Engineering high affinity antigen-binders: Beyond conventional antibodies.

For decades, antibodies have remained the archetypal binding proteins that can be rapidly produced with high affinity and specificity against virtually any target. A conventional antibody is still considered the prototype of a binding molecule. It is therefore not surprising that antibodies are routinely used in basic scientific and biomedical research, analytical workflows, molecular diagnostics etc. and represent the fastest growing sector in the field of biotechnology. However, several limitations associated with conventional antibodies, including stringent requirement of animal immunizations, mammalian cells for expression, issues on stability and aggregation, bulkier size and the overall time and cost of production has propelled evolution of concepts along alternative antigen binders. Rapidly evolving protein engineering approaches and high throughput screening platforms have further complemented the development of myriads of classes of non-conventional protein binders including antibody derived as well as non-antibody based molecular scaffolds. These non-canonical binders are finding use across disciplines of which diagnostics and therapeutics are the most noteworthy.

Immunotherapy guided precision medicine in solid tumors.

Cancer is no longer recognized as a single disease but a collection of diseases each with its defining characteristics and behavior. Even within the same cancer type, there can be substantial heterogeneity at the molecular level. Cancer cells often accumulate various genetic mutations and epigenetic alterations over time, leading to a coexistence of distinct subpopulations of cells within the tumor. This tumor heterogeneity arises not only due to clonal outgrowth of cells with genetic mutations, but also due to interactions of tumor cells with the tumor microenvironment (TME). The latter is a dynamic ecosystem that includes cancer cells, immune cells, fibroblasts, endothelial cells, stromal cells, blood vessels, and extracellular matrix components, tumor-associated macrophages and secreted molecules. The complex interplay between tumor heterogeneity and the TME makes it difficult to develop one-size-fits-all treatments and is often the cause of therapeutic failure and resistance in solid cancers. Technological advances in the post-genomic era have given us cues regarding spatial and temporal tumor heterogeneity. Armed with this knowledge, oncologists are trying to target the unique genomic, epigenetic, and molecular landscape in the tumor cell that causes its oncogenic transformation in a particular patient. This has ushered in the era of personalized precision medicine (PPM). Immunotherapy, on the other hand, involves leveraging the body's immune system to recognize and attack cancer cells and spare healthy cells from the damage induced by radiation and chemotherapy. Combining PPM and immunotherapy represents a paradigm shift in cancer treatment and has emerged as a promising treatment modality for several solid cancers. In this chapter, we summarise major types of cancer immunotherapy and discuss how they are being used for precision medicine in different solid tumors.

A journey from omics to clinicomics in solid cancers: Success stories and challenges.

The word 'cancer' encompasses a heterogenous group of distinct disease types characterized by a spectrum of pathological features, genetic alterations and response to therapies. According to the World Health Organization, cancer is the second leading cause of death worldwide, responsible for one in six deaths and hence imposes a significant burden on global healthcare systems. High-throughput omics technologies combined with advanced imaging tools, have revolutionized our ability to interrogate the molecular landscape of tumors and has provided unprecedented understanding of the disease. Yet, there is a gap between basic research discoveries and their translation into clinically meaningful therapies for improving patient care. To bridge this gap, there is a need to analyse the vast amounts of high dimensional datasets from multi-omics platforms. The integration of multi-omics data with clinical information like patient history, histological examination and imaging has led to the novel concept of clinicomics and may expedite the bench-to-bedside transition in cancer. The journey from omics to clinicomics has gained momentum with development of radiomics which involves extracting quantitative features from medical imaging data with the help of deep learning and artificial intelligence (AI) tools. These features capture detailed information about the tumor's shape, texture, intensity, and spatial distribution. Together, the related fields of multiomics, translational bioinformatics, radiomics and clinicomics may provide evidence-based recommendations tailored to the individual cancer patient's molecular profile and clinical characteristics. In this chapter, we summarize multiomics studies in solid cancers with a specific focus on breast cancer. We also review machine learning and AI based algorithms and their use in cancer diagnosis, subtyping, prognosis and predicting treatment resistance and relapse.

Genetic association of IL1B gene variants with primary glaucoma in a North Indian Punjabi cohort: An original study and meta-analysis.

Interleukin (IL) 1B is an important candidate gene in glaucoma pathogenesis as it affects the survival of retinal ganglion cells (RGCs). In the present study, -511T/C and +3953C/T polymorphisms in the IL1B were assessed as genetic risk factors for primary open angle (POAG) and angle closure glaucoma (PACG) in a North Indian Punjabi cohort comprising 867 samples (POAG cases = 307; PACG cases = 133 and controls = 427). Genetic association, diplotype and linkage disequilibrium (LD) analyses were performed. Corrections for confounding variables and multiple testing were applied. An updated meta-analysis was also performed. Pooled OR with 95% CI was calculated for dominant, over dominant, and recessive models. Level of heterozygosity among studies was tested using I2 statistic with fixed or random effect model based on the extent of heterogeneity. For -511T > C polymorphism, a positive association was observed with PACG under dominant (p = 0.038; OR = 0.65; pcorr = 0.011; OR = 0.55) and over dominant models (p = 0.010; OR = 0.59; pcorr = 0.001; OR = 0.46). Significant association of +3953C > T was also observed with POAG under dominant (p = 0.011; OR = 1.46; pcorr = 0.018; OR = 1.48) and PACG under recessive models (p < 0.0001; OR = 4.47; pcorr<0.0001; OR = 4.06). While C-C diplotype provided protection against primary glaucoma (0.67-fold; p = 0.0004), T-T and T-C diplotypes predisposed individuals to higher risk (1.31-fold; p = 0.030 and 1.36-fold; p = 0.022 respectively). In meta-analysis, a significant association between +3453 C>T and POAG was observed under dominant (pooled OR = 1.33, p = 0.0046) and over dominant (pooled OR = 1.25; p = 0.0269) models with overall heterogeneity of 15% and 0% respectively. The study provides strong evidence of IL1B variants in modifying genetic susceptibility to primary glaucoma in the targeted North Indian Punjabi population. Replication of the present findings in other populations, and functional studies are warranted to further assess the relevance of IL1B variants in the pathogenesis of primary glaucoma.

Recent advances in co-digestion conjugates for anaerobic digestion of food waste.

Anaerobic digestion (AD) is a biological process that breaks down organic waste materials, such as food waste (FW) that produces biogas and digestate. The biogas can be utilized as biofuel, and digestate could be applied as fertilizer. However, AD of FW alone has limitations on optimal degradation, digester stability and biogas yield. Co-digestion of FW along with other organic wastes such as animal manure, agricultural residue, sewage sludge and industrial organic waste, has shown substantial improvement in degradation process with increased biogas yield. The inadequacies in FW for optimum AD, like low carbon-to-nitrogen ratio (C/N ratio), lack of trace elements and irregular particle sizes, can be nullified by adding appropriate co-digestion conjugates. This review aims to describe the characteristic inadequacies of FW and examines the effect on mesophilic co-digestion of FW with animal manure, waste sludge and agricultural wastes for biogas production optimization. A critical review on the impact of pretreatment and co-digestion to enrich the methane (CH4) content in biogas has been performed. The review also examines the microbial community shift due to co-digestion, which is critical for the stability of an anaerobic digester. Finally, it discusses the prospects and challenges for the widespread application of the co-digestion technique as an effective organic waste management practice.

Prediction of an immunogenic peptide ensemble and multi-subunit vaccine for Visceral leishmaniasis using bioinformatics approaches.

Visceral Leishmaniasis (VL) is a neglected tropical disease of public health importance in the Indian subcontinent. Despite consistent elimination initiatives, the disease has not yet been eliminated and there is an increased risk of resurgence from active VL reservoirs including asymptomatic, post kala azar dermatitis leishmaniasis (PKDL) and HIV-VL co-infected individuals. To achieve complete elimination and sustain it in the long term, a prophylactic vaccine, which can elicit long lasting immunity, is desirable. In this study, we employed immunoinformatic tools to design a multi-subunit epitope vaccine for the Indian population by targeting antigenic secretory proteins screened from the Leishmania donovani proteome. Out of 8014 proteins, 277 secretory proteins were screened for their cellular location and proteomic evidence. Through NCBI BlastP, unique fragments of the proteins were cropped, and their antigenicity was evaluated. B-cell, HTL and CTL epitopes as well as IFN-ɣ, IL-17, and IL-10 inducers were predicted, manually mapped to the fragments and common regions were tabulated forming a peptide ensemble. The ensemble was evaluated for Class I MHC immunogenicity and toxicity. Further, immunogenic peptides were randomly selected and used to design vaccine constructs. Eight vaccine constructs were generated by linking random peptides with GS linkers. Synthetic TLR-4 agonist, RS09 was used as an adjuvant and linked with the constructs using EAAK linkers. The predicted population coverage of the constructs was ∼99.8 % in the Indian as well as South Asian populations. The most antigenic, nontoxic, non-allergic construct was chosen for the prediction of secondary and tertiary structures. The 3D structures were refined and analyzed using Ramachandran plot and Z-scores. The construct was docked with TLR-4 receptor. Molecular dynamic simulation was performed to check for the stability of the docked complex. Comparative in silico immune simulation studies showed that the predicted construct elicited humoral and cell-mediated immunity in human host comparable to that elicited by Leish-F3, which is a promising vaccine candidate for human VL.

Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug.

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.

Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism.

Metabolic features of the tumor microenvironment (TME) antagonize anti-tumor immunity. We hypothesized that T cell infiltrated tumors with a known antigen should exhibit superior clinical outcomes, though some fare worse given unfavorable metabolic features leveraging T cell-infiltrated (Thi), human papillomavirus-related (HPV+) head and neck squamous cell carcinomas (HNSC) to test this hypothesis. Expression of 2,520 metabolic genes were analyzed among Thi HPV+ HNSCs stratified by high-risk molecular subtype. RNAseq data from The Cancer Genome Atlas (TCGA; 10 cancer types), single cell RNAseq data, and an immunotherapy-treated melanoma cohort were used to test the association between metabolic gene expression and clinical outcomes and contribution of tumor versus stromal cells to metabolic gene expression. Polyamine (PA) metabolism genes were overexpressed in high-risk, Thi HPV+ HNSCs. Genes involved in PA biosynthesis and transport were associated with T cell infiltration, recurrent or persistent cancer, overall survival status, primary site, molecular subtype, and MYC genomic alterations. PA biogenesis gene sets were associated with tumor intrinsic features while myeloid cells in HPV+ HNSCs were enriched in PA catabolism, regulatory, transport, putrescine, and spermidine gene set expression. PA gene set expression also correlated with IFNγ or cytotoxic T cell ssGSEA scores across TCGA tumor types. PA transport ssGSEA scores were associated with poor survival whereas putrescine ssGSEA scores portended better survival for several tumor types. Thi melanomas enriched in PA synthesis or combined gene set expression exhibited worse anti-PD-1 responses. These data address hurdles to anti-tumor immunity warranting further investigation of divergent polyamine metabolism in the TME.

Therapeutic approaches for the treatment of head and neck squamous cell carcinoma-An update on clinical trials.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer with a tobacco consumption and infection with high-risk human papillomavirus (HPV) being major risk factors. Despite advances in numerous therapy modalities, survival rates for HNSCC have not improved considerably; a vast number of clinical outcomes have demonstrated that a combination strategy (the most well-known docetaxel, cisplatin, and 5-fluorouracil) is the most effective treatment choice. Immunotherapy that targets immunological checkpoints is being tested in a number of clinical trials, either alone or in conjunction with chemotherapeutic or targeted therapeutic drugs. Various monoclonal antibodies, such as cetuximab and bevacizumab, which target the EGFR and VEGFR, respectively, as well as other signaling pathway inhibitors, such as temsirolimus and rapamycin, are also being studied for the treatment of HNSCC. We have reviewed the primary targets in active clinical studies in this study, with a particular focus on the medications and drug targets used.

A Dual-Channel PPG Readout System With Motion-Tolerant Adaptability for OLED-OPD Sensors.

An adaptive PPG (Photoplethysmography) readout system for a dual-channel OLED-OPD flexible sensor is designed and developed with motion artifact (<1Hz) and ambient lighting interference successfully compensated without any additional motion sensors. The compensation is made possible by adopting multi-feedbacks and an additional reference OPD channel to cancel effectively DC drifts. In result, the quality of measured PPG is improved to the level such that long-time, continuous quality monitoring of bio-sign such as heart rate (HR) is possible. The readout is designed with an auto-programmable band-pass trans-impedance amplifier (TIA) of a 100dbΩ gain with a continuous-type DC-current cancellation loop. The rest of the readout consists of a 0.5 Hz low-pass filter, an additional second-order band-pass filter (0.1-10Hz), a difference amplifier, a motion reference channel, an analog multiplexer, a programmable gain amplifier (PGA), a digital control and a programmable DAC-PWM based auto-intensity tuned OLED driver. The readout is fabricated in an area of 9 mm2 via the TSMC 180nm process. The experiment result shows that the developed OLED-OPD readout senses well as small as 1nA current, with a measured dynamic range >90dB (1nA to 100 µA) and input-referred noise of 0.26 nA/√H, with power consumption of 460µW. The DC drift is successfully reduced to 1% of its average. The accuracy for heart rate is 96%.

Angiogenin Released from ABCB5+ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis.

Severe angiopathy is a major driver for diabetes-associated secondary complications. Knowledge on the underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+ stromal precursors at the edge of nonhealing diabetic wounds in a murine db/db model, closely mirroring human type 2 diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+ stromal precursors. This compensates for the profoundly reduced angiogenin expression in nontreated murine chronic diabetic wounds. Silencing of angiogenin in ABCB5+ stromal precursors before injection significantly reduced angiogenesis and delayed wound closure in diabetic db/db mice, implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining stromal precursors-based therapies of nonhealing diabetic foot ulcers and other pathologies with impaired angiogenesis.

Is enucleation followed by peripheral ostectomy and Carnoy's solution application an adequate treatment for Odontogenic keratocyst? A case series with up to five years of follow up / A enucleação seguida da osteotomia periférica e a aplicação de solução de Carnoy é um tratamento adequado para o ceratocisto odontogênico? Uma série de casos com acompanhamento de até cinco anos

Objective: To evaluate the treatment outcome of enucleation and peripheral ostectomy with the use of Carnoy's solution for management of Odontogenic keratocyst. Material and Methods: 17 patients with OKC who reported from 2011 to 2015 were included. All the cases were treated by enucleation and peripheral ostectomy of 0.5mm followed by Carnoy's solution cauterization for 4 minutes. All patients were followed up for 4-5 years. Results: All the cases were followed-up by using serial panoramic radiography and clinical evaluation at regular intervals. No recurrence was reported in any of the cases. Conclusion: Treatment of Odontogenic keratocyst by enucleation and 0.5mm of peripheral ostectomy, followed by Carnoy's solution cauterization for 4 minutes is an effective treatment with zero recurrence rates for five years of follow-up (AU)

Objetivo: Avaliar o resultado do tratamento de enucleação e osteotomia periférica com o uso de solução de Carnoy para o manejo do ceratocisto odontogênico (OKC). Material e Métodos: 17 pacientes com OKC com acompanhamento de 2011 a 2015 foram incluídos. Todos os casos foram tratados através da enucleação e osteotomia periférica de 0,5 mm, seguido da cauterização com solução de Carnoy por 4 minutos. Todos os pacientes foram acompanhados por 4-5 anos. Resultados: Todos os casos foram acompanhados por meio de séries de radiografias panorâmicas e avaliação clínica em intervalos regulares. Nenhuma recorrência foi reportada em nenhum dos casos. Conclusão: O tratamento de ceratocisto odontogênico por meio da enucleação e osteotomia periférica de 0,5mm, seguido da cauterização com solução de Carnoy por 4 minutos é um tratamento efetivo com zero taxa de recorrência em um acompanhamento de 5 anos. (AU)

Use of Foley's catheter as a tourniquet for the management of vascular lesion of lip in Mowat-Wilson syndrome.

BACKGROUND: Vascular malformation of lower lip is a very rare anomaly. The lesion leads to facial asymmetry, difficulty in speech and eating and drooling of saliva. Treatment goals include symmetrical reconstruction of the lip with minimal scarring, provide adequate bulk for the reconstruction of vermillion, in toto removal of the lesion and prevent recurrence. The most common complication during surgical removal of these lesions includes blood loss and profuse bleeding which leads to poor visibility, increased operation time and postoperative requirement of blood transfusion. Therefore, the use of sclerosing agent is recommended before surgical removal. This may help in decreasing bleeding during surgery but not in all cases. CASE REPORT: Here, we report the use of Foley's catheter for the management of a high flow lesion of lower lip in a 12-year-old patient diagnosed with Mowat-Wilson syndrome. This technique helped in providing bloodless field which lead to minimal blood loss and good visibility intraoperatively.

Suggestive evidence of genetic association of -572G > C polymorphism with primary open angle glaucoma in a North Indian Punjabi population.

BACKGROUND: IL6 is an important candidate gene implicated in the pathogenesis of glaucoma. The present study assessed the genetic association of -174G > C and -572G > C polymorphisms in the IL6 promoter region with primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) in a north Indian Punjabi cohort. METHODS: 910 subjects (313 POAG, 148 PACG cases and 449 controls) were recruited. Genotyping was done by TaqMan assays. Genetic association was tested under different genetic models using Plink. Diplotype and linkage disequilibrium (LD) analysis was done through Haploview. Association of clinical parameters with the genotypes was assessed by one-way ANOVA. Adjustment for potential confounding variables was done by binary logistic regression. IL6 levels were measured in POAG patients and controls. RESULTS: 572G > C variant showed marginal difference in genotype frequency between pooled cases and POAG subgroup with respect to controls (p = 0.042; OR = 1.33; and p = 0.041; OR = 1.37). The GC genotype conferred 1.37-fold protection under codominant model in POAG cases (p = 0.034, OR = 1.37, 95% CI = 1.02-1.85; pcorr = 0.025, OR = 1.45, 95% CI = 1.04-2.02). The mean value for IOP was elevated among cases having 'CC' genotype at the -572G > C locus (p = 0.037). Lower levels of IL6 were detected in POAG patients in plasma samples (p = 0.0001). CONCLUSION: The study reports suggestive evidence for -572G > C variant in IL6 in affecting genetic susceptibility to POAG in the targeted North Indian Punjabi cohort. A correlation of IL6 levels in aqueous humor (AH) and systemic circulation in POAG was observed, the functional and diagnostic relevance of which may be further investigated.

Signal transducer and activator of transcription-3 mediated neuroprotective effect of interleukin-6 on cobalt chloride mimetic hypoxic cell death in R28 cells.

BACKGROUND: Hypoxic injury to retinal ganglionic cells and adjoining glia is implicated in glaucomatous optic neuropathy. The present study evaluates the effect of IL-6 on R28 retinal precursor cell line exposed to hypoxic injury. METHODS AND RESULTS: Apoptotic cell death induced by hypoxia mimetic CoCl2 in R28 cells with or without IL-6 treatment was measured using cell viability assays and apoptotic markers. Oxidative stress was also measured. Hypoxia induced by mimetic CoCl2 led to a time and concentration dependent apoptosis of cells mediated by disruption of mitochondrial membrane potential and activation of caspase 3. Cells pre-treated with IL-6 demonstrated significantly higher viability and mitochondrial integrity under hypoxic conditions. A critical role of STAT3 was observed in mediating the cytoprotective effects of IL-6. Treatment of cells with IL-6 led to STAT3-mediated expression of the Bcl-2 family proteins and MnSOD. CONCLUSIONS: The data from the present study indicate cytoprotective role of IL-6 and suggest a previously unreported mechanism of neuroprotection via STAT3 mediated signaling.

Association of TGFB -509C>T promoter polymorphism with primary angle closure glaucoma in a North Indian Punjabi cohort.

PURPOSE: Transforming growth factor beta (TGFB) is an important candidate gene implicated in glaucoma pathogenesis because it affects retinal ganglionic cell survival. The present study assessed the genetic association of -509C > T variant in the TGFB promoter region with primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) in a North Indian Punjabi population. METHOD: A total of 867 subjects (307 POAG, 133 PACG cases and 427 controls) were recruited from the targeted population. Genotyping was done by PCR-RFLP method and the data was analyzed using PLINK software (v1.07). Logistic regression under different genetic models was applied and genotype phenotype correlation was assessed by one-way ANOVA. RESULT: A statistically significant difference in the frequency of heterozygotes among PACG cases (53.16%) and controls (30.07%) (p = 0.0002) was observed. Genetic model analysis revealed that mutant "TT" genotype conferred 2-fold risk towards PACG development under recessive model (p = 0.0019) while dominant model and co-dominant model provided 0.62 and 0.37 fold protection against PACG (p = 0.025 and p = 0.0001, respectively). Data segregation based on sex revealed a strong protective effect of heterozygous 'CT' genotype against progression of PACG among females (p = 0.002, OR = 0.37, 95% CI = 0.19-0.70), but conferred 2.14-fold risk among female POAG subjects (p = 0.013). CONCLUSION: The study revealed a strong genetic association of -509C > T variant in TGFB with PACG in females. There is a need to replicate the results in a larger PACG cohort in other populations and further assess the contribution of sex specific factors in modifying genetic susceptibility to PACG.

Neutrophils and Visceral Leishmaniasis: Impact on innate immune response and cross-talks with macrophages and dendritic cells.

Neutrophils with their array of microbicidal activities are the first innate immune cells to guard against infection. They are also most crucial for the host's initial defense against Leishmania parasites which cause clinically diverse diseases ranging from self-healing cutaneous leishmaniasis (CL) to a more severe visceral form, visceral leishmaniasis (VL). Neutrophils are recruited in large numbers at the infection site after bite of sandfly, which is the vector for the disease. The initial interaction of neutrophils with the parasites may modulate the subsequent innate and adaptive immune responses and hence affect the disease outcome. The purpose of this review is to comprehensively appraise the role of neutrophils during the early stages of Leishmania infection with a focus on the visceral form of the disease. In the past decade, new insights regarding the role of neutrophils in VL have surfaced which have been extensively elaborated in the present review. In addition, since much of the information regarding neutrophil-Leishmania early interaction has accumulated through studies on mouse models of CL, these studies are also revisited. We begin by reviewing the factors which drive the recruitment of neutrophils at the site of injection by the sandfly. We then discuss the studies delineating the molecular mechanisms involved in the uptake of the Leishmania parasite by neutrophils and how the parasite subverts their microbicidal functions. In the end, the interaction of infected neutrophils with macrophages and dendritic cells is summarized.

External temperature sensor assisted a new low power photoplethysmography readout system for accurate measurement of the bio-signs.

This study presents an external temperature sensor assisted a new low power, time-interleave, wide dynamic range, and low DC drift photoplethysmography (PPG) signal acquisition system to obtain the accurate measurement of various bio signs in real-time. The designed chip incorporates a 2-bit control programmable transimpedance amplifier (TIA), a high order filter, a 3:8 programmable gain amplifier (PGA) and 2 × 2 organic light-emitting diode (OLED) driver. Temperature sensor is used herein to compensate the adverse effect of low-skin-temperature on the PPG signal quality. The analog front-end circuit is implemented in the integrated chip with chip area of 2008 µm × 1377 µm and fabricated via TSMC T18 process. With the standard 1.8 V, the experimental result shows that the measured current sensing range is 20 nA-100 uA. The measured dynamic range of the designed readout circuit is 80 dB. The estimated signal to noise ratio is 60 dB@1 uA, and the measured input referred noise is 60.2 pA/Hz½. The total power consumption of the designed chip is 31.32 µW (readout) + 1.62 mW (OLED driver@100% duty cycle). The non-invasive PPG sensor is applied to the wrist artery of the 40 healthy subjects for sensing the pulsation of the blood vessel. The experimental results show that for every 1 °C decrease in mean ambient temperature tends to 0.06 beats/min, 0.125 mmHg and 0.063 mmHg increase in hear rate (HR), systolic (SBP) and diastolic (DBP), respectively. Similarly, for every 1 °C increase in mean ambient temperature tends to 0.13 beats/min, 0.601 mmHg and 0.121 mmHg increase in HR, SBP and DBP, respectively. The measured accuracy and standard error for the HR estimation are 96%, and - 0.022 ± 2.589 beats/minute, respectively. The oxygen stauration (SpO2) measurement results shows that the mean absolute percentage error is less than 5%. The resultant errors for the SBP and DBP measurement are - 0.318 ± 5.19 mmHg and - 0.5 ± 1.91 mmHg, respectively.

A Comparative Study Between Concentric Single-Needle Puncture Technique and Conventional 2-Needle Technique for Temporomandibular Joint Arthrocentesis Plus Corticosteroid Injections.

The purpose of the study was to compare 2 techniques of arthrocentesis, to find out the efficacy of one over the other at various parameters, and to contribute to the scarce literature of these 2 techniques. Forty patients reported with a chief complaint of pain in temporomandibular joint (TMJ), clicking in TMJ, and restricted mouth opening were included in this study. Twenty patients were divided into 2 groups, all reporting with temporomandibular disorders. Group A was treated with 2-needle technique of arthrocentesis, while group B underwent concentric needle technique of arthrocentesis under local anesthesia with Ringer's lactate solution. The operating time was found to be less in concentric needle technique (mean: 25.36 minutes) compared to 2-needle technique (mean: 42.82 minutes), and the difference was found to be statistically significant. Concentric needle technique proved to be a better alternative for TMJ arthrocentesis as it has quite a lot of advantages over 2-needle technique.

IL-10 and TGF-ß Induced Arginase Expression Contributes to Deficient Nitric Oxide Response in Human Visceral Leishmaniasis.

Nitric oxide (NO) is an anti-microbial effector of the innate immune system which plays major role in non-specific killing of various pathogens including protozoan parasites. However, due to subversion of the host's immune processes by pathogens, suboptimal production of NO is frequently found in many infection models. Previous studies have shown suppressed NO production during Leishmania donovani infection, the causative agent of visceral leishmaniasis (VL). Availability of L-Arginine, a semi-essential amino acid is required for inducible nitric oxide synthase (iNOS) mediated NO production. However, arginase is another enzyme, which if expressed concomitantly, may strongly compete for L-Arginine, and suppress NO production by iNOS. In the present study, plasma nitrite and arginase levels were measured in VL patients before and after successful drug treatment, endemic and non-endemic healthy donors. We observed significantly lower NO levels in the plasma of VL patients as compared to endemic controls, which improved significantly post-treatment. Significantly elevated arginase activity was also observed in the plasma of VL patients, which may be associated with NO deficiency. VL patients also showed significantly higher levels of IL-10 and TGF-ß, which are known to regulate expression of arginase in various immune cells. In vitro studies with human peripheral blood mononuclear cells (PBMCs) further corroborated the role of IL-10 and TGF-ß in arginase mediated suppression of NO production.