial to excellent (Krippendorff alpha, 0.681-1.000). Scores for overall image quality (whole head and neck, neck only, and head only), pulsation artifact, muscular contour delineation, vessel contour delineation, motion artifact, and differentiation between mucosa and pharyngeal muscles were significantly better for spiral GRE than for cartesian GRE and cartesian TSE for all readers (p < .05). Scores for lesion conspicuity (whole head and neck, neck only, and head only), quality of fat suppression, flow artifact, and foldover artifact were not significantly different between spiral GRE and the cartesian sequences for any reader (p > .05). Dental material artifact scores were significantly worse for spiral GRE than the other sequences for all readers (p < .05). The mean maximum extent of dental material artifact was 39.6 ± 25.5 (SD) mm for spiral GRE, 35.6 ± 24.3 mm for cartesian GRE, and 29.6 ± 21.4 mm for cartesian TSE; the mean CNR was 221.1 ± 94.5 for spiral GRE, 151.8 ± 85.7 for cartesian GRE, and 153.0 ± 63.2 for cartesian TSE (p < .001 between spiral GRE and other sequences for both measures). CONCLUSION. Three-dimensional spiral GRE improves subjective image quality and CNR of head and neck MRI with shorter scan time versus cartesian sequences, though it exhibits larger dental material artifact. CLINICAL IMPACT. A spiral sequence may help overcome certain challenges of conventional cartesian sequences for head and neck MRI.

Consensus Guidelines for the Definition of Time-to-Event End Points in Image-guided Tumor Ablation: Results of the SIO and DATECAN Initiative.

There is currently no consensus regarding preferred clinical outcome measures following image-guided tumor ablation or clear definitions of oncologic end points. This consensus document proposes standardized definitions for a broad range of oncologic outcome measures with recommendations on how to uniformly document, analyze, and report outcomes. The initiative was coordinated by the Society of Interventional Oncology in collaboration with the Definition for the Assessment of Time-to-Event End Points in Cancer Trials, or DATECAN, group. According to predefined criteria, based on experience with clinical trials, an international panel of 62 experts convened. Recommendations were developed using the validated three-step modified Delphi consensus method. Consensus was reached on when to assess outcomes per patient, per session, or per tumor; on starting and ending time and survival time definitions; and on time-to-event end points. Although no consensus was reached on the preferred classification system to report complications, quality of life, and health economics issues, the panel did agree on using the most recent version of a validated patient-reported outcome questionnaire. This article provides a framework of key opinion leader recommendations with the intent to facilitate a clear interpretation of results and standardize worldwide communication. Widespread adoption will improve reproducibility, allow for accurate comparisons, and avoid misinterpretations in the field of interventional oncology research. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

Paclitaxel-Coated Balloon for the Treatment of Infrainguinal Disease: 12-Month Outcomes in the All-Comers Cohort of BIOLUX P-III Global Registry.

Purpose: To further investigate the safety and performance of the Passeo-18 Lux drug-coated balloon (DCB) for the treatment of atherosclerotic infrainguinal disease under real-world conditions. Materials and Methods: BIOLUX P-III is an international, prospective, observational registry (ClinicalTrials.gov identifier NCT02276313) conducted at 41 centers in Europe, Asia, and Australia with follow-up visits at 6, 12, and 24 months. Of 700 patients (mean age 70.0±10.2 years; 439 men) with 863 lesions in the all-comers cohort, 330 (47.1%) patients had diabetes and 234 (37.7%) had chronic limb-threatening ischemia. The majority (79.3%) of lesions were in the femoropopliteal segment; of all lesions, 645 (74.9%) were calcified and 99 (11.5%) had in-stent restenosis (ISR). The mean lesion length was 84.7±73.3 mm. The primary clinical endpoint was major adverse events (MAEs) within 6 months, a composite of device- and procedure-related mortality through 30 days, major target limb amputation, and clinically-driven target lesion revascularization (TLR). The primary performance endpoint was clinically-driven TLR within 12 months. Results: At 6 and 12 months, freedom from MAEs was 94.0% and 89.5% in the all-comers cohort: 95.0% and 91.2% in the femoropopliteal group and 95.3% and 88.0% in the ISR subgroup, respectively. Freedom from clinically-driven TLR at 12 months was 93.1% in the all-comers cohort, 93.9% in the femoropopliteal lesions, and 89.4% for ISR lesions. All-cause mortality was 6.1% in the all-comers cohort: 5.9% in both the femoropopliteal and ISR subgroups. There were no device- or procedure-related deaths at up to 12 months. The Rutherford category improved in >80% of all subgroups at 12 months. Conclusion: In a real-world patient population, the safety and performance of the Passeo-18 Lux DCB for the treatment of atherosclerotic infrainguinal lesions are maintained, with good performance outcomes and low complication rates at 12 months.

Mid-term results of MR-guided high-intensity focused ultrasound treatment for relapsing superficial desmoids.

PURPOSE: Desmoids are locally infiltrative, nonmalignant soft tissue tumors. Surgery, radiation therapy, and chemotherapy have been the mainstay of treatment, but relapse is common and side effects can result in significant morbidity. MR-HIFU is increasingly recognized as an alternative treatment modality. We assessed the success rate of MR-HIFU for the treatment of extra-abdominal desmoids at our institute. MATERIALS AND METHODS: Five patients with relapsing desmoid tumors (three males, two females; age range 40-79 years) were treated using the Sonalleve system in an outpatient setting without general anesthesia. Changes in total tumor volumes were measured with a tumor tracking software. Adverse events were documented. RESULTS: MR-HIFU was successful in all patients without severe side effects. Follow up ranged from 13 to 60 months. Three patients required more than one treatment session. In 3 patients with small lesions (mean = 9.7 mL), complete ablation was achieved with no evidence of viable tumor on follow up MRI at an average of 35.7 months, while in two patients with larger lesions (mean = 46 mL) the targeted tumor volumes decreased by 73% at 14 months. Skin injuries comprised first- and second-degree burns and were observed with short distance to skin (mean = 0.9 cm) and proximity to bone (i.e. ribs). Skin burns healed within weeks with topical treatment. CONCLUSION: MR-HIFU shows good mid-term result for extra-abdominal desmoids with complete response for small lesions and stabilization of larger lesions. MR-HIFU for desmoids can be performed under regional anesthesia/sedation as outpatients.

Long segment 3D double inversion recovery (DIR) hypersignal on MRI in glaucomatous optic neuropathy.

BACKGROUND: In this retrospective study the relationship between intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness and pathologic hypersignal in optic nerve segments on 3D double inversion recovery (DIR) MR sequence in 21 patients with proven glaucoma of different origin was evaluated. METHODS: All patients were examined on a 3 T MR Philips® scanner. Pathologic optic nerve DIR hypersignal was determined in four different nerve segments. IOP was measured in mmHg by applanation tonometry. RNFL thickness was measured in µm with optical coherence tomography (OCT Heidelberg Engineering Spectralis® apparatus). Wilcoxon rank sum tests, student's t-tests and (multivariate) linear regression models were appied. RESULTS: 3D DIR hypersignal was present in 17 (41.5%) optic nerves. 3D DIR hypersignal was not related to ischemic or demyelinating optic nerve pathology but was associated with increased IOP (19.8 [24-18]; versus 15.45; [18.85-13.75] mmHg; p = 0.008) and decreased RNFL thickness (61.06 ± 12.1 versus 82.5 ± 21.6 µm; p < 0.001) in comparison to optic nerves of glaucoma patients without DIR hypersignal. Specifically, presence of DIR hypersignal in optic nerves in at least one optic nerve segment lowered RNFL thickness on average by 17.54 µm (p = 0.005) in comparison to optic nerves without DIR hypersignal. CONCLUSIONS: In patients with glaucomatous optic neuropathy (GON) and pathologic optic nerve DIR hypersignal, significantly increased IOP and significantly decreased RNFL thickness values are present. DIR hypersignal seems to be a marker for disease severity in GON related to decreased RNFL thickness and may thus represent long-segment severe axonal degeneration in optic nerves in patients with GON. Venous congestion and edema within the optic nerve related to high IOP may contribute to the DIR hypersignal as well.

Postpartum Bone Marrow Edema at the Sacroiliac Joints May Mimic Sacroiliitis of Axial Spondyloarthritis on MRI.

OBJECTIVE: The objective of our study was to compare MRI findings in the sacroiliac joints of postpartum women (as a model of mechanical changes) and women with known axial spondyloarthritis (as an inflammatory model). SUBJECTS AND METHODS: For this prospective multicenter age-matched, case-control study, sacroiliac joint MRI examinations of 30 healthy women (mean age, 34.0 years) in the early postpartum period (mechanical group) and 30 age-matched women (mean age, 33.8 years) with known axial spondyloarthritis (retrospective inflammatory group) were compared. Blinded to clinical information, readers assessed MR images using the following scoring systems: Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index, Berlin method, Assessment of Spondyloarthritis International Society (ASAS) criteria, and SPARCC MRI structural score. Descriptive statistics as percentages of the different findings (i.e., bone marrow edema [BME], erosion, fatty bone marrow replacement, backfill, ankylosis) and scores between groups and between delivery modes were compared. RESULTS: In the postpartum group, 63.3% (19/30) of women showed BME around the sacroiliac joints compared with 86.7% (26/30) of women in the spondyloarthritis group (based on ASAS criteria). Erosions were uncommon in the postpartum group (10.0% [3/30] postpartum vs 56.7% [17/30] spondyloarthritis). Fatty bone marrow replacement, backfill, and ankylosis were not seen in the postpartum group. In subjects with positive MRI findings for sacroiliitis based on ASAS criteria, the SPARCC MRI index (mean ± SD, 13.6 ± 14.5 vs 13.0 ± 10.7; p = 0.818) and Berlin method (4.5 ± 3.0 and 5.5 ± 3.5, p = 0.378) were not different between the postpartum and spondyloarthritis groups. Scores were not different between birth modalities. CONCLUSION: Pregnancy-induced BME at the sacroiliac joints, as a result of prolonged mechanical stress, was present in 63.3% of women who underwent MRI during the early postpartum period and may mimic sacroiliitis of axial spondyloarthritis.

Bacterial contamination of ultrasound probes in different radiological institutions before and after specific hygiene training: do we have a general hygienical problem?

OBJECTIVES: Aim was to investigate hygienic conditions of ultrasound probes before and after hygiene training in radiology institutions in comparison to bacterial contamination in public places. METHODS: In three radiology departments, bacterial contamination was evaluated using baseline agar plates for cultures taken from 36 ultrasound probes. Afterwards teams were trained by a hygiene service centre and 36 ultrasound probes were routinely disinfected with regular disinfecting wipes and then evaluated. In comparison, bacterial contamination in public places (bus poles, n = 11; toilet seats, n = 10) were analysed. Plates were routinely incubated and the number of colony forming units (CFU) analysed. RESULTS: Cultures taken from the probes showed a median of 53 CFU before and 0 CFU after training (p < 0.001). Cultures taken from public places showed a median of 4 CFU from toilets and 28 from bus poles and had lower bacterial load in comparison to ultrasound probes before training (p = 0.055, toilets; p = 0.772, bus poles), without statistical significance. CONCLUSIONS: Bacterial contamination of ultrasound probes prior to hygiene training proved to be high and showed higher bacterial load than toilets seats or bus poles. Radiologists should be aware that the lack of hygiene in the field of ultrasound diagnostics puts patients at risk of healthcare-associated infections. KEY POINTS: • Hospital-associated infections are a problem for patient care. • Hygiene training of staff prevents bacterial contamination of ultrasound probes. • Disinfection of ultrasound probes is an easy method to protect patients.

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.

Pilot study on the detection of antiandrogen resistance using serial diffusion-weighted imaging of bone metastases in prostate cancer.

PURPOSE: To evaluate serial apparent diffusion coefficient (ADC) measurements of bone metastases in prostate cancer to determine whether antiandrogen resistance can be detected and time to progression estimated. MATERIALS AND METHODS: Diffusion-weighted imaging (DWI) was performed at 1.5T in nine patients with treatment-naïve metastatic prostate cancer (20 lesions) before antiandrogen treatment, after 1, 2, and 3 months of treatment, and thereafter every 4 months over 31 months or until antiandrogen resistance was detected. Tumor volumes were stable over time. Time courses of the ADCs when averaged over entire lesions and on functional diffusion maps (fDMs) were analyzed using marginal linear model (MLM) analysis. RESULTS: Starting at 1 month, MLM analysis revealed decreasing mean ADCs (P = 0.001) over time. Simultaneously, the percentage of voxels with significantly higher ADCs decreased (P = 0.004), whereas the percentage of voxels with significantly lower ADCs increased (P < 0.001) on fDMs. Both mean ADCs (P = 0.042) and percentages of voxels with significantly higher ADCs on fDMs (P = 0.039) decreased more rapidly over time in patients with a shorter progression-free interval (PFI). Likewise, higher (P = 0.001) and more rapidly increasing (P = 0.002) percentages of voxels with significantly lower ADCs on fDMs were associated with a shorter PFI. CONCLUSION: The results of our pilot study suggest that the evolution of ADCs over time may permit early identification of antiandrogen resistance in bone metastases. J. Magn. Reson. Imaging 2016;43:1407-1416.

UV-triggered affinity capture identifies interactions between the Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) and antimalarial agents in live parasitized cells.

A representative of a new class of potent antimalarials with an unknown mode of action was recently described. To identify the molecular target of this class of antimalarials, we employed a photo-reactive affinity capture method to find parasite proteins specifically interacting with the capture compound in living parasitized cells. The capture reagent retained the antimalarial properties of the parent molecule (ACT-213615) and accumulated within parasites. We identified several proteins interacting with the capture compound and established a functional interaction between ACT-213615 and PfMDR1. We surmise that PfMDR1 may play a role in the antimalarial activity of the piperazine-containing compound ACT-213615.

Residual Popliteal Aneurysm Perfusion Leading to Embolic Complications: A Case Report.

Introduction: Surgical management of popliteal artery aneurysms has been described for half a century. Long term development of the excluded aneurysm sac in the popliteal segment however remains widely unknown, with only a few small series describing outcomes. Residual aneurysm perfusion has the potential to lead to serious complications. Report: A 63 year old man presents with skin and soft tissue necrosis of the right calf two years after proximal and distal aneurysm ligation and great saphenous vein bypass for a popliteal artery aneurysm. Computed tomography and magnetic resonance angiography show perfusion of the excluded aneurysm as well as extensive necrosis of the gastrocnemius muscle. Direct angiography of the aneurysm demonstrated retrograde aneurysm perfusion due to insufficient distal ligation with recurrent micro-embolisation to the calf via geniculate arteries. Coiling of the geniculate arteries was performed, plugging the connection to the tibiofibular trunk and embolisation of the aneurysm sac. After the intervention, no flow was seen in the aneurysm sac and the patient made full recovery. Discussion: Residual aneurysm sac perfusion can lead to complications long after successful aneurysm exclusion. Follow-up after surgery of popliteal aneurysms should include observation of the excluded aneurysm sac with control of residual blood flow. For persistent sac perfusion, aneurysm enlargement or symptoms, further treatment should be considered. Surgical aspects such as complete transection of the artery after aneurysm ligation or end to end anastomosis of the bypass may be considered, to prevent such complications.

Transfemoral hepatic vein catheterization reduces procedure time in double vein embolization.

BACKGROUND: Double vein embolization with simultaneous embolization of the portal and hepatic vein aims to grow the future liver remnant in preparation for major hepatectomy. Transvenous hepatic vein embolization is usually done via a transjugular access. The purpose of this study is to describe the transfemoral approach as an alternative option and to discuss potential advantages. RESULTS: Twenty-three patients undergoing hepatic vein embolization via a transjugular (n = 10) or transfemoral access (n = 13) were evaluated retrospectively. In all cases the portal vein embolization was done first. All procedures were technically successful. There were no peri-interventional complications. Only two patients were not able to proceed to surgery. Standardized future liver remnant hypertrophy was non-inferior with the transfemoral approach compared to the transjugular route. Procedure time was significantly shorter in the transfemoral access group (40 ± 13 min) compared to the transjugular group (67 ± 13 min, p < 0.001). CONCLUSION: Transfemoral hepatic vein embolization is feasible, safe, and faster due to easier catheterization, improved stability, and simpler patient preparation. These findings will need to be validated in larger studies.

Differential NMR spectroscopy reactions of anterior/posterior and right/left insular subdivisions due to acute dental pain.

OBJECTIVES: The insular cortex has an important role within the cerebral pain circuitry. The aim of this study was to measure metabolic alterations by MR spectroscopy due to experimentally induced trigeminal pain in the anterior/posterior and right/left insular subdivisions. METHODS: Sixteen male volunteers were investigated using magnetic resonance (MR) spectroscopy before, during and after experimentally induced dental pain. Biphasic bipolar electric current pulses of 1 ms duration were administered based on the subjectively determined pain threshold. Volunteers were instructed to rate every stimulus using a MR compatible rating scale. RESULTS: Due to the pain stimulation a significant absolute increase in glutamate (Glu, F = 6.1; P = 0.001), glutamine (Gln, F = 11.2; P = 0.001) as well as glutamate/glutamine (Glx, F = 17.7; P = 0.001) were observed, whereas myo-inositol (mI, F = 9.5;P = 0.001) showed a significant drop. Additionally, these metabolites showed a significant effect towards lateralisation, meaning that metabolic concentration differed either in left or right insular subdivision. Creatine demonstrated also an absolute significant decrease during stimulation (F = 2.8; P = 0.022) with a significant anterior-posterior difference (F = 40.7; P = 0.001). CONCLUSIONS: Results confirm that the insular cortex is a metabolically high active region in pain processing within the brain. Quantitative metabolic changes show that there is a distinct but locally diverse neurometabolic activity under acute pain. The known cytoarchitectonic subdivisions show different metabolic reactions and give new insights into pain-processing physiology.

Pharmacokinetics, pharmacodynamics, and tolerability of ACT-077825, a new direct renin inhibitor after multiple-ascending doses in healthy subjects.

This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCτ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin concentration and plasma renin activity (PRA). ACT-077825 dose dependently increased active renin on days 1 and 7 and inhibited PRA dose dependently only on day 1. On day 7, the maximal PRA inhibition was attained after 250 mg of ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared with placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000-mg group and a dose of 500 mg of ACT-077825 was identified as the maximum tolerated dose. Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in patients with hypertension.

Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold.

A novel series of anti-malarials, based on a hydroxy-ethyl-amine scaffold, initially identified as peptidomimetic protease inhibitors is described. Combination of the hydroxy-ethyl-amine anti-malarial phramacophore with the known Mannich base pharmacophore of amodiaquine (57) resulted in promising in vivo active novel derivatives.

Insula-specific H magnetic resonance spectroscopy reactions in heavy smokers under acute nicotine withdrawal and after oral nicotine substitution.

The aim of this study was to clarify whether addiction-specific neurometabolic reaction patterns occur in the insular cortex during acute nicotine withdrawal in tobacco smokers in comparison to nonsmokers. Fourteen male smokers and 10 male nonsmokers were included. Neurometabolites of the right and the left insular cortices were quantified by magnetic resonance spectroscopy (MRS) on a 3-Tesla scanner. Three separate MRS measurements were performed in each subject: among the smokers, the first measurement was done during normal smoking behavior, the second measurement during acute withdrawal (after 24 h of smoking abstinence), and the third shortly after administration of an oral nicotine substitute. Simultaneously, craving, withdrawal symptoms, and CO levels in exhaled air were determined during the three phases. The participants in the control group underwent the same MR protocol. In the smokers, during withdrawal, the insular cortex showed a significant increase in glutamine (Gln; p = 0.023) as well as a slight increase not reaching significance for glutamine/glutamate (Glx; p = 0.085) and a nonsignificant drop in myoinositol (mI; p = 0.381). These values tended to normalize after oral nicotine substitution treatment, even though differences were not significant: Gln (p = 0.225), Glx (p = 0.107) and mI (p = 0.810). Overall, the nonsmokers (control group) did not show any metabolic changes over all three phases (p > 0.05). In smokers, acute nicotine withdrawal produces a neurometabolic reaction pattern that is partly reversed by the administration of an oral nicotine substitute. The results are consistent with the expression of an addiction-specific neurometabolic shift in the brain and confirm the fact that the insular cortex seems to play a possible role in nicotine dependence.

Abductor tendon tears are associated with hypertrophy of the tensor fasciae latae muscle.

OBJECTIVE: To evaluate the association between hypertrophy of the tensor fasciae latae muscle and abductor tendon tears. MATERIALS AND METHODS: Thirty-five patients who underwent MRI of the abductor tendons of the hip were included in this retrospective study. A subgroup of 18 patients was examined bilaterally. The area of the tensor fasciae latae muscle and the area of the sartorius muscle (size reference) were quantified at the level of the femoral head, and a ratio was calculated. Two radiologists assessed the integrity of the gluteus medius and minimus tendon in consensus. Data were analyzed with a Mann-Whitney U test. RESULTS: Sixteen out of 35 patients (46 %) had a tear of the gluteus medius or minimus tendon. The ratio of the area of the tensor fasciae latae to the sartorius muscle was significantly higher (p = .028) in the group with an abductor tendon tear (median 2.25; Interquartile Range [IQR] = 1.97-3.21) compared to the group without any tears (median 1.91; IQR = 1.52-2.26). The bilateral subanalysis showed that in patients without a tear, the ratio of the two areas did not differ between each side (p = .966), with a median of 1.54 (primary side) and 1.76 (contralateral side). In patients with an abductor tendon tear the ratio was significantly higher (p = .031) on the side with a tear (median 2.81) compared to the contralateral healthy side (1.67). CONCLUSION: Patients with abductor tendon tears showed hypertrophy of the tensor fasciae latae muscle when compared to the contralateral healthy side and to patients without a tear.

Identification of a new chemical class of antimalarials.

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC(50)) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential.