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Interferometric scattering (iSCAT) microscopy is a label-free optical method capable of detecting single proteins, localizing their binding positions with nanometer precision, and measuring their mass. In the ideal case, iSCAT is limited by shot noise such that collection of more photons should extend its detection sensitivity to biomolecules of arbitrarily low mass. However, a number of technical noise sources combined with speckle-like background fluctuations have restricted the detection limit in iSCAT. Here, we show that an unsupervised machine learning isolation forest algorithm for anomaly detection pushes the mass sensitivity limit by a factor of 4 to below 10 kDa. We implement this scheme both with a user-defined feature matrix and a self-supervised FastDVDNet and validate our results with correlative fluorescence images recorded in total internal reflection mode. Our work opens the door to optical investigations of small traces of biomolecules and disease markers such as α-synuclein, chemokines and cytokines.

Cancer survivors who have undergone hematopoietic cell transplantation (HCT) are at risk for myocardial dysfunction. Children who receive allogenic HCT encounter systemic inflammation resulting in tachycardia and hypertension. The effect of these abnormalities on myocardial function is not known. The aim of this study was to determine whether cardiac dysfunction early after HCT can be predicted by tachycardia or hypertension, within a retrospective single-center sample of pediatric HCT recipients. Early tachycardia or hypertension was defined as a majority of values taken from infusion date to 90 days post-infusion being abnormal. Ejection fraction

Sequential protocols combining salvage chemotherapy with reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute myeloid leukemia (AML) have been studied more than a decade. Purpose of this retrospective analysis was to evaluate the anti-leukemic efficacy and toxicity of FLAG-IDA protocol (fludarabine, cytarabine, and idarubicin) followed by treosulfan-based conditioning for patients with active AML. From January 2014 to November 2019, a total of 29 active AML patients [median age, 64 years (range, 23–73)] were treated. All patients completed protocol regimen and were transplanted. Five patients (17%) had grade 3–4 toxicities; therefore, treosulfan was substituted with total body irradiation (TBI) non-myeloablative conditioning. Six (20%) patients died within 30 post-transplant days, all from infectious complications. Out of 23 evaluable patients on day 30, 22 (96%) achieved complete hematologic remission with full donor chimerism. Non-relapse mortality (NRM) rates at 1 and 3 years were 22% and 49%, respectively. Median overall survival (OS) was 12 (95% CI, 4–20) months. OS and disease-free survival were 50% and 46% at 1 year and 28% and 17% at 2 years, respectively. Age, gender, disease burden, number of previous lines, and comorbidity score did not predict survival. Sequential strategy combining FLAG-IDA and treosulfan may offer a salvage option for few selected patients with active AML; however, high NRM presents a major obstacle to treatment success. Future efforts should focus on reducing NRM by moderating regimen intensity and by better selection of patients.

Fundamental knowledge of the active site requirements for the selective activation of C–O bonds over heterogeneous catalysts is required to design multistep processes for the synthesis of complex chemicals. Here we employ reaction kinetics measurements, extensive catalyst characterization, first principles calculations and microkinetic modelling to reveal metal oxides as a general class of catalysts capable of selectively cleaving C–O bonds with unsaturation at the α position, at a moderate temperature and H2 pressure. Strikingly, metal oxides are considerably more active catalysts than commonly employed VIIIB and IB transition metal catalysts. We identify the normalized Gibbs free energy of oxide formation as both a reactivity and a catalyst stability descriptor and demonstrate the generality of the radical-mediated, reverse Mars–van Krevelen C–O bond activation mechanism on oxygen vacancies, previously established only for RuO2. Importantly, we provide evidence that the substrate plays an equally key role to the catalyst in C–O bond activation. Metal oxides have been identified as a promising class of catalysts for carbon–oxygen bond cleavage in the context of biomass valorization, although the systematic understanding of their reactivity remains elusive. Now, a combination of catalytic screening and first principles calculations provide important insights into this family of catalysts.

Peripheral nerve sheath tumors (PNSTs) account for ~ 5% of soft tissue neoplasms and are responsible for a wide spectrum of morbidities ranging from localized neuropathy to fulminant metastatic spread and death. MR imaging represents the gold standard for identification of these neoplasms, however, current anatomic MR imaging markers do not reliably detect or differentiate benign and malignant lesions, and therefore, biopsy or excision is required for definitive diagnosis. Diffusion-weighted MR imaging (DWI) serves as a useful tool in the evaluation and management of PNSTs by providing functional information regarding the degree of diffusion, while diffusion tensor imaging (DTI) aids in determining the directional information of predominant diffusion and has been shown to be particularly useful for pre-operative planning of these tumors by delineating healthy and pathologic fascicles. The article focuses on these important neurogenic lesions, highlighting the current utility of diffusion MR imaging and future directions including computerized radiomic analysis. KEY POINTS: • Anatomic MRI is moderately accurate in differentiating benign from malignant PNST. • Diffusion tensor imaging facilitates pre-operative planning of PNSTs by depicting neuropathy and tractography. • Radiomics will likely augment current observer-based diagnostic criteria for PNSTs.

Purpose Medullary thyroid carcinoma (MTC) is characterized by a high rate of metastasis. In this study we evaluated the ability of [18F]DOPA PET/ceCT to stage MTC in patients with suspicious thyroid nodules and pathologically elevated serum calcitonin (Ctn) levels prior to total thyroidectomy and lymph node (LN) dissection. Methods A group of 32 patients with sonographically suspicious thyroid nodules and pathologically elevated basal Ctn (bCtn) and stimulated Ctn (sCtn) levels underwent DOPA PET/ceCT prior to surgery. Postoperative histology served as the standard of reference for ultrasonography and DOPA PET/ceCT region-based LN staging. Univariate and multivariate regression analyses as well as receiver operating characteristic analysis were used to evaluate the correlations between preoperative and histological parameters and postoperative tumour persistence or relapse. Results Primary MTC was histologically verified in all patients. Of the 32 patients, 28 showed increased DOPA decarboxylase activity in the primary tumour (sensitivity 88%, mean SUVmax 10.5). Undetected tumours were exclusively staged pT1a. The sensitivities of DOPA PET in the detection of central and lateral metastatic neck LN were 53% and 73%, in contrast to 20% and 39%, respectively, for neck ultrasonography. Preoperative bCtn and carcinoembryonic antigen levels as well as cN1b status and the number of involved neck regions on DOPA PET/ceCT were predictive of postoperative tumour persistence/relapse in the univariate regression analysis (P

Along our way towards the advanced saccharide-sensitive probes, three novel electroactive iminoboronate regioisomers of [(ferrocenylimino)methyl]phenylboronic acid have been synthesized. The ortho, meta, and para regioisomers were characterized structurally by NMR, MS, FT-IR, UV/Vis and their electrochemical behavior in aqueous solution was studied using cyclic voltammetry. The obtained results confirmed different behavior of the ortho isomer due to an interaction of boronic acid moiety with the proximate imine group of the iminoferrocenyl residue.

Strongyloides stercoralis is not hyperendemic in European countries but has been increasing in prevalence due to migration and travel. The infection is characterized by a mostly asymptomatic course or nonspecific symptoms in healthy subjects. However, immunosuppression or chemotherapy have been described as leading triggers for Strongyloides stercoralis hyperinfection syndrome and may have a fatal course. A post hoc analysis was performed among renal transplant patients during a 5-year period. Plasma samples of two hundred kidney allograft recipients were retrospectively analyzed for Strongyloides stercoralis seropositivity by established ELISA testing. Positive Strongyloides stercoralis serology was found in 3% of allograft recipients. One patient developed a life-threatening hyperinfection syndrome. His Strongyloides IgG signal had been elevated for years before the outbreak of the disease. Stronglyoides infections in transplant recipients are an important issue that physicians also in Central Europe should be aware of, given the risk of hyperinfection syndrome and the challenges in clinical diagnosis. Our study suggests that recipient and donor screening should be recommended in kidney transplantation programs in Central Europe as Strongyloides infection rates increase and its prevalence may be underestimated. Further research is needed to understand why some Strongyloides stercoralis seropositive individuals develop hyperinfection syndrome and others do not.

The aim of this review is to investigate whether changes in olfactory bulb volume relate to changes in specific olfactory functions. We studied currently available peer-reviewed articles on the volume of the human olfactory bulb that also included a psychophysical measure of olfactory function. In the present review, we observed a very clear and consistent correlation between general olfactory function and olfactory bulb (OB) volume. We were not able to find a clear relationship between a specific smell component and OB volume, even when analyzing pathologic conditions separately. In some cases, changes were observed for different subtests, but these changes did not significantly correlate with OB volume or had only a borderline correlation. In other cases, we found contradictory data. Several factors may contribute to the difficulties in finding correlations with the different components of smell: (1) the OB volume may be influenced by information from olfactory receptor neurons (bottom-up effect), information from central nervous system (top-down effect) and by direct damage; (2) most pathologic conditions affect more than one area of the olfactory pathway; (3) small sample sizes of hyposmic subjects were used. We believe that it is necessary to do further studies with larger numbers of subjects to answer the currently investigated question.

In this study we examine the experiences of 70 therapists who treated children identified as suffering from posttraumatic distress following the shared traumatic reality of war (the Second Lebanon War between Israel and Hezbollah). The data are based mainly on qualitative research methods: focus groups, therapy narratives, and “member-checking” interviews, supplemented by quantitative data from questionnaires. Nearly all the therapists reported being affected by the war and half of them reported additional vicarious traumatization resulting from exposure to the children’s experiences. Therapy work with children was experienced as particularly challenging, yet involving high levels of work satisfaction. The perception of an intergenerational and concurrent “common-fate” between the therapists and the children contributed to increased empathy and the forming of an emotionally intense and care-giving relationship with the children. The therapy focused mostly on emphasizing the children’s strengths and building strategies for coping, and provided the therapists with a sense of agency and helpfulness. It also allowed the therapists an opportunity to rework their own traumatic childhood memories that tended to emerge unexpectedly during the sessions. Concurrently, posttraumatic distress experienced by the therapists seemed to present a potential barrier for their therapeutic availability and to lead to a defensive avoidance of the children’s painful memories. Therapists found the work itself, in addition to the use of individual psychotherapy, supervision, and peer-support to be helpful in coping with their primary and secondary traumatic reactions.

Targeted therapy in hormone refractory prostate cancer (HRPC) is currently under evaluation in many trials. The effect of androgen deprivation therapy (ADT) on many targets in prostate cancer is incompletely known. For the first time, immunohistochemical expression of the platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), vascular endothelial growth factor C (VEGF-C), mammalian target of rapamycin (mToR), p70 ribosomal protein S6 kinase 1 (PS6K), human epidermal growth factor receptor 2 (c-erbB-2), and carbonic anhydrase IX (CA9) was evaluated in 44 patients with prostate carcinoma treated with or without ADT, at biopsy time and after radical prostatectomy. PDGFR, VEGF-C, mToR, and PS6K expression was significantly reduced (p = 0.002, p = 0.035, p = 0.025, and p = 0.033, respectively) after ADT, whereas expression of EGFR, c-erbB-2, and CA9 was not influenced by ADT. In conclusion, targeting PDGFR, VEGF-C, mToR, or PS6K after ADT should be considered with precaution, as those targets can severely be altered or functionally deregulated by ADT.

To determine the role of BCRP in nitrofurantoin (NF) transport in JAr cells and the possible contribution of OATP2B1, P-gp and MRPs to this transport. Cells were incubated with various BCRP, P-gp, MRPs, organic anion transporting polypeptide (OAT) and OATP2B1 inhibitors for 15 min, followed by incubation for 30 min with NF, with or without the inhibitors mentioned earlier. NF cytotoxicity was examined using neutral red (NR) assay. Intracellular NF levels were analyzed by HPLC. NR assay showed that incubation conditions with NF (as carried out in our experiments) were not cytotoxic. Incubation with specific inhibitors of BCRP (FTC, Chrysin and Novobiocin), showed a significant increase in NF accumulation in the cells. Inhibitors of OATP2B1 (EGCG and BSP) had no influence on NF accumulation. Specific inhibitors of P-gp and MRPs (Verapamil and Indomethacin, respectively) also had no influence on NF accumulation in JAr cells. NF is probably a specific substrate of BCRP, and BCRP has a major active role in NF transport in JAr cells. For the first time, we showed, that P-gp, MRPs, and the OATP2B1, probably have a negligible contribution to NF transport in JAr cells.

Placental transfer of Levofloxacin (LF), a broad spectrum fluoroquinolone antibiotic, and its inhibition was investigated in BeWo cells, a human trophoblast cell line.The experiments of LF uptake by BeWo cells were performed after preincubation and in the presence of the P-glycoprotein inhibitors (Cyclosporin A, Verapamil and Quercetin), the organic anion/cation transporter inhibitor (Cimetidine) and the MCT substrates (lactic acid and salicylic acid).P-glycoprotein inhibitors increased the uptake of LF by BeWo cells. The increase in LF accumulation by Cyclosporin A, Verapamil and Quercetin was by 30, 90 and 80%, respectively. Cimetidine, the organic cation inhibitor, increased the transport of LF by 48%. Lactic acid and salicylic acid, the MCT substrates, initially decreased the accumulation of LF by 30% and subsequently increased the uptake of LF by 500 and 53%, respectively.The uptake of LF by human trophoblast cells is mediated by multiple transporters as well as passive diffusion.

We investigated the effectiveness of lanreotide for the treatment of active acromegaly in a retrospectively multicenter case series including 53 patients (24 male, 29 female; mean age at diagnosis, 49.5 +/- 13.9 years) with acromegaly treated with lanreotide in nine different centers. Mean tumor diameter was 20 +/- 13 mm; mean basal levels of growth hormone (GH) and insulin-like growth factor I (IGF-I) were 21.3 +/- 26.3 and 579 +/- 177 mug/l, respectively. The primary mode of treatment was surgery in 70% of patients. Twenty-nine patients received only lanreotide (Prolonged Release, Autogel), whereas 24 subjects were also treated with octreotide at another treatment stage. Primary therapy with lanreotide was administered in five patients. Maximal monthly dose of lanreotide Autogel (n = 44) was 60 mg in 45%, 90 mg in 26%, 120 mg in 21% and 180 mg in 8%. During 36 months of lanreotide treatment, mean IGF-I levels decreased from 443 +/- 238 to 276 +/- 147 mug/l (P0.001), and mean GH levels, from 5.2 +/- 6.4 to 3.2 +/- 3.0 mug/l (P0.001). IGF-I levels normalized in 51% of patients and decreased by50% towards normal in 32%; the normalization rate was higher in women (65%) than men (33%, P = 0.04). Safe random GH levels (/=2 mug/l) were achieved in 49% of patients. Both IGF-I normalization and safe GH levels were reached in 32% of the cohort. Lanreotide is an effective treatment for active acromegaly. Female sex was associated with higher rates of IGF-I normalization.

Background Germplasm collections are an important source for plant breeding, especially in fruit trees which have a long duration of juvenile period. Thus, efforts have been made to study the diversity of fruit tree collections. Even though mango is an economically important crop, most of the studies on diversity in mango collections have been conducted with a small number of genetic markers. Results We describe a de novo transcriptome assembly from mango cultivar ‘Keitt’. Variation discovery was performed using Illumina resequencing of ‘Keitt’ and ‘Tommy Atkins’ cultivars identified 332,016 single-nucleotide polymorphisms (SNPs) and 1903 simple-sequence repeats (SSRs). Most of the SSRs (70.1 %) were of trinucleotide with the preponderance of motif (GGA/AAG)n and only 23.5 % were di-nucleotide SSRs with the mostly of (AT/AT)n motif. Further investigation of the diversity in the Israeli mango collection was performed based on a subset of 293 SNPs. Those markers have divided the Israeli mango collection into two major groups: one group included mostly mango accessions from Southeast Asia (Malaysia, Thailand, Indonesia) and India and the other with mainly of Floridian and Israeli mango cultivars. The latter group was more polymorphic (FS = −0.1 on the average) and was more of an admixture than the former group. A slight population differentiation was detected (FST = 0.03), suggesting that if the mango accessions of the western world apparently was originated from Southeast Asia, as has been previously suggested, the duration of cultivation was not long enough to develop a distinct genetic background. Conclusions Whole-transcriptome reconstruction was used to significantly broaden the mango’s genetic variation resources, i.e., SNPs and SSRs. The set of SNP markers described in this study is novel. A subset of SNPs was sampled to explore the Israeli mango collection and most of them were polymorphic in many mango accessions. Therefore, we believe that these SNPs will be valuable as they recapitulate and strengthen the history of mango diversity. Electronic supplementary material The online version of this article (doi:10.1186/s12870-015-0663-6) contains supplementary material, which is available to authorized users.

Background Realtime MR enables radiation free guidance for right heart catheterization (RHC). In addition to catheter navigation for sampling of invasive pressures and blood oxygen saturations, MR permits concomitant assessment of cardiac chamber volumes and cardiac output with phase contrast flow measurements. By performing repeat measurements under different physiological provocations (e.g. saline volume challenge, inhaled nitric oxide, or exercise), diagnostic yield increases by revealing symptoms and pathologic findings not apparent at rest. Herein we present the NIH experience of MR RHC to date.

Purpose To describe the results of 125I plaque brachytherapy of uveal melanomas anterior to the equator in terms of local control and the associated complications while trying to identify their risk factors (patients' demographic data, ocular, and tumour characteristics). Methods Retrospective analysis of a series of patients treated by 125I between 1990 and 2000 in a single institution. The main outcome measures are evaluation of local tumour control and complications associated with 125I plaque brachytherapy of these melanomas. Results During the study period, 136 patients were treated for an anterior tumour. The median follow-up was 62 months. The overall 5-year survival rate was 88.3%, the 5-year metastasis rate was 4% and the local recurrence rate was 1.5%. The mean final visual acuity was 20/40. The ocular complications most frequently observed at 5 years were cataract (50.3%), maculopathy (18.3%), intraocular inflammation (19.3%), and glaucoma (10.6%). Optic neuropathy, retinal detachment, keratitis, and intravitreous haemorrhage were also described. Risk factors for worse survival were age greater than 65 years and initial tumour thickness greater than 4 mm. Risk factors for the development of cataract were age more than 65 years old, male gender, and tumour diameter of more than 10 mm. Risk factors for intraocular inflammation were tumour thickness of more than 4 mm and invasion of the ciliary body. Conclusions The use of 125I plaque brachytherapy to treat melanomas situated anterior to the equator allows good local and systemic control with a low rate of macular and optic disc complications. The most frequent complication was cataract formation.

The 1278insTATC is the most prevalent beta-hexosaminidase A ( HEXA) gene mutation causing Tay-Sachs disease (TSD), one of the four lysosomal storage diseases (LSDs) occurring at elevated frequencies among Ashkenazi Jews (AJs). To investigate the genetic history of this mutation in the AJ population, a conserved haplotype (D15S981:175-D15S131:240-D15S1050:284-D15S197:144-D15S188:418) was identified in 1278insTATC chromosomes from 55 unrelated AJ individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the insertion was found to be 40+/-12 generations (95% confidence interval: 30-50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th-9th century. This corresponds with the demographic expansion of AJs in central Europe, following the founding of the Ashkenaz settlement in the early Middle Ages. The results are consistent with the geographic distribution of the main TSD mutation, 1278insTATC being more common in central Europe, and with the coalescent times of mutations causing two other LSDs, Gaucher disease and mucolipidosis type IV. Evidence for the absence of a determinant positive selection (heterozygote advantage) over the mutation is provided by a comparison between the estimated age of 1278insTATC and the probability of the current AJ frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust parsimonious hypothesis explaining the spread of 1278insTATC-linked TSD in AJ individuals.

Patients who are infected with human immunodeficiency virus type 1 (HIV-1) frequently present with neurological and psychiatric symptoms. Kynurenic acid (KYNA), an intermediate metabolite of L-kynurenine (L-KYN), is a neuroprotectant and a broad-spectrum antagonist at excitatory amino acid (EAA) receptors. The present study examines the biosynthetic machinery of KYNA in the frontal cortex and cerebellum of 25 HIV-1 and 16 control (CO) patients. We measured the contents of L-KYN and KYNA and the activity of enzymes synthesizing KYNA, kynurenine aminotransferases I and II (KAT I and KAT II). The KYNA level was significantly increased in the frontal cortex (209 +/- 38% of CO; p0.05) and moderately increased in the cerebellum (164 +/- 31% of CO) of HIV-1 brains as compared with controls. The bioprecursor of KYNA, L-KYN, was increased in frontal cortex (188 +/- 45% of CO) and cerebellum (151 +/- 16% of CO; p0.05). The elevated KYNA in frontal cortex correlated with significant increases of KAT I (341 +/- 95% of CO; p0.05) and KAT II (141 +/- 8% of CO; p0.05). In the cerebellum, a high KYNA content was in the line with increased KAT I (262 +/- 52% of CO; p0.05) activity, while KAT II was in a control range (85 +/- 12% of CO). This study demonstrates that HIV-1 infection associates with elevated KYNA synthesis in the brain. In contrast to KAT II, KAT I was prominently increased in both brain regions investigated. Differences in neurochemical parameters of KYNA metabolism between frontal cortex and cerebellum suggests selective tissue damage. Drugs which influence the synthesis of the endogenous neuroprotectant KYNA may become useful in the therapy of neuropsychiatric manifestations of HIV-1 infected patients.

Background Invasive right heart catheterization plays a central role in the investigation of patients with cardiac and pulmonary vascular disease. Physiological provocations during invasive heart catheterization augment the diagnostic yield and can provide useful prognostic information. MRI catheterization combines invasive hemodynamic measurements with MRI structural and functional evaluations thus providing superior diagnostic information than either test alone. An additional benefit to both patient and operator is no ionizing radiation, which is of particular value in pediatric patients.

Background We have begun to perform routine and research MRI right heart catheterization in adults and research MRI catheterization in children. We report our technologist workflow. Methods Scanner preparation: The scanner facade and bore are covered with adhesive clear sterile drapes and surface coils enveloped in sterile plastic bags. A MR catheterization pack contains only non-ferromagnetic supplies. Sterile

Proton therapy offers potentially considerable advantages in the management of slow-growing, poorly resectable or non-resectable tumors resistant to x-rays and located close to critical radiosensitive anatomical structures, such as the brain stem of the spinal cord. Among over 13,000 irradiated patients in the USA, Europe, and Japan, two major clinical indications have been documented: 1. The conservative management of choroidal melanomas, in which 98% 5-year local control can be expected at the price of low toxicity and visual preservation in approximately half of them. 2. The curative management of low-grade chondrosarcomas and chordomas of the base of the skull and cervical spine, leading to, in combination with maximal tumor resection, 84%-94% long-term survival. Other ongoing studies concern prostate, head and neck carcinomas as well as various intracranial tumors. Radiosurgical programs are being conducted generally with single fractions and under stereotactic conditions.

Mature teratoma of the pancreas is an unusual tumor. Like all teratomas it results from abnormal embryonal development of toti potent cells. Their contents may vary and may consist of ectodermal, endodermal, and mesodermal tissues. The radiologic appearance of these lesions depends on the proportions of various tissues of which they are composed. We report, to our knowledge, the first description of its CT and MR appearances.