Multiple myeloma screening within a fracture liaison service (FLS).

Multiple myeloma (MM) remains incurable. Although early diagnosis improves outcomes, it has been unclear which populations to target for screening with serum electrophoresis, serum free light chains and urine electrophoresis. Here, we assessed the value of MM screening in a Fracture Liaison Service, finding that 1 per 195 fragility fractures has undiagnosed MM, which can be expedited to Haematology Services. PURPOSE: A key role of the Fracture Liaison Service (FLS) is screening for secondary causes of osteoporosis. In 2019, the Royal Osteoporosis Society recommended that all patients attending FLS who are recommended anti-osteoporosis therapy have universal screening for myeloma based on serum electrophoresis, serum free light chains and urine electrophoresis. Here, we examined the impact of universal myeloma screening within an FLS. METHODS: We sampled all patients seen by the Oxfordshire FLS between January and April 2018. The completion rates and outcomes of screening were checked using the hospital and FLS databases. RESULTS: Of 950 patients identified by the FLS, 628 were eligible for MM screening; 473 (75%) of these were female, and the average age was 78.4 years. Overall, 584 had some form of myeloma screening, of which 577 (92%) had serum electrophoresis, 525 (84%) had serum free light chains and 407 (65%) had urine electrophoresis measured. A total of 327 (59%) patients had complete screening. Three patients (0.5%) had newly diagnosed myeloma and were urgently referred to Haematology Services. Furthermore, 46 (8%) patients had a detectable serum paraprotein with a likely diagnosis of monoclonal gammopathy of uncertain significance (MGUS) and referred for community annual surveillance according to local guidelines. CONCLUSION: Addition of universal myeloma screening to laboratory testing identified myeloma in 1 per 195 patients, and its precursor state MGUS in 1 per 13 patients, which may have otherwise been missed. Further analysis with long-term follow-up is needed to clearly define the value of diagnosing MGUS within the FLS setting and establish the benefits vs. costs and methods to improve screening completion rates.

Potential of pyrethroid-synergised pyrethrum on stored product insects and implications for use as prophylactic sprays.

The study was conducted to evaluate the synergistic effects of 2% pyrethrum extract with synthetic pyrethroids on the mortality of stored product insects. Contact toxicity was performed at variable concentrations observing mortality at 12, 24 and 48 h durations. The results of the present study indicated that, pyrethrum + deltamethrin combination (25:1 ratio) was effective on the adults of Rhyzopertha dominica (F.) and Tribolium castaneum (Herbst). On the other hand, pyrethrum + cypermethrin combination proved effective against Sitophilus oryzae (L.). The efficacy of the tested combination showed reasonable increase in mortality response in treated insects over increasing exposures. At 48 h, 450 ppm pyrethrum + deltamethrin combination induced 25, 90 and 97% mortalities in S. oryzae, T. castaneum and R. dominica adults; while, pyrethrum-cypermethrin combination recorded 75, 45 and 75% mortalities respectively. On the other hand, it was observed that, among the pyrethrum alone treatments i.e. at 300, 450 and 600 ppm concentrations, maximum mortality (62.5%) was observed in S. oryzae exposed to 600 ppm pyrethrum for 48 h. The effective LC50 concentrations for pyrethrum (600 ppm) + deltamethrin combination was estimated to be as 0.1987 and 0.7039 µl/cm2 for R. dominica and T. castaneum adults respectively. Contrastingly, for treatments with S. oryzae, a LC50 value of 0.8673 µl/cm2 was recorded for pyrethrum (600 ppm) + cypermethrin mixture. This investigation strengthens the fact that pyrethrum along with pyrethroids is effective against storage insect pests which can be promisingly a safer insecticidal combination.

Antimicrobial and in vitro wound healing properties of novel clay based bionanocomposite films.

The present study investigates the development of methyl cellulose (MC)-sodium alginate (SA)-montmorillonite (MMT) clay based bionanocomposite films with interesting wound healing properties. The differential scanning calorimetry analysis of the composite films revealed presence of single glass transition temperature (Tg) confirming the miscible nature of the ternary blended films. The increase in MMT ratio in the composite films reduced the mobility of biopolymer chains (MC/SA) which increased the Tg of the film. Thermogravimetric analysis showed that dispersion of clay (MMT) at nano level significantly delayed the weight loss that correlated with higher thermal stability of the composite films. It was observed that the developed films were able to exhibit antimicrobial activity against four typical pathogenic bacteria found in the presence of wound. The developed films were able to significantly inhibit (10 mg/ml) the growth of Enterococcus faecium and Pseudomonas aeruginosa. In vitro scratch assay indicated potential wound closure activities of MC-2-4 bionanocomposite films at their respective highest subtoxic doses. In conclusion, these ternary bionanocomposite films were found to be promising systems for wound healing applications.

pH dependent poly[2-(methacryloyloxyethyl)trimetylammonium chloride-co-methacrylic acid]hydrogels for enhanced targeted delivery of 5-fluorouracil in colon cancer cells.

Stimuli responsive hydrogels have shown enormous potential as a carrier for targeted drug delivery. In this study we have developed novel pH responsive hydrogels for the delivery of 5-fluorouracil (5-FU) in order to alleviate its antitumor activity while reducing its toxicity. We used 2-(methacryloyloxyethyl) trimetylammonium chloride a positively charged monomer and methacrylic acid for fabricating the pH responsive hydrogels. The released 5-FU from all except hydrogel (GEL-5) remained biologically active against human colon cancer cell lines [HT29 (IC50 = 110-190 µg ml(-1)) and HCT116 (IC50 = 210-390 µg ml(-1))] but not human skin fibroblast cells [BJ (CRL2522); IC50 ≥ 1000 µg ml(-1)]. This implies that the copolymer hydrogels (1-4) were able to release 5-FU effectively to colon cancer cells but not normal human skin fibroblast cells. This is probably due to the shorter doubling time that results in reduced pH in colon cancer cells when compared to fibroblast cells. These pH sensitive hydrogels showed well defined cell apoptosis in HCT116 cells through series of events such as chromatin condensation, membrane blebbing, and formation of apoptotic bodies. No cell killing was observed in the case of blank hydrogels. The results showed the potential of these stimuli responsive polymer hydrogels as a carrier for colon cancer delivery.

Kinetic behaviour of calf intestinal alkaline phosphatase with pNPP.

The hydrolysis of p-nitrophenyl phosphate (pNPP) by calf intestinal alkaline phosphatase (CIAP) was investigated with respect to kinetic parameters such as V(max), K(m) and K(cat) under varying pH, buffers, substrate concentration, temperature and period of incubation. Highest activity was obtained with Tris-HCl at pH 11, while in the case of glycine-NaOH buffer the peak activity was recorded at pH 9.5. The enzyme showed the following kinetic characteristics with pNPP in 50 mM Tris-HCl at pH 11 and 100 mM glycine-NaOH at pH 9.5 at an incubation temperature of 37 degrees C: V(max), 3.12 and 1.6 micromoles min(-1) unit(-1); K(m), 7.6 x 10(-4) M and 4 x 10(-4) M; and K(cat), 82.98 s(-1) and 42.55 s(-1), respectively. CIAP displayed a high temperature optimum of 45 degrees C at pH 11. The kinetic behaviour of the enzyme under different parameters suggested that the enzyme might undergo subtle conformational changes in response to the buffers displaying unique characteristics. Bioprecipitation of Cu2+ from 50 ppm of CuCl2 solution was studied where 64.3% of precipitation was obtained. P(i) generated from CIAP-mediated hydrolysis of pNPP was found to bind with copper and precipitated as copper-phosphate. Thus, CIAP could be used as a test candidate in bioremediation of heavy metals from industrial wastes through generation of metal-phosphate complexes.

Synthesis, characterization, and antimicrobial activity of nano-hydroxyapatite-zinc for bone tissue engineering applications.

The bone implants used in tissue repair are susceptible to infections caused by staphylococci, specifically Staphylococcus aureus. Hence, the development of better biological materials that provide antimicrobial activity in bone tissue engineering is required. The nanoparticles of hydroxyapatite (nHAp) and nHAp dopped with Zn (nHAp-Zn) were prepared by the wet chemical method and the ion exchange method, respectively. They were characterized using SEM, AFM, FTIR and XRD. The antibacterial activity of nHAp and nHAp-Zn was determined with Gram-negative and Gram-positive bacterial strains. The results indicated that nHAp alone was acting as an inert matrix and when substituted with Zn, it showed better antibacterial activity. The nHAp-Zn was found to be non-toxic to osteoprogenitor cells. Thus, due to the antimicrobial property of nHAp-Zn nanoparticles, we suggest that they would have potential applications towards bone tissue engineering.

The ORNATE India Project: United Kingdom-India Research Collaboration to tackle visual impairment due to diabetic retinopathy.

INTRODUCTION: The ORNATE India project is funded by the UK Research and Innovation (UKRI) through the Global Challenges Research Fund. The aim is to build research capacity and capability in India and the UK to tackle global burden of diabetes-related visual impairment. As there are over 77 million people with diabetes in India, it is challenging to screen every person with diabetes annually for sight-threatening diabetic retinopathy (DR). Therefore, alternate safe approaches need to be developed so that those at-risk of visual impairment due to DR is identified promptly and treated. METHODS: The project team utilised diverse global health strategies and research methods to co-design work packages to build research capacity and capability to ensure effective, affordable and efficient DR services are made available for the population. The strategies and methods employed included health system strengthening; implementation science; establishing care pathways; co-designing collaborative studies on affordable technologies, developing quality standards and guidelines to decrease variations in care; economic analysis; risk modelling and stratification. Five integrated work packages have been developed to deal with all aspects of DR care. These included implementation of a DR screening programme in the public health system in a district in Kerala, evaluating regional prevalence of diabetes and DR and assessing ideal tests for holistic screening for diabetes and its complications in 20 areas in India, utilising artificial intelligence on retinal images to facilitate DR screening, exploring biomarker and biosensor research to detect people at risk of diabetes complications, estimating cost of blindness in India and risk modelling to develop risk-based screening models for diabetes and its complications. A large collaborative network will be formed to propagate research, promote shared learning and bilateral exchanges between high- and middle-income countries to tackle diabetes-related blindness.

Symptomatic oral squamous papilloma of the uvula - a rare incidental finding.

Oral squamous papillomas are benign neoplasms of the oral cavity that occur commonly on the palate. Albeit benign and often asymptomatic, they may still cause concern due to their appearance, which may mimic other malignant oral pathologies. Human papillomavirus (HPV) is usually implicated in papilloma pathogenesis. We present a rare case of symptomatic oral squamous papilloma arising from the uvula and causing tongue and throat irritation. This benign lesion was excised with electrocautery.

Correction: Long-term clinical outcomes in a cohort of patients with solitary plasmacytoma treated in the modern era.

[This corrects the article DOI: 10.1371/journal.pone.0219857.].

Long-term clinical outcomes in a cohort of patients with solitary plasmacytoma treated in the modern era.

BACKGROUND: The risk of recurrence of solitary plasmacytoma (SP)/progression to MM is well established, but patient, imaging and treatment factors influencing risk of progression require further evaluation. METHODS: This is a retrospective analysis of 66 SP patients (23 UK, 43 Brazil) diagnosed 1989-2016. Patient baseline characteristics were recorded. The incidence of progression to MM was calculated, including biochemical and imaging findings and the treatment modality received. Survival estimates were determined by Kaplan-Meier analyses. RESULTS: With a median follow-up of 53.6 months the 5 year overall survival (OS) was 90.7% (95%CI 79-96%). The median progression free survival (PFS) from diagnosis was 61 months. Cumulative incidence of progression to MM was 49.9% at 5 years (95% CI 35.6-62.6%) and was significantly higher with bone plasmacytoma (47.2%, 95%CI 31.9-61.1%), than an extramedullary location (8.3%, 95%CI 0.4-32.3%, Gray test p = 0.0095)). The majority of patients with solitary bony plasmacytoma (SBP) received radiotherapy (RT) (51/53, 96.2%) whereas most extramedullary cases were treated with surgical resection (7/13, 53.8%). A small proportion of SBP patients received additional upfront chemotherapy, with 5/6 in remission after a median follow-up (FU) of 10 years. The diagnostic yield of surveillance functional FU imaging without other indications of relapse/progression was low. The positive predictive value of functional FU imaging was high but with a low negative predictive value, especially in cases of suspected relapse/progression. CONCLUSION: Our data suggests functional imaging should be used if clinical suspicion of relapse/progression, rather than a routine surveillance tool, and upfront adjuvant chemotherapy is worthy of prospective evaluation.

Rhizoremediation of metals: harnessing microbial communities.

With the increasing successful stories of decontamination, different strategies for metal remediation are gaining importance and popularization in developing countries. Rhizoremediation, is one such promising option that harnesses the impressive capabilities of microorganisms associated with roots to degrade organic pollutants and transform toxic metals. Since it is a plant based in-situ phytorestoration technique it is proven to be economical, efficient and easy to implement under field conditions.Plants grown in metal contaminated sites harbor unique metal tolerant and resistant microbial communities in their rhizosphere. These rhizo-microflora secrete plant growth promoting substances, siderophores, phytochelators to alleviate metal toxicity, enhance the bioavailability of metals (phytoremediation) and complexation of metals (phytostabilisation). Selection of right bacteria/consortia and inoculation to seed/ roots of suitable plant species will widen the perspectives of rhizoremediation.

Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 assimilate cholesterol and modulate ABCA1, CD36, NPC1L1 and SCARB1 in vitro.

There is growing interest in the use of probiotic lactic acid bacteria (LAB) for prevention of hypercholesterolaemia. This study assessed the cholesterol lowering ability of Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 in growth media. Both LAB yielded >98% (39.2 µg/ml) cholesterol lowering in growth media. Nile Red staining indicated direct assimilation of cholesterol by the LAB. The LAB were then explored for their prophylactic (pre-treatment of HT29 cells with LAB prior to cholesterol exposure) and biotherapeutic (treatment of HT29 cells with LAB after exposure to cholesterol) use against short and prolonged exposure of HT29 cells to cholesterol, respectively. For HT29 cells pre-treated with LAB, cholesterol lowering was accompanied by down-regulation of ATP-binding cassette family transporter-type A1 (ABCA1), cluster of differentiation 36 (CD36) and scavenger receptor class B member 1 (SCARB1). HT29 cells treated with LAB after prolonged exposure to cholesterol source, on the other hand, was associated with up-regulation of ABCA1, restoration of CD36 to basal level and down-regulation of Neimann-Pick C1-Like 1 (NPC1L1). The present findings implied the potential use of LAB4 and LAB12 as part of the strategies in prevention and management of hypercholesterolaemia.

High Per formance and Flexible Supercapacitors based on Carbonized Bamboo Fibers for Wide Temperature Applications.

High performance carbonized bamboo fibers were synthesized for a wide range of temperature dependent energy storage applications. The structural and electrochemical properties of the carbonized bamboo fibers were studied for flexible supercapacitor applications. The galvanostatic charge-discharge studies on carbonized fibers exhibited specific capacity of ~510F/g at 0.4 A/g with energy density of 54 Wh/kg. Interestingly, the carbonized bamboo fibers displayed excellent charge storage stability without any appreciable degradation in charge storage capacity over 5,000 charge-discharge cycles. The symmetrical supercapacitor device fabricated using these carbonized bamboo fibers exhibited an areal capacitance of ~1.55 F/cm(2) at room temperature. In addition to high charge storage capacity and cyclic stability, the device showed excellent flexibility without any degradation to charge storage capacity on bending the electrode. The performance of the supercapacitor device exhibited ~65% improvement at 70 °C compare to that at 10 °C. Our studies suggest that carbonized bamboo fibers are promising candidates for stable, high performance and flexible supercapacitor devices.

Effect of orally administered soy milk fermented with Lactobacillus plantarum LAB12 and physical exercise on murine immune responses.

Probiotics are live microorganisms that confer health benefits through the gastrointestinal microbiota. This nutritional supplement may benefit athletes who undergo rigorous training by maintaining their gastrointestinal functions and overall health. In this study the influence of moderate physical exercise using a graded treadmill exercise, alone or in combination with the consumption of a soy product fermented with Lactobacillus plantarum LAB12 (LAB12), on tumour necrosis factor alpha (TNF-α) responses was investigated in a murine model. Male BALB/c mice were randomly divided into four groups of six mice each (control, exercise alone, LAB12 and LAB12 + exercise). Mice treated with the potential probiotic LAB12 were orally gavaged for 42 days. At autopsy, blood and spleen from the animals were collected. The splenocytes were cultured in the presence of a mitogen, concanavalin A (Con A). The amount of TNF-α produced by the Con A-stimulated splenocytes was quantified using ELISA, while their proliferation was determined using the [(3)H]-thymidine incorporation method. This study shows that LAB12-supplemented and exercise-induced mice showed marked increase (P<0.05) in cell proliferation compared to the control animals. TNF-α production was suppressed (P<0.05) in the LAB12 group compared to the untreated mice. These results demonstrate that supplementation with LAB12 has immunomodulatory effects, under conditions of moderate physical exercise, which may have implications for human athletes. Further investigation in human trials is warranted to confirm and extrapolate these findings.

Monocyclic L-nucleosides with type 1 cytokine-inducing activity.

A series of 1,2,4-triazole L-nucleosides were synthesized and evaluated for their ability to stimulate type 1 cytokine production by activated human T cells in direct comparison to the known active agent ribavirin. Among the compounds prepared, 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamide (5, ICN 17261) was found to be the most uniformly potent compound. Conversion of the 3-carboxamide group of 5 to a carboxamidine functionality resulted in 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (10), which induced cytokine levels comparable to 5 for two of the three type 1 cytokines examined. Modification of the carbohydrate moiety of 5 provided compounds of reduced activity. Significantly, ICN 17261 offers interesting immunomodulatory potential for the treatment of diseases where type 1 cytokines play an important role.

Synthesis and antitumor activity of certain 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazines related to formycin prepared via ring closure of a 1,2,4-triazine precursor.

Several 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazines related to formycin were prepared and tested for their antitumor activity in cell culture. Dehydrative coupling of 3-amino-6-hydrazino-1,2,4-triazin-5(4H)-one (5) with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid (6a) and further ring closure of the reaction product (7) provided 6-amino-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazolo[3,4- f]-1,2,4-triazin-8(7H)-one (8). Condensation of 5 with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid chloride (6b), followed by ring annulation, also gave 8 in good yield. Debenzoylation of 8 furnished the guanosine analogue 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazin -8(7H)-one (4b). Thiation of 8 with P2S5, followed by debenzoylation of the thiated product (11a), afforded 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazin -8(7H)- thione (11b). Methylation of the sodium salt of 11a gave the 8-methylthio derivative (10), which on ammonolysis furnished 6,8-diamino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazine (9). Diazotization of 10 with tert-butyl nitrite (TBN) and SbCl3 in 1,2-dichloroethane gave the corresponding 6-chloro derivative (12a). Reaction of 10 with TBN in THF in the absence of a halogen source gave 8-(methylthio)-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4- triazolo[3,4-f]-1,2,4-triazine (12b). Ammonolysis of 12b gave the azaformycin A analogue 8-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[3,4-f]-1,2,4-triazine (3), which on deamination afforded 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4- f]-1,2,4-triazin-8(7H)-one (4a). The azaformycin A analogue (3) showed pronounced inhibitory effects against L1210, WIL2, and CCRF-CEM cell lines with ID50 values ranging from 5.0 to 7.3 microM.

Nucleoside peptides. 10. Synthesis and T-cell immunostimulatory properties of certain peptide derivatives of 6-azacadeguomycin.

Several amino acid and peptide conjugates of 6-azacadeguomycin (6-amino-1-beta-D-ribofuranosyl-4,5-dihydro-4-oxopyrazolo[3,4-d]py rimidine- 3-carboxylic acid, 2) have been prepared in good yields, via a two-step procedure involving 1-hydroxybenzotriazole and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride mediated coupling of 2 with an appropriately protected amino acid or peptide, followed by ammonolysis. Thus, condensation of 2 with L-phenylalanine methyl ester, glycine ethyl ester, and L-glutamic acid diethyl ester gave the corresponding protected linear nucleoside peptides (3, 5 and 7, respectively). Subsequent ammonolysis of 3, 5 and 7 furnished L-phenylalanine amide (4), glycine amide (6) and L-glutamic acid diamide (8) conjugates of 6-azacadeguomycin, respectively. Saponification of 7 gave the corresponding L-glutamic acid derivative 9. A similar coupling of 2 with L-phenylalaninyl-N epsilon-nitro-L-arginine methyl ester trifluoroacetate and subsequent ammonolysis (after catalytic hydrogenation) gave L-phenylalaninyl-L-arginine amide conjugate (12) of 6-azacadeguomycin. Compounds 2, 4, 6, 8, 9, and 12 were evaluated for their ability to potentiate T-cell responses to plant mitogens, in comparison with cadeguomycin (1). Compounds 4, 6, and 9 exhibited an increase in the T-cell proliferation in a dose-dependent manner.

Synthesis and antitumor evaluation in mice of certain 7-deazapurine (pyrrolo[2,3-d]pyrimidine) and 3-deazapurine (imidazo[4,5-c]pyridine) nucleosides structurally related to sulfenosine, sulfinosine, and sulfonosine.

7-Deaza (pyrrolo[2,3-d]pyrimidine) and 3-deaza (imidazo[4,5-c]pyridine) congeners of sulfenosine (5a and 9), sulfinosine (6a and 10), and sulfonosine (7a) have been prepared and evaluated for their antileukemic activity in mice. Amination of 2-amino-7-beta-D-ribofuranosylpyrrolo[2,3-d]pyrimidine-4(3H)-th ion e (4a) and its 2'-deoxy analogue (4c) with a chloramine solution gave the corresponding 4-sulfenamides (5a and 5c, respectively), which on selective oxidation with m-chloroperoxybenzoic acid (MCPBA) gave the respective diastereomeric 2-amino-7-beta-D-ribofuranosyl-pyrrolo[2,3-d]pyrimidine-4-sulfinamide (7-deazasulfinosine, 6a) and its 2'-deoxy derivative (6c). A similar amination of 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine-4(3H)- thione (4b) gave the corresponding 4-sulfenamide derivative (5b). Oxidation of 5b with 1 molar equiv of MCPBA furnished (R,S)-7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine- 4- sulfinamide (6b), whereas use of excess of MCPBA afforded the corresponding sulfonamide derivative (7b). Treatment of 3-deaza-6-thioguanosine (8) with a chloramine solution gave 3-deazasulfenosine (6-amino-1-beta-D- ribofuranosylimidazo[4,5-c]pyridine-4-sulfenamide, 9). Controlled oxidation of 9 with MCPBA afforded 3-deazasulfinosine (10). As gauged by increases in the mean postinoculation life spans of L1210 inoculated mice, none of these nucleosides exhibited biologically significant activity (T/C greater than or equal to 125). Even so, antileukemic activity appeared to be influenced, albeit not uniformly, by structural modifications in the base and carbohydrate moieties of sulfenosine and sulfinosine. Thus, while several of the compounds were lacking in cytotoxic activity, eight others (4c, 5a, 5c, 6a, 6b, 7b, 9, and 10) were estimated to have reduced body burdens of viable L1210 cells by 16-77%.