Physicochemical characterization of inorganic deposits associated with granulomas in cutaneous sarcoidosis.

BACKGROUND: Sarcoidosis, characterized by epithelioid granulomas, is considered to be caused by a complex interplay between genetics and environmental agents. It has been hypothesized that exogenous inorganic particles as crystalline silica could be a causal or adjuvant agent in sarcoidosis onset. OBJECTIVES: To investigate the location, frequency and physicochemical characteristics of foreign materials and mineral tissue deposits in the granulomatous area of cutaneous sarcoidosis. METHODS: Skin biopsies (n = 14) from patients diagnosed with cutaneous sarcoidosis (mean age 43 years; 11 patients with extracutaneous involvement) were investigated using polarized light examination (PLE), µFourier Transform Infra-Red (µFT-IR) spectroscopy and Field Emission Scanning Electron Microscopy coupled with Energy Dispersive X-ray Spectroscopy (FE-SEM/EDX). RESULTS: Combined PLE, µFT-IR, FE-SEM/EDX analysis allowed to characterize mineral deposits in 7/14 biopsies (50%). It identified crystalline silica (SiO2 ) inside granulomas in three biopsies and calcite (CaCO3 ) at their periphery in 4. CONCLUSION: This study emphasizes the need of using combined methods for assessment of mineral deposits in granulomatous diseases. According to the location and characteristics of deposits, we can hypothesize that SiO2 particles contribute to the granuloma formation, whereas CaCO3 deposits are related to the granuloma biology. However, the significance of the association between SiO2 deposits and sarcoidosis is still disputed.

Nanotechnology combined therapy: tyrosine kinase-bound gold nanorod and laser thermal ablation produce a synergistic higher treatment response of renal cell carcinoma in a murine model.

OBJECTIVE: To investigate tyrosine kinase inhibitors (TKI) and gold nanorods (AuNRs) paired with photothermal ablation in a human metastatic clear cell renal cell carcinoma (RCC) mouse model. Nanoparticles have been successful as a platform for targeted drug delivery in the treatment of urological cancers. Likewise, the use of nanoparticles in photothermal tumour ablation, although early in its development, has provided promising results. Our previous in vitro studies of nanoparticles loaded with both TKI and AuNRs and activated with photothermal ablation have shown significant synergistic cell kill greater than each individual arm alone. This study is a translation of our initial findings to an in vivo model. MATERIALS AND METHODS: Immunologically naïve nude mice (athymic nude-Foxn1nu ) were injected subcutaneously bilaterally in both flanks (n = 36) with 2.5 × 106 cells of a human metastatic renal cell carcinoma cell line (RCC 786-O). Subcutaneous xenograft tumours developed into 1-cm palpable nodules. AuNRs encapsulated in human serum albumin protein (HSA) nanoparticles were synthesised with or without a TKI and injected directly into the tumour nodule. Irradiation was administered with an 808-nm light-emitting diode laser for 6 min. Mice were humanely killed 14 days after irradiation; tumours were excised, formalin fixed, paraffin embedded, and evaluated for size and the percentage of necrosis by a genitourinary pathologist. The untreated contralateral flank tumours were used as controls. RESULTS: In mice that did not receive irradiation, TKI alone yielded 4.2% tumour necrosis on the injected side and administration of HSA-AuNR-TKI alone yielded 11.1% necrosis. In the laser-ablation models, laser ablation alone yielded 62% necrosis and when paired with HSA-AuNR there was 63.4% necrosis. The combination of laser irradiation and HSA-AuNR-TKI had cell kill rate of 100%. CONCLUSIONS: In the absence of laser irradiation, TKI treatment alone or when delivered via nanoparticles produced moderate necrosis. Irradiation with and without gold particles alone also improves tumour necrosis. However, when irradiation is paired with gold particles and drug-loaded nanoparticles, the combined therapy showed the most significant and synergistic complete tumour necrosis of 100% (P < 0.05). This study illustrates the potential of combination nanotechnology as a new approach in the treatment of urological cancers.

Safety and early effectiveness of robot-assisted partial nephrectomy for large angiomyolipomas.

OBJECTIVE: To evaluate a multicentre series of robot-assisted partial nephrectomy (RAPN) performed for the treatment of large angiomyolipomas (AMLs). PATIENTS AND METHODS: Between 2005 and 2016, 40 patients with large or symptomatic AMLs underwent RAPN at five academic centres in the USA. Patient demographics, AML characteristics, operative and postoperative clinical outcomes were recorded and analysed. Surgical outcomes were compared between patients who underwent selective arterial embolisation (SAE) before RAPN and patients who did not undergo pre-RAPN SAE. RESULTS: The median (interquartile range [IQR]) tumour diameter was 7.2 (5-8.5) cm, and the median (IQR) nephrometry score was 9 (7-10). Six patients (15%) had a history of tuberous sclerosis and 11 (28%) had previously undergone SAE. The median (IQR) operative time and warm ischaemia time was 207 (180-231) and 22.5 (16-28) min, respectively. A non-clamping technique was used in eight (20%) patients. The median (IQR) estimated blood loss was 200 (100-245) mL, and four patients (10%) received blood transfusion postoperatively. One intraoperative complication occurred (2.5%), and seven postoperative complications occurred in six patients (15%). During a median (IQR) follow-up of 8 (1-15) months, none of the patients developed AML-related symptoms. The median estimated glomerular filtration rate preservation rate was 95%. There were no differences in operative or perioperative outcomes between patients who underwent SAE before RAPN and those who did not. CONCLUSIONS: Robot-assisted partial nephrectomy appears to be a safe primary or secondary (post-SAE) treatment for large AMLs, with a favourable perioperative morbidity profile and excellent functional preservation. Longer follow-up is required to fully evaluate therapeutic efficacy.

The use of personal flotation devices in the Northeast lobster fishing industry: An examination of the decision-making process.

BACKGROUND: This study explored perspectives of Northeast commercial lobstermen regarding the use of personal flotation devices (PFDs). Researchers sought to identify factors contributing to low PFD use, and motivators that could lead to increased use of PFDs. METHODS: This qualitative research (n = 72) included 25 commercial fishermen who participated in in-depth, semi-structured interviews, and 47 attendees of Lobstermen's meetings who engaged in focus groups. RESULTS: The results showed substantial barriers to PFD use. Fishermen described themselves as being proactive about safety whenever possible, but described a longstanding tradition of not wearing PFDs. Key factors integrally linked with the lack of PFD use were workability, identity/social stigma, and risk diffusion. CONCLUSION: Future safety interventions will need to address significant barriers to PFD use that include issues of comfort and ease of use, as well as social acceptability of PFDs and reorientation of risk perceptions related to falls overboard.

Role of adhesion between asperities in the formation of elastic solid/solid contacts.

We investigated the formation of a contact between a smooth sphere of elastomer and a micro-patterned elastomer substrate. We focussed our attention on the transition between a contact only established at the top of the pillars, and a mixed contact with a central zone of full contact surrounded by a top contact corona, which was observed when the normal load was increased. The full contact zone always nucleated with a finite radius, and the transition appears to be a first-order transition, with a hysteresis due to the creation of an adhesive zone between the pillars. We propose to include the effect of the new inter-pillar adhesion to produce a realistic treatment of the mechanics of these complex contacts. This new approach quantitatively accounts for the evolution of the observed jump in the radius of the full contact with the geometrical parameters of the pattern.

Diagnoses associated with the greatest years of potential life lost for in-hospital deaths in the United States, 1988-2010.

OBJECTIVE: Premature mortality is a public health concern that can be quantified as years of potential life lost (YPLL). Studying premature mortality from in-hospital mortality can help guide hospital initiatives and resource allocation. This paper identified the diagnosis categories associated with in-hospital deaths that account for the highest YPLL and their trends over time. STUDY DESIGN: Retrospective review of the Nationwide Inpatient Sample (NIS), 1988-2010. METHODS: Using the NIS, YPLL on patients hospitalized in the United States from 1988 to 2010 was calculated. Hospitalizations were categorized by related principal diagnoses using the Healthcare Cost and Utilization Project (HCUP) single-level Clinical Classification Software (CCS) definitions. RESULTS: Between 1988 and 2010, total in-hospital estimated mortality of 20,154,186 people accounted for 198,417,257 YPLL (9.84 YPLL per in-hospital mortality; 8,626,837 estimated annual mean YPLL). The ten highest YPLL diagnosis categories accounted for 51% of the overall YPLL. The liveborn disease category (i.e., in-hospital live births) was the most common principal diagnosis and accounted for the highest YPLL at 1,070,053. The septicemia category accounted for the second highest YPLL at 548,922. The highest in-hospital mortality rate (20.8%) was associated with adult respiratory failure/insufficiency/arrest. The highest estimated in-hospital annual mean deaths occurred in patients with pneumonia at 69,134. For all in-hospital mortality, the inflation adjusted total in-hospital charges per YPLL was highest for acute myocardial infarction at $9292 per YPLL. CONCLUSIONS: Using YPLL, a framework has been provided to compare the impact of premature in-hospital mortality from dissimilar diseases. The methodology and results may be used to help guide further investigation of hospital quality initiatives and resource allocation.

A neuroimaging measure to capture heterogeneous patterns of atrophy in Parkinson's disease and dementia with Lewy bodies.

INTRODUCTION: Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) show heterogeneous brain atrophy patterns which group-average analyses fail to capture. Neuroanatomical normative modelling overcomes this by comparing individuals to a large reference cohort. Patient-specific atrophy patterns are measured objectively and summarised to index overall neurodegeneration (the 'total outlier count'). We aimed to quantify patterns of neurodegenerative dissimilarity in participants with PD and DLB and evaluate the potential clinical relevance of total outlier count by testing its association with key clinical measures in PD and DLB. MATERIALS AND METHODS: We included 108 participants with PD and 61 with DLB. PD participants were subclassified into high and low visual performers as this has previously been shown to stratify those at increased dementia risk. We generated z-scores from T1w-MRI scans for each participant relative to normative regional cortical thickness and subcortical volumes, modelled in a reference cohort (n = 58,836). Outliers (z < -1.96) were aggregated across 169 brain regions per participant. To measure dissimilarity, individuals' Hamming distance scores were calculated. We also examined total outlier counts between high versus low visual performance in PD; and PD versus DLB; and tested associations between these and cognition. RESULTS: There was significantly greater inter-individual dissimilarity in brain-outlier patterns in PD poor compared to high visual performers (W = 522.5; p < 0.01) and in DLB compared to PD (W = 5649; p < 0.01). PD poor visual performers had significantly greater total outlier counts compared to high (ß = -4.73 (SE = 1.30); t = -3.64; p < 0.01) whereas a conventional group-level GLM failed to identify differences. Higher total outlier counts were associated with poorer MoCA (ß = -0.55 (SE = 0.27), t = -2.04, p = 0.05) and composite cognitive scores (ß = -2.01 (SE = 0.79); t = -2.54; p = 0.02) in DLB, and visuoperception (ß = -0.67 (SE = 0.19); t = -3.59; p < 0.01), in PD. CONCLUSIONS: Neuroanatomical normative modelling shows promise as a clinically informative technique in PD and DLB, where patterns of atrophy are variable.

Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas.

The gene defect for hereditary papillary renal carcinoma (HPRC) has recently been mapped to chromosome 7q, and germline mutations of MET (also known as c-met) at 7q31 have been detected in patients with HPRC (ref. 2). Tumours from these patients commonly show trisomy of chromosome 7 when analysed by cytogenetic studies and comparative genomic hybridization (CGH). However, the relationship between trisomy 7 and MET germline mutations is not clear. We studied 16 renal tumours from two patients with documented germline mutations in exon 16 of MET. Fluorescent in situ hybridization (FISH) analysis showed trisomy 7 in all tumours. To determine whether the chromosome bearing the mutant or wild-type MET gene was duplicated, we performed duplex PCR and phosphoimage densitometry using polymorphic microsatellite markers D7S1801 and D7S1822, which were linked to the disease gene locus, and D1S1646 as an internal control. We determined the parental origin of chromosome alleles by genotyping parental DNA. In all 16 tumours there was an increased signal intensity (2:1 ratio) of the microsatellite allele from the chromosome bearing the mutant MET compared with the allele from the chromosome bearing the wild-type MET. Our study demonstrates a non-random duplication of the chromosome bearing the mutated MET in HPRC and implicates this event in tumorigenesis.

Unidirectional thermal effects in current-induced domain wall motion.

We report experimental evidence of thermal effects on the displacement of vortex walls in NiFe nanostrips. With the use of nanosecond current pulses, a unidirectional motion of the magnetic domain walls towards the hotter part of the nanostrips is observed, in addition to current-induced domain wall motion. By tuning the heat dissipation in the samples and modeling the heat diffusion, we conclude that this unidirectional motion can only be explained by the presence of a temperature profile along the nanostrip. A quantitative analysis of the experiments shows that, on top of the classical thermodynamic pressure on the domain wall, another force, probably the magnonic spin Seebeck effect, is displacing the domain walls.

Thalamic white matter macrostructure and subnuclei volumes in Parkinson's disease depression.

Depression is a common non-motor feature of Parkinson's disease (PD) which confers significant morbidity and is challenging to treat. The thalamus is a key component in the basal ganglia-thalamocortical network critical to the pathogenesis of PD and depression but the precise thalamic subnuclei involved in PD depression have not been identified. We performed structural and diffusion-weighted imaging (DWI) on 76 participants with PD to evaluate the relationship between PD depression and grey and white matter thalamic subnuclear changes. We used a thalamic segmentation method to divide the thalamus into its 50 constituent subnuclei (25 each hemisphere). Fixel-based analysis was used to calculate mean fibre cross-section (FC) for white matter tracts connected to each subnucleus. We assessed volume and FC at baseline and 14-20 months follow-up. A generalised linear mixed model was used to evaluate the relationship between depression, subnuclei volume and mean FC for each thalamic subnucleus. We found that depression scores in PD were associated with lower right pulvinar anterior (PuA) subnucleus volume. Antidepressant use was associated with higher right PuA volume suggesting a possible protective effect of treatment. After follow-up, depression scores were associated with reduced white matter tract macrostructure across almost all tracts connected to thalamic subnuclei. In conclusion, our work implicates the right PuA as a relevant neural structure in PD depression and future work should evaluate its potential as a therapeutic target for PD depression.

[Revisiting the chemical diversity in prostatic calculi: a SEM and FT-IR investigation]. / Diversité chimique des calculs prostatiques : une investigation par MEB et spectroscopie infrarouge.

OBJECTIVE: Revisiting the chemical diversity of the crystalline phases of prostatic calculi by means of SEM and FT-IR analysis. METHODS: A set of 32 prostatic calculi has been studied by FT-IR and SEM. RESULTS: FT-IR analysis has determined the chemical composition of each prostatic calculus and the SEM observation has described the morphology of the calculi surfaces and layers. Infrared analysis revealed that 90.7% of the stones were mainly composed of calcium phosphates. However, several mineral phases previously not reported in prostatic calculi were observed, as brushite or octocalcium phosphate pentahydrate. CONCLUSION: Prostatic calculi exhibited a diversity of crystalline composition and morphology. As previously reported for urinary calculi, relationships between composition and morphology of prostatic stones and étiopathogenic conditions could be of interest in clinical practice.

Rewarding feedback after correct visual discriminations has both general and specific influences on visual cortex.

Reward can influence visual performance, but the neural basis of this effect remains poorly understood. Here we used functional magnetic resonance imaging to investigate how rewarding feedback affected activity in distinct areas of human visual cortex, separating rewarding feedback events after correct performance from preceding visual events. Participants discriminated oriented gratings in either hemifield, receiving auditory feedback at trial end that signaled financial reward after correct performance. Greater rewards improved performance for all but the most difficult trials. Rewarding feedback increased blood-oxygen-level-dependent (BOLD) signals in striatum and orbitofrontal cortex. It also increased BOLD signals in visual areas beyond retinotopic cortex, but not in primary visual cortex representing the judged stimuli. These modulations were seen at a time point in which no visual stimuli were presented or expected, demonstrating a novel type of activity change in visual cortex that cannot reflect modulation of response to incoming or anticipated visual stimuli. Rewarded trials led on the next trial to improved performance and enhanced visual activity contralateral to the judged stimulus, for retinotopic representations of the judged visual stimuli in V1. Our findings distinguish general effects in nonretinotopic visual cortex when receiving rewarding feedback after correct performance from consequences of reward for spatially specific responses in V1.

Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes.

Accumulating data show that the tyrosine protein kinase Zap-70 plays an essential role in T cell receptor-mediated signal transduction. However, the model of action, as well as the physiologically relevant substrates of Zap-70, have not been determined. We have attempted to identify a 120-kD tyrosine-phosphorylated protein (p120) that associates with Zap-70 in activated T lymphocytes. The results of our analyses showed that p120 is largely encoded by the c-cbl protooncogene. Furthermore, the association of Zap-70 with c-Cbl was shown to be induced by T cell receptor stimulation, implying that it required posttranslational modification of one or both of these products. FynT, but not Lck, also associated with c-Cbl in activated T cells. Finally, using a heterologous system, it was demonstrated that the ability of Zap-70 to cause tyrosine phosphorylation of p120c-cbl was dependent on Lck- or FynT-mediated signals. As c-Cbl can associate with several other signaling molecules, it may couple Zap-70 to downstream effectors during T cell activation.

The first alpha helix of interleukin (IL)-2 folds as a homotetramer, acts as an agonist of the IL-2 receptor beta chain, and induces lymphokine-activated killer cells.

Interleukin (IL)-2 interacts with two types of functional receptors (IL-2Ralphabetagamma and IL-2Rbetagamma) and acts on a broad range of target cells involved in inflammatory reactions and immune responses. For the first time, we show that a chemically synthesized fragment of the IL-2 sequence can fold into a molecule mimicking the quaternary structure of a hemopoietin. Indeed, peptide p1-30 (containing amino acids 1-30, covering the entire alpha helix A of IL-2) spontaneously folds into an alpha-helical homotetramer and stimulates the growth of T cell lines expressing human IL-2Rbeta, whereas shorter versions of the peptide lack helical structure and are inactive. We also demonstrate that this neocytokine interacts with a previously undescribed dimeric form of IL-2Rbeta. In agreement with its binding to IL-2Rbeta, p1-30 activates Shc and p56(lck) but unlike IL-2, fails to activate Janus kinase (Jak)1, Jak3, and signal transducer and activator of transcription 5 (STAT5). Unexpectedly, we also show that p1-30 activates Tyk2, thus suggesting that IL-2Rbeta may bind to different Jaks depending on its oligomerization. At the cellular level, p1-30 induces lymphokine-activated killer (LAK) cells and preferentially activates CD8(low) lymphocytes and natural killer cells, which constitutively express IL-2Rbeta. A significant interferon gamma production is also detected after p1-30 stimulation. A mutant form of p1-30 (Asp20-->Lys), which is likely unable to induce vascular leak syndrome, remains capable of generating LAK cells, like the original p1-30 peptide. Altogether, our data suggest that p1-30 has therapeutic potential.

Integration of heterogeneous expression data sets extends the role of the retinol pathway in diabetes and insulin resistance.

MOTIVATION: Type 2 diabetes is a chronic metabolic disease that involves both environmental and genetic factors. To understand the genetics of type 2 diabetes and insulin resistance, the DIabetes Genome Anatomy Project (DGAP) was launched to profile gene expression in a variety of related animal models and human subjects. We asked whether these heterogeneous models can be integrated to provide consistent and robust biological insights into the biology of insulin resistance. RESULTS: We perform integrative analysis of the 16 DGAP data sets that span multiple tissues, conditions, array types, laboratories, species, genetic backgrounds and study designs. For each data set, we identify differentially expressed genes compared with control. Then, for the combined data, we rank genes according to the frequency with which they were found to be statistically significant across data sets. This analysis reveals RetSat as a widely shared component of mechanisms involved in insulin resistance and sensitivity and adds to the growing importance of the retinol pathway in diabetes, adipogenesis and insulin resistance. Top candidates obtained from our analysis have been confirmed in recent laboratory studies.

Conductance fluctuations and field asymmetry of rectification in graphene.

We investigate conductance fluctuations as a function of carrier density n and magnetic field in diffusive mesoscopic samples made from monolayer and bilayer graphene. We show that the fluctuations' correlation energy and field, which are functions of the diffusion coefficient, have fundamentally different variations with n, illustrating the contrast between massive and massless carriers. The field dependent fluctuations are nearly independent of n, but the n-dependent fluctuations are not universal and are largest at the charge neutrality point. We also measure the second-order conductance fluctuations (mesoscopic rectification). Its field asymmetry, due to electron-electron interaction, decays with conductance, as predicted for diffusive systems.

Transport and elastic scattering times as probes of the nature of impurity scattering in single-layer and bilayer graphene.

Transport and elastic scattering times, tau{tr} and tau{e}, are experimentally determined from the carrier density dependence of the magnetoconductance of monolayer and bilayer graphene. Both times and their dependences on carrier density are found to be very different in the monolayer and the bilayer. However, their ratio tau{tr}/tau{e} is found to be close to 1.8 in the two systems and nearly independent of the carrier density. These measurements give insight on the nature (neutral or charged) and range of the scatterers. Comparison with theoretical predictions suggests that the main scattering mechanism in our samples is due to strong (resonant) scatterers of a range shorter than the Fermi wavelength, likely candidates being vacancies, voids, adatoms or short-range ripples.

Magnetization reversal in Pt/Co(0.5 nm)/Pt nano-platelets patterned by focused ion beam lithography.

Arrays of ultrathin Pt/Co(0.5 nm)/Pt nano-platelets with lateral sizes ranging from 30 nm to 1 µm have been patterned by focused ion beam (FIB) lithography under a weak Ga(+) ion fluence. From polar magneto-optical Kerr microscopy it is demonstrated that nano-platelets are ferromagnetic with perpendicular anisotropy down to a size of 50 nm. The irradiation process creates a magnetically soft ring at the nano-platelet periphery in which domain nucleation is initiated at a low field. The magnetization reversal in nano-platelets can be interpreted using a confined droplet model. All of the results prove that ultimate FIB patterning is suitable for preparing discrete magnetic recording media or small magnetic memory elements and nano-devices.

Network-based analysis of affected biological processes in type 2 diabetes models.

Type 2 diabetes mellitus is a complex disorder associated with multiple genetic, epigenetic, developmental, and environmental factors. Animal models of type 2 diabetes differ based on diet, drug treatment, and gene knockouts, and yet all display the clinical hallmarks of hyperglycemia and insulin resistance in peripheral tissue. The recent advances in gene-expression microarray technologies present an unprecedented opportunity to study type 2 diabetes mellitus at a genome-wide scale and across different models. To date, a key challenge has been to identify the biological processes or signaling pathways that play significant roles in the disorder. Here, using a network-based analysis methodology, we identified two sets of genes, associated with insulin signaling and a network of nuclear receptors, which are recurrent in a statistically significant number of diabetes and insulin resistance models and transcriptionally altered across diverse tissue types. We additionally identified a network of protein-protein interactions between members from the two gene sets that may facilitate signaling between them. Taken together, the results illustrate the benefits of integrating high-throughput microarray studies, together with protein-protein interaction networks, in elucidating the underlying biological processes associated with a complex disorder.

Measurement of the tilt of a moving domain wall shows precession-free dynamics in compensated ferrimagnets.

One fundamental obstacle to efficient ferromagnetic spintronics is magnetic precession, which intrinsically limits the dynamics of magnetic textures. We experimentally demonstrate that this precession vanishes when the net angular momentum is compensated in domain walls driven by spin-orbit torque in a ferrimagnetic GdFeCo/Pt track. We use transverse in-plane fields to provide a robust and parameter-free measurement of the domain wall internal magnetisation angle, demonstrating that, at the angular compensation, the DW tilt is zero, and thus the magnetic precession that caused it is suppressed. Our results highlight the mechanism of faster and more efficient dynamics in materials with multiple spin lattices and vanishing net angular momentum, promising for high-speed, low-power spintronic applications.