Phase 2 Trial of Difelikefalin in Notalgia Paresthetica.

BACKGROUND: Notalgia paresthetica is a neuropathic disorder characterized by pruritus in a circumscribed region of the upper back. Difelikefalin, a selective kappa opioid receptor agonist, has shown efficacy in other chronic pruritic conditions and is being investigated for the treatment of notalgia paresthetica. METHODS: In this phase 2, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, patients with moderate-to-severe pruritus caused by notalgia paresthetica to receive 2 mg of oral difelikefalin or placebo twice daily for 8 weeks. The primary outcome was the change from baseline at week 8 in the weekly mean score on the daily Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). The secondary clinical outcomes were itch-related quality-of-life and itch-related sleep measures. RESULTS: A total of 126 patients were enrolled; 62 patients were assigned to receive difelikefalin, and 63 were assigned to receive placebo. One patient who had been assigned to receive difelikefalin withdrew consent before the first dose and is not included in the main analyses. The mean baseline WI-NRS score was 7.6 (indicating severe itch) in each group. The change from baseline in the weekly mean WI-NRS score at week 8 was -4.0 points in the difelikefalin group and -2.4 points in the placebo group (difference in change, -1.6 points; 95% confidence interval, -2.6 to -0.6; P = 0.001). The results for the secondary outcomes generally did not support those of the primary analysis. Headache, dizziness, constipation, and increased urine output occurred more frequently in the difelikefalin group than in the placebo group. CONCLUSIONS: Among patients with notalgia paresthetica, oral treatment with difelikefalin resulted in modestly greater reductions in itch intensity scores than placebo over a period of 8 weeks but was associated with adverse events. Larger and longer trials are needed to assess the efficacy and safety of difelikefalin treatment in this disorder. (Funded by Cara Therapeutics; KOMFORT ClinicalTrials.gov number, NCT04706975.).

Pre and Post-Operative Alterations of the Gastrointestinal Microbiome Following Bariatric Surgery.

Obesity in the United States is increasing at a startling rate, with more individuals turning towards bariatric surgery as treatment. A noteworthy aspect of obesity pathology is its interplay with the gastrointestinal microbiome. The gastrointestinal microbiome comprising trillions of microorganisms affects the dynamics of digestion, energy expenditure, and neurologic mechanisms that affect dietary preference. This literature review used PubMed to search for articles about obesity, gastrointestinal microbiome, and bariatric surgery. The researchers used Medical Subject Heading keywords, and then the relevant literature was selected and filtered using inclusion and exclusion criteria. This study aims to review the temporal relationship of gastrointestinal microbiome changes after bariatric surgery in association with the success and failure of treatment along with the factors that may have altered the gastrointestinal microbiome other than the anatomical aspect of bariatric surgery.

Surface-Enhanced Raman Spectroscopy for Rapid Screening of Cinnamon Essential Oils.

Cinnamon essential oil is used in food flavoring, food preservation, and for complementary medicine. The most common types of cinnamon used in essential oils are true cinnamon (Cinnamomum verum) and cassia cinnamon (Cinnamomum cassia). True cinnamon is commonly adulterated with cassia cinnamon because it is cheaper. However, cassia cinnamon contains higher concentrations of coumarin which has been shown to have adverse health effects. There is a need to develop simple, nondestructive, rapid screening methods for quality control and food authentication and to identify adulteration of cinnamon essential oil. Currently, the most common methods to screen for coumarin in cinnamon include high-performance liquid chromatography (HPLC) and gas chromatography (GC). However, these methods require time-consuming sample preparation and detection. Vibrational spectroscopy methods are emerging as a promising alternative for rapid, nondestructive screening for food safety applications. In this study, a rapid screening method has been developed to examine cinnamon essential oils using surface-enhanced Raman spectroscopy (SERS). The experimental spectra were compared to theoretical calculations using the DFT method BP86/6-311++G(d,p) basis set. The limit of detection of coumarin was determined to be 1 × 10-6 M or 1.46 mg/L using SERS with colloid paste substrates. Furthermore, 1:16 dilutions of cinnamaldehyde and 1:8 dilutions of eugenol were detected using SERS which can help determine if the cinnamon essential oil was made from bark or from leaves. Seven commercially available cinnamon essential oils were also analyzed and compared to reference solutions. SERS was able to discriminate between essential oils primarily composed of cinnamaldehyde and those composed of eugenol. Furthermore, the SERS method detected peaks that are attributed to coumarin in two of the commercially available samples. To date, this is the first time SERS has been used to rapidly screen cinnamon essential oils.

A Phase 2 Randomized Trial of Apremilast in Patients with Atopic Dermatitis.

A phase 2, double-blind, placebo-controlled trial evaluated apremilast efficacy, safety, and pharmacodynamics in adults with moderate to severe atopic dermatitis. Patients were randomly assigned to receive placebo, apremilast 30 mg twice daily (APR30), or apremilast 40 mg twice daily (APR40) for 12 weeks. During weeks 12-24, all patients received APR30 or APR40. A biopsy substudy evaluated atopic dermatitis-related biomarkers. Among 185 randomly assigned intent-to-treat patients at week 12, a dose-response relationship was observed; APR40 (n = 63), but not APR30 (n = 58), led to statistically significant improvements (vs. placebo, n = 64) in Eczema Area and Severity Index (mean [standard deviation] percent change from baseline = -31.6% [44.6] vs. -11.0% [71.2], P < 0.04; primary endpoint). mRNA expression of T helper type 17/T helper type 22-related markers (IL-17A, IL-22, and S100A7/A8; P < 0.05) showed the highest reductions with APR40, with minimal changes in other immune axes. Safety with APR30 was largely consistent with apremilast's known profile (common adverse events: nausea, diarrhea, headache, and nasopharyngitis). With APR40, adverse events were more frequent, and cellulitis occurred (n = 6). An independent safety monitoring committee discontinued the APR40 dosage. APR40 showed modest efficacy and decreased atopic dermatitis-related biomarkers in moderate to severe atopic dermatitis patients. Adverse events, including cellulitis, were more frequent with APR40, which was discontinued during the trial. Clinical Trial Registration Number: NCT02087943 (clinicaltrials.gov).

Tip-enhanced Raman spectroscopy (TERS) for in situ identification of indigo and iron gall ink on paper.

Confirmatory, nondestructive, and noninvasive identification of colorants in situ is of critical importance for the understanding of historical context and for the long-term preservation of cultural heritage objects. Although there are several established techniques for analyzing cultural heritage materials, there are very few analytical methods that can be used for molecular characterization when very little sample is available, and a minimally invasive approach is required. Tip-enhanced Raman spectroscopy (TERS) is a powerful analytical technique whose key features include high mass sensitivity, high spatial resolution, and precise positioning of the tip. In the current proof-of-concept study we utilized TERS to identify indigo dye and iron gall ink in situ on Kinwashi paper. In addition, TERS was used to identify iron gall ink on a historical document with handwritten text dated to the 19th century. We demonstrate that TERS can identify both of these colorants directly on paper. Moreover, vibrational modes from individual components of a complex chemical mixture, iron gall ink, can be identified. To the best of our knowledge, this is the first demonstration of in situ TERS for colorants of artistic relevance directly on historical materials. Overall, this work demonstrates the great potential of TERS as an additional spectroscopic tool for minimally invasive compositional characterization of artworks in situ and opens exciting new possibilities for cultural heritage research.

Silver colloidal pastes for dye analysis of reference and historical textile fibers using direct, extractionless, non-hydrolysis surface-enhanced Raman spectroscopy.

Surface-enhanced Raman spectroscopy (SERS) is an ideal tool for analyzing dyes on historical textiles because it requires very little sample compared to other available analytical methods and analysis can be done directly on the fiber. This paper reports on the first systematic study of the use of citrate-reduced silver colloidal pastes for the direct, extractionless, non-hydrolysis detection of dyes directly on wool, silk, cotton, and flax fibers. This type of study provides greater insight into the optimal conditions required for accurate analysis of dyes in historical samples. In this work, Ag colloidal pastes were characterized using localized surface plasmon resonance and scanning electron microscopy. The pastes were then employed for SERS analysis of twelve reference samples of different vegetal and animal fibers dyed with cochineal and eleven dyed with brazilwood. Furthermore, six historical textiles from an important collection of Mariano Fortuny (1871-1949) textiles at the Art Institute of Chicago were also examined, to test the efficacy of the paste on aged samples, and to shed light on Fortuny's fascinating production techniques. A mixture of cochineal and brazilwood was detected in some of the historical samples demonstrating, for the first time, simultaneous identification of these colorants used in combination. In addition, the findings give substance to the claim that Fortuny kept using natural dyes at a time when many new and attractive synthetic products became available.

Near-infrared surface-enhanced Raman spectroscopy (NIR-SERS) for the identification of eosin Y: theoretical calculations and evaluation of two different nanoplasmonic substrates.

This work demonstrates the development of near-infrared surface-enhanced Raman spectroscopy (NIR-SERS) for the identification of eosin Y, an important historical dye. NIR-SERS benefits from the absence of some common sources of SERS signal loss including photobleaching and plasmonic heating, as well as an advantageous reduction in fluorescence, which is beneficial for art applications. This work also represents the first rigorous comparison of the enhancement factors and the relative merits of two plasmonic substrates utilized in art applications; namely, citrate-reduced silver colloids and metal film over nanosphere (FON) substrates. Experimental spectra are correlated in detail with theoretical absorption and Raman spectra calculated using time-dependent density functional theory (TDDFT) in order to elucidate molecular structural information and avoid relying on pigment spectral libraries for dye identification.

In vivo, transcutaneous glucose sensing using surface-enhanced spatially offset Raman spectroscopy: multiple rats, improved hypoglycemic accuracy, low incident power, and continuous monitoring for greater than 17 days.

This paper presents the latest progress on quantitative, in vivo, transcutaneous glucose sensing using surface enhanced spatially offset Raman spectroscopy (SESORS). Silver film over nanosphere (AgFON) surfaces were functionalized with a mixed self-assembled monolayer (SAM) and implanted subcutaneously in Sprague-Dawley rats. The glucose concentration was monitored in the interstitial fluid of six separate rats. The results demonstrated excellent accuracy and consistency. Remarkably, the root-mean-square error of calibration (RMSEC) (3.6 mg/dL) and the root-mean-square error of prediction (RMSEP) (13.7 mg/dL) for low glucose concentration (<80 mg/dL) is lower than the current International Organization Standard (ISO/DIS 15197) requirements. Additionally, our sensor demonstrated functionality up 17 days after implantation, including 12 days under the laser safety level for human skin exposure with only one time calibration. Therefore, our SERS based sensor shows promise for the challenge of reliable continuous glucose sensing systems for optimal glycemic control.

Structural, morphological, and kinetic studies of ß-amyloid peptide aggregation on self-assembled monolayers.

The misfolding and aggregation of ß-amyloid peptides (Aß) into amyloid fibrils, a process that has been pathologically linked to the onset of Alzheimer's disease, is dependent on the presence of a heterogeneous surface (e.g., cell membrane). Understanding of the kinetics of amyloid fibril formation and associated structural transition from monomers to intermediates and eventually to fibrils is critical for the development of viable therapeutic agents. In this work, using circular dichroism (CD), atomic force microscopy (AFM), surface plasmon resonance (SPR), and molecular dynamics (MD) simulations, we studied the adsorption, aggregation, and conformational changes of Aß(1-42) from fresh monomers to fully grown fibrils on four model self-assembled monolayers (SAMs): hydrophobic CH(3)-terminated SAM, hydrophilic OH-terminated SAM, negatively charged COOH-terminated SAMs, and positively charged NH(2)-terminated SAM. The seeding effect of Aß(1-42) on the kinetics of Aß aggregation on different SAMs is also examined. The CD, AFM, and SPR data show that all of these SAMs greatly accelerate the formation of ß-sheets and amyloid fibrils through surface-enhanced interactions, but Aß(1-42) peptides preferentially adsorb on a hydrophobic CH(3)-SAM and a positively charged NH(2)-SAM with much stronger interactions than on a hydrophilic OH-SAM and a negatively charged COOH-SAM. MD simulations further reveal that hydrophobic interactions present a general driving force for Aß adsorption on all SAMs. As Aß aggregates grow into larger species by packing hydrophobic C-terminals to form a hydrophobic core while exposing hydrophilic and negatively charged N-terminals to solution, electrostatic interactions become more strengthened when they interact with the SAMs especially for the COOH-SAM and the NH(2)-SAM. Thus, both hydrophobic and electrostatic interactions contribute differently to different Aß-SAM systems and to different aggregation stages. A postulated mechanism is proposed to describe the structure and kinetics of Aß aggregation from aqueous solution to the SAMs, providing valuable insights into Aß aggregation on biological cell membranes.

Transcutaneous glucose sensing by surface-enhanced spatially offset Raman spectroscopy in a rat model.

This letter presents the first quantitative, in vivo, transcutaneous glucose measurements using surface enhanced Raman spectroscopy (SERS). Silver film over nanosphere (AgFON) surfaces were functionalized with a mixed self-assembled monolayer (SAM) and implanted subcutaneously in a Sprague-Dawley rat. The glucose concentration was monitored in the interstitial fluid. SER spectra were collected from the sensor chip through the skin using spatially offset Raman spectroscopy (SORS). The combination of SERS and SORS is a powerful new approach to the challenging problem of in vivo metabolite and drug sensing.

Alpha-synuclein in alpha-helical conformation at air-water interface: implication of conformation and orientation changes during its accumulation/aggregation.

Alpha-synuclein, a natively unstructured protein important in the neuropathology of Parkinson's disease, was found to form a Langmuir monolayer in an alpha-helical conformation with its helical axis parallel to the air-water interface. This study sheds light on the role of vesicles in neuronal cells in the accumulation/aggregation of alpha-synuclein.

An analysis of 30 cases of myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a clonal disorder of pluripotential stem cells of the bone marrow. The purpose of the study was to obtain epidemiological data of MDS. Thirty cases of MDS presented from April 1998 to May 2006 are included in this study. Complete blood counts were performed in an automated cell counter. Bone marrow aspiration, trephine biopsy and chromosomal study were carried out. The dry film was stained using a Romanwasky stain and Perl's stain. Fifteen cases were male and 15 cases were female. The mean age at presentation was 55 years (range 8-73 years). A majority of the patients presented with weakness (63.33%). Autoimmune manifestations in the form of joint pain were present in 13.33%. Patients were symptomatic for a prolonged period before diagnosis could be reached (average 358.8 days). A majority of the patients had MDS-refractory anemia (MDS-RA) or MDS-RA with excess blasts (MDS-RAEB-2) at presentation. Three patients had chromosomal abnormalities (27.27%). Eight patients (26.7%) were relatively young at presentation, less than 50 years of age. Three (10%) were children. A majority of the patients opted for symptomatic treatment only.

LSPR Imaging: Simultaneous Single Nanoparticle Spectroscopy and Diffusional Dynamics.

A wide-field localized surface plasmon resonance (LSPR) imaging method using a liquid crystal tunable filter (LCTF) is used to measure the scattering spectra of multiple Ag nanoparticles in parallel. This method provides the ability to characterize moving Ag nanoparticles by measuring the scattering spectra of the particles while simultaneously tracking their motion. Consequently, single particle diffusion coefficients can be determined. As an example, several single Ag nanoprisms are tracked, the LSPR scattering spectrum of each moving particle is obtained, and the single particle diffusion coefficient is determined from its trajectory. Coupling diffusion information with spectral information in real time is a significant advance and addresses many scientific problems, both fundamental and biological, such as cell membrane protein diffusion, functional plasmonic distributions, and nanoparticle growth mechanisms.

Progress toward an in vivo surface-enhanced Raman spectroscopy glucose sensor.

BACKGROUND: In this report, we detail our current work towards developing a surface-enhanced Raman spectroscopy (SERS) based sensor for in vivo glucose detection. Despite years of innovations in the development of blood glucose monitors, there remains a need for accurate continuous glucose sensors to provide care to rising numbers of diagnosed diabetes patients and mitigate secondary health complications associated with this metabolic disorder. METHODS: SERS is a highly specific and sensitive optical technique suitable for direct detection of glucose. The SERS effect is highly distance dependent, thus the glucose molecules need to be within a few nanometers or adsorbed to an SERS-active surface. In our sensor, this is achieved with a self-assembled monolayer (SAM) that facilitates reversible interactions between glucose molecules and the surface. The amount of glucose near the surface is proportional to its concentration in the surrounding environment. RESULTS: We determined that the SAM-functionalized surface is stable for at least 10 days and provides rapid, reversible partitioning. In vitro experiments in bovine plasma as well as in vivo experiments in rats demonstrated quantitative detection. CONCLUSIONS: We show successful use of the SERS glucose sensor in rats, making it the first in vivo SERS sensor. Furthermore, we demonstrate free space transdermal detection of a SERS signal through the rat's skin as an initial step toward developing a transcutaneous sensor.

Biosensing with plasmonic nanosensors.

Recent developments have greatly improved the sensitivity of optical sensors based on metal nanoparticle arrays and single nanoparticles. We introduce the localized surface plasmon resonance (LSPR) sensor and describe how its exquisite sensitivity to size, shape and environment can be harnessed to detect molecular binding events and changes in molecular conformation. We then describe recent progress in three areas representing the most significant challenges: pushing sensitivity towards the single-molecule detection limit, combining LSPR with complementary molecular identification techniques such as surface-enhanced Raman spectroscopy, and practical development of sensors and instrumentation for routine use and high-throughput detection. This review highlights several exceptionally promising research directions and discusses how diverse applications of plasmonic nanoparticles can be integrated in the near future.

An analysis of 8 cases of factor X deficiency.

BACKGROUND: Factor X deficiency is a rare coagulation defect. There are occasional reports of factor X deficiency from India. Difficulty in accurate diagnosis and non-availability of ideal treatment is discussed. METHODS: Eight cases of factor X deficiency, diagnosed from 1992 to 2007 are reported here RESULTS: Seven were male while one was female. Seven patients were symptomatic from early childhood. One patient became symptomatic from 18 years of age. Factor X assay was done in 4 patients, 3 had severe deficiency and one had mild deficiency. One patient had associated factor IX deficiency. Three patients had repeated bleeding episodes requiring multiple transfusions. Two patients had intracranial bleed and one had umbilical cord bleeding at birth. There was no mortality. No patient received prophylactic transfusion. CONCLUSIONS: Factor X deficiency is a rare coagulation defect. Hereditary deficiency should be distinguished from acquired deficiency. CNS, joints and skin are the common sites of bleeding.

Surface-enhanced Raman spectroscopy.

The ability to control the size, shape, and material of a surface has reinvigorated the field of surface-enhanced Raman spectroscopy (SERS). Because excitation of the localized surface plasmon resonance of a nanostructured surface or nanoparticle lies at the heart of SERS, the ability to reliably control the surface characteristics has taken SERS from an interesting surface phenomenon to a rapidly developing analytical tool. This article first explains many fundamental features of SERS and then describes the use of nanosphere lithography for the fabrication of highly reproducible and robust SERS substrates. In particular, we review metal film over nanosphere surfaces as excellent candidates for several experiments that were once impossible with more primitive SERS substrates (e.g., metal island films). The article also describes progress in applying SERS to the detection of chemical warfare agents and several biological molecules.

Lactate and sequential lactate-glucose sensing using surface-enhanced Raman spectroscopy.

Lactate production under anaerobic conditions is indicative of human performance levels, fatigue, and hydration. Elevated lactate levels result from several medical conditions including congestive heart failure, hypoxia, and diabetic ketoacidosis. Real-time detection of lactate can therefore be useful for monitoring these medical conditions, posttrauma situations, and in evaluating the physical condition of a person engaged in strenuous activity. This paper represents a proof-of-concept demonstration of a lactate sensor based on surface-enhanced Raman spectroscopy (SERS). Furthermore, it points the direction toward a multianalyte sensing platform. A mixed decanethiol/mercaptohexanol partition layer is used herein to demonstrate SERS lactate sensing. The reversibility of the sensor surface is characterized by exposing it alternately to aqueous lactate solutions and buffer without lactate. The partitioning and departitioning time constants were both found to be approximately 30 s. In addition, physiological lactate levels (i.e., 6-240 mg/dL) were quantified in phosphate-buffered saline medium using multivariate analysis with a root-mean-square error of prediction of 39.6 mg/dL. Finally, reversibility was tested for sequential glucose and lactate exposures. Complete partitioning and departitioning of both analytes was demonstrated.

In vivo glucose measurement by surface-enhanced Raman spectroscopy.

This paper presents the first in vivo application of surface-enhanced Raman scattering (SERS). SERS was used to obtain quantitative in vivo glucose measurements from an animal model. Silver film over nanosphere surfaces were functionalized with a two-component self-assembled monolayer, and subcutaneously implanted in a Sprague-Dawley rat such that the glucose concentration of the interstitial fluid could be measured by spectroscopically addressing the sensor through an optical window. The sensor had relatively low error (RMSEC = 7.46 mg/dL (0.41 mM) and RMSEP = 53.42 mg/dL (2.97 mM).

Surface enhanced Raman spectroscopy: new materials, concepts, characterization tools, and applications.

Surface-enhanced Raman spectroscopy (SERS) is currently experiencing a renaissance in its development driven by the remarkable discovery of single molecule SERS (SMSERS) and the explosion of interest in nanophotonics and plasmonics. Because excitation of the localized surface plasmon resonance (LSPR) of a nanostructured surface or nanoparticle lies at the heart of SERS, it is important to control all of the factors influencing the LSPR in order to maximize signal strength and ensure reproducibility. These factors include material, size, shape, interparticle spacing, and dielectric environment. All of these factors must be carefully controlled to ensure that the incident laser light maximally excites the LSPR in a reproducible manner. This article describes the use of nanosphere lithography for the fabrication of highly reproducible and robust SERS substrates for both fundamental studies and applications. Atomic layer deposition (ALD) is introduced as a novel fabrication method for dielectric spacers to study the SERS distance dependence and control the nanoscale dielectric environment. Wavelength scanned SER excitation spectroscopy (WS SERES) measurements show that enhancement factors approximately 10(8) are obtainable from NSL-fabricated surfaces and provide new insight into the electromagneticfield enhancement mechanism. Tip-enhanced Raman spectroscopy (TERS) is an extremely promising new development to improve the generality and information content of SERS. A 2D correlation analysis is applied to SMSERS data. Finally, the first in vivo SERS glucose sensing study is presented.