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Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines—based on available evidence from mostly observational studies—suggest using aspirin. If proven to be non-inferior to vitamin K antagonists, aspirin might be preferable, due to its ease of use and lower cost. We aimed to test the non-inferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection. We did a multicentre, randomised, open-label, non-inferiority trial in ten stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalised ratio [INR] 2·0–3·0) for 90 days. Randomisation was computer-generated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major haemorrhage, or death) and MRI outcomes (new ischaemic or haemorrhagic brain lesions) in the per-protocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Non-inferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460. Between Sept 11, 2013, and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI −4 to 21], non-inferiority p=0·55). Thus, non-inferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischaemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial haemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group. Our findings did not show that aspirin was non-inferior to vitamin K antagonists in the treatment of cervical artery dissection. Swiss National Science Foundation, Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, Academic Society Basel.

Introduction: Combined intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) are the recommended treatment options for acute ischemic stroke (AIS). It is unclear whether earlier IVT and MT management can predict complete vessel recanalization. Methods: In this single-center retrospective observational study, we included 81 consecutive subjects with proximal middle cerebral artery AIS (age 70.5 ± 14.2 years, 53% female) who had both IVT and MT. We assessed recanalization after mechanical procedure according to modified thrombolysis in cerebral infarction (TICI) score as well as the National Institute of Health Stroke Scale (NIHSS) score at 24 h. Outcomes were modified Rankin Scale (mRS) at discharge, mRS at 3 months, death at 3 months, and prevalence of intracerebral hemorrhage during hospitalization. Results: Multinomial logistic regression (χ 2 = 49.4, p = 0.0075, pseudo-R 2 = 0.26) showed that complete recanalization (TICI score = 3) was predicted by lower door-to-MT time (p = 0.014, 95% confidence interval (CI) = −0.09 to −0.01) and lower symptoms-to-IVT time (p = 0.045, 95% CI = −0.038 to −0.0004). An NIHSS score ≥10 at 24 h was predicted by higher baseline NIHSS (p < 0.0001) and lower TICI score (p = 0.009). Lower NIHSS at 24 h predicted a good outcome according to mRS at 3 months (p = 0.006). Similarly, higher NIHSS at 24 h was a predictor of death at 3 months (p = 0.013). Conclusions: The present study suggests that bridging therapy may improve vascular recanalization when both IVT and MT are performed earlier.

Diabetic polyneuropathy (DPN) shares overlapping clinical and electrodiagnostic features with chronic inflammatory demyelinating polyneuropathy (CIDP), which complicates the differential diagnosis of CIDP in diabetic patients. 32 patients with diabetes mellitus and CIDP, 68 patients with CIDP without diabetes, 83 patients with DPN, and 28 diabetic patients without polyneuropathy were examined using clinical scores (Overall Neuropathy Limitation Scale (ONLS), Neuropathy Symptom Score, Neuropathy Deficit Score), nerve conduction studies, and nerve ultrasound (Ultrasound Pattern Sum Score (UPSS)). The ONLS was significantly higher in the CIDP patients with diabetes than in DPN (median [interquartile range]: 4.0 [3.0] vs. 0 [1.0], p  < 0.001) as well as the UPSS (4.0 [6.0] vs. 0 [2.9], p  < 0.001). Multiple binary logistic regression revealed UPSS and ONLS as statistically significant predictors to differentiate between CIDP with diabetes and DPN. Receiver operating characteristic curve analysis showed the ONLS with an area under the curve (AUC) of 0.918 (95% CI: 0.868-0.0.967, p  < 0.001). The UPSS total score had an AUC of 0.826 (95% CI: 0.743–0.909, p  < 0.001). An UPSS ≥ 2.5 had a sensitivity of 77.4% and a specificity of 68.7% to detect CIDP. An ONLS ≥ 1.5 had a sensitivity of 87.1% and a specificity of 81.9% to detect CIDP. ROC curve analysis of a composite score of ONLS and UPSS revealed an AUC of 0.959 (95% CI: 0.928–0.991, p  < 0.001). CIDP is an important differential diagnosis in people with diabetes mellitus. This study reports that the UPSS is well suited to differentiate between DPN and CIDP.

The neurological severity of a spinal cord injury (SCI) is commonly classified according to the American Spinal Injury Association (ASIA) Impairment Scale (AIS). The aim of this study was to assess the course of the AIS following SCI, and to discern the nature of any changes in the classification that occur. Assessments were performed in a European cohort of SCI patients within 2 weeks and at 1, 3, 6, and 12 months after the initial injury. Overall, about 70% of the patients initially diagnosed as AIS A did not convert, as did 90% of the AIS D patients. When only evaluating patients with complete datasets, 68% did not convert, while the AIS category improved in 30% of patients and deteriorated in 2%. A change in the last sacral segments (40%), motor improvement (31%), sensory improvement (19%), and a change in the neurological level of the SCI (10%) contributed to or accompanied the AIS conversion. When the AIS remained unchanged between successive assessment points, there was no change in the number of muscles graded three or more (NMG3+) in 73% of the transitions. An improvement in AIS was associated with a gain in NMG3+ in 49% of the transitions, while an aggravation in AIS was accompanied by a loss in NMG3+ in 10% of the transitions. These results, documenting a substantial amount of spontaneous AIS conversions, should be taken into consideration when designing clinical trials to assess the effects of potential new treatments for SCI.

The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.

Azole drugs selectively target fungal sterol biosynthesis and are critical to our antifungal therapeutic arsenal. However, resistance to this class of drugs, particularly in the major human mould pathogen Aspergillus fumigatus, is emerging and reaching levels that have prompted some to suggest that there is a realistic probability that they will be lost for clinical use. The dominating class of pan-azole resistant isolates is characterized by the presence of a tandem repeat of at least 34 bases (TR34) within the promoter of cyp51A, the gene encoding the azole drug target sterol C14-demethylase. Here we demonstrate that the repeat sequence in TR34 is bound by both the sterol regulatory element binding protein (SREBP) SrbA, and the CCAAT binding complex (CBC). We show that the CBC acts complementary to SrbA as a negative regulator of ergosterol biosynthesis and show that lack of CBC activity results in increased sterol levels via transcriptional derepression of multiple ergosterol biosynthetic genes including those coding for HMG-CoA-synthase, HMG-CoA-reductase and sterol C14-demethylase. In agreement with these findings, inactivation of the CBC increased tolerance to different classes of drugs targeting ergosterol biosynthesis including the azoles, allylamines (terbinafine) and statins (simvastatin). We reveal that a clinically relevant mutation in HapE (P88L) significantly impairs the binding affinity of the CBC to its target site. We identify that the mechanism underpinning TR34 driven overexpression of cyp51A results from duplication of SrbA but not CBC binding sites and show that deletion of the 34 mer results in lack of cyp51A expression and increased azole susceptibility similar to a cyp51A null mutant. Finally we show that strains lacking a functional CBC are severely attenuated for pathogenicity in a pulmonary and systemic model of aspergillosis.

PurposeTo assess whole-body magnetic resonance imaging (wb-MRI) for detection of biochemical recurrence in comparison to 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) in prostate cancer (Pca) patients after radical prostatectomy.MethodsThis was a prospective trial including 28 consecutive patients (mean age 65.3 ± 9.0 years) with newly documented biochemical recurrence of Pca (mean prostate-specific antigen, PSA, 2.09 ± 1.95 ng/ml) following radical prostatectomy. All patients underwent both wb-MRI including a dedicated pelvic imaging protocol and PET/CT with 166 ± 35 MBq 68Ga-PSMA within a time window of 11 ± 10 days. PET/CT and MRI datasets were separately evaluated regarding Pca lesion count, type, localization and diagnostic confidence (three-point Likert scale, 1–3) by two nuclear medicine specialists and two radiologists, respectively. The reference standard was based on histopathological results, PSA levels following targeted salvage irradiation and follow-up imaging. Lesion-based and patient-based detection rates were compared using the chi-squared test. Differences in diagnostic confidence were assessed using the Welch test.ResultsA total of 56 Pca lesions were detected in 20 of the 28 patients. 68Ga-PSMA PET/CT detected 56 of 56 lesions (100%) in 20 patients (71.4%), while wb-MRI detected 13 lesions (23.2%) in 11 patients (39.3%). The higher detection rate with 68Ga-PSMA PET/CT was statistically significant on both a per-lesion basis (p < 0.001) and a per-patient basis (p = 0.0167). In 8 patients (28.6%) no relapse was detectable by either modality. All lesions detected by wb-MRI were also detected by 68Ga-PSMA PET/CT. Additionally, 68Ga-PSMA PET/CT provided superior diagnostic confidence in identifying Pca lesions (2.7 ± 0.7 vs. 2.3 ± 0.6, p = 0.044).Conclusion68Ga-PSMA PET/CT significantly out-performed wb-MRI in the detection of biochemical recurrence in Pca patients after radical prostatectomy.

Study design A prospective non-randomised clinical study. Animals A study group with 18 posttraumatic dogs before surgery and a control group with nine healthy dogs. Methods Two different examiners evaluated the pain using two multidimensional pain scales (the Canine Acute Pain Scale of the Colorado State University (CSU-CAPS) and the Modified Glasgow Pain Scale (MGPS)) before the administration of methadone. During the administration of methadone, the Parasympathetic Tone Activity (PTA) was measured. In the control group, the PTA was measured without administration of methadone. In the statistical evaluation, correlation between PTA value and pain scores, and the predictive value of the PTA value in determining whether the animal was classified as painful was investigated. In addition, the results of the different pain scales and the results of the different examiners were compared. Results The average PTA values of the control group were 45.67 (± 13.64). Two of nine (22.22%) animals in the control group have their average PTA value above the ‘pain-free state’ of 50. The average PTA values of the study group were 56.16 (± 15.11) and 51.05 (± 13.24) before and after methadone administration, respectively. Comparing the average values of the study group 30 s before methadone administration with the average values of the control group, there was no significant difference ( p  = 0.5403). Examiner A (experienced) classified 14 of 16 animals (87.5%) with the CSU-CAPS, and examiner A2 (inexperienced) classified 7 of 16 patients (43.75%) as painful. In 56.25% of the cases, both examiners (A and A2) reached the same decision when using CSU-CAPS. When using the MGPS, 10 of 18 patients (55.56%) reached the intervention level regardless of the examiner. In 88.89% of the cases, the two examiners reached the same decision; there is a highly positive correlation between the two examiners (Spearman correlation coefficient rs  = 0.84). There was no correlation between the monitor and score values of both pain scales with either examiner. Conclusion The PTA monitor on the awake animal was not suitable for pain detection. There were no statistically significant correlations of PTA scores with pain scale scores, regardless of the examiner. Similarly, the tendency for the study group to have lower PTA scores indicates that PTA also appears to be influenced by environmental factors.

Salt intake is associated with hypertension, but the mechanisms by which salt affects blood pressure remain unclear. Agnes Machnik et al . now show that mononuclear cells such as macrophages respond to dietary salt intake by producing the growth factor VEGF-C, leading to expansion of the lymphatic capillary network. Interference with this response in rats fed a high-salt diet exacerbates the increase in blood pressure caused by a high-salt diet pages 487–488 .. In salt-sensitive hypertension, the accumulation of Na + in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na + accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc ) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD. Our data show that TonEBP–VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.

Dopamine (DA) receptor and transporter dysfunctions play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD), bipolar disorder (BD) in the manic (BD ) or depressive (BD ) state and schizophrenia (SZ). We performed a PUBMED search, which provided a total of 239 imaging studies with either positron emission tomography (PET) or single-proton emission computed tomography (SPECT). In these studies, DA transporter binding, D receptor (R) binding, D R binding, DA synthesis and/or DA release in patients with the primary diagnosis of acute AD (n=310), MDD (n=754), BD (n=15), BD (n=49) or SZ (n=1532) were compared to healthy individuals. A retrospective analysis revealed that AD, MDD, BD , BD and SZ differed as to affected brain region(s), affected synaptic constituent(s) and extent as well as direction of dysfunction in terms of either sensitization or desensitization of transporter and/or receptor binding sites. In contrast to AD and SZ, in MDD, BD and BD , neostriatal DA function was normal, whereas MDD, BD , and BD were characterized by the increased availability of prefrontal and frontal DA. In contrast to AD, MDD, BD and BD , DA function in SZ was impaired throughout the nigrostriatal and mesolimbocortical system with an increased availability of DA in the striatothalamocortical and a decreased availability in the mesolimbocortical pathway.