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Background: Hyponatremia, dened as a serum sodium concentration 0.05). The odds of complications (including death) was 2.91 times in the cases with hyponatremia as compared to cases with normal serum sodium levels, 2.47 times in the cases with mild hyponatremia as compared to cases with normal serum sodium levels, 3.42 times in the cases with moderate hyponatremia as compared to cases with normal serum sodium levels and 25 times in the cases severe hyponatremia as compared to cases with normal serum sodium levels. Conclusion: It can be concluded that the severity of MI is more in cases with hyponatremia and hyponatremia is associated with poorer outcomes in terms of complications post MI and mortality.

CD229 has been found to be a useful plasma cell (PC) gating marker in multiple myeloma (MM). This study analyses the expression profile of CD229 on various bone marrow compartments namely, PC, non-PC and hematogones (HGs) using Multiparameter flow cytometry (MFC). Furthermore, it evaluates the ability of CD229 to delineate normal PC (NPC) from aberrant PC (APC) in measurable residual disease assessment (MRD) in MM.Bone marrow aspirates from patients diagnosed with MM (per standard IMWG criteria) were collected in EDTA and processed for MFC using a single tube 14-color antibody panel as per standard operating procedure.A total of 74 patients with a diagnosis of MM (26 treatment naïve and 48 on therapy) were evaluated. The expression of CD229 was homogenous on both the PC and HG compartments as compared to CD138 and CD38. On comparing the expression of individual markers, it was found to be statistically significant between PC, HGs and non-PC for all three markers (p 0.001). APC showed lower median expression of CD38 and higher median expression of CD138 and CD229 as compared to NPC and was found to be statistically significant for all markers (p 0.001). In terms of differential expression on NPC and APC; CD38 was found to be the most aberrantly expressed (70%; 52/74) followed by CD229 (7%; 5/74) and CD138 (5%; 4/74).CD229 can be used for the identification of PC and due to relatively homogenous expression; it can be used as a suitable marker for targeted therapies. However, precise discrimination of NPC from APC cannot be reliably achieved with CD229, limiting its utility as a useful marker of diagnostic relevance and MRD assessment in MM.

Disorders of sexual development are a heterogeneous group of disorders in which chromosomal, gonadal or anatomical sex development is atypical. The majority of these children are recognized at birth by ambiguous genitalia. Legal and societal pressures require the physician and parents to assign sex rapidly. Though sex assignment is undebated in several disorders of sexual development, many others need an individualized approach to gender-related concerns. Gender dysphoria is prevalent in disorders of sexual development, and early gender-defining surgeries have potentially lifelong consequences. We use two cases, one of partial androgen insensitivity and another of simple virilizing congenital adrenal hyperplasia to illustrate that in disorders of sexual development, the ethical management principles remain the same at their core despite the vast differences in phenotypes. Sex assignment should maximize functional, psychological and sexual needs. Sex assigned should coincide with gender identity. We propose that we manage such children with the mutual participation of the physician, parents and the child. Though the parents and the physician have the child's best interests when making a decision, the child's developing autonomy should be protected. The communication of the health provider to the parent must be honest if early sex assignment is difficult.

The expression pattern of common antigens including cytoplasmic kappa/lambda ratio (cyKLR) was evaluated by flow cytometric immunophenotyping (FCMI) to explore their relevance in discriminating normal and aberrant plasma cells (NPC and APC, respectively) across spectrum of plasma cell proliferative disorders (PCPD).In this prospective analysis, 791 samples from PCPD (treatment naive = 455; partially treated = 336) were evaluated for expression of CD38, CD138, CD45, CD19, CD56, CD27, CD81, CD117, Cy-kappa, and Cy-lambda using FCMI.Amongst the entire cohort, 20.7% (n = 164) samples displayed only APC, 21% (n = 165) only NPC and 58% (n = 462) showed coexistence of NPC and APC. Using pattern-based recognition (PBR) for three common patterns (CD19 vs. CD56; CD27 vs. CD56 and CD19 vs. CD27), APC was separable from NPC in 93% samples. In 6.5% samples, the gating markers contributed in APC-NPC differentiation and in the remaining 0.5% CD117 and CD81 proved useful. Clonality assessment was found to be crucial to label plasma cell compartment as completely normal or aberrant in 42% cases with either all NPC or all APC. Sixty one out of 462 cases (13%) revealed cyKLR within normal reference range and in these cases; abnormal cyKLR was demonstrable only after gating APC separately based on PBR.Fair discrimination between NPC and APC is achievable in all PCPD samples using eight markers (Gating: CD38, CD138, CD45; PBR:CD19, CD56, CD27; clonality: Cy-kappa and Cy-lambda). Thus, combined assessment of clonality and immunophenotypic aberrancies is required for accurate, reliable and precise assessment of NPC and APC compartments in PCPD.

Neuromyelitis Optica spectrum disorder or Devic's disease is an autoimmune disease characterized by by acute inammation of the optic nerve and spinal cord. A relapsing disease course is common, especially in untreated patients. In more than 80% cases it is caused by immunoglobulin G autoantibodies to aquaporin 4 the most abundant water channel protein in the central nervous system. Episodes of optic neuritis and myelitis can be simultaneous or successive.

CD34 and HLA-DR negativity is often used as a characteristic immunophenotypic feature of acute promyelocytic leukaemia (APL) that differentiates APL from other subtypes of acute myeloid leukaemia (AML). However, other subtypes of AML, without expression of CD34 and HLA-DR antigens, have also been reported.We analysed the HLA-DR negative de novo non-APL AML cases by dividing HLA-DR negative non-APL group into 2 sub-groups based on CD34 expression and compared the characteristics of CD34 negative HLA-DR negative with CD34 positive HLA-DR negative non-APL AML cases with respect to morphologic, immunophenotypic, molecular and clinical parameters.There were 70 cases (8.54%) which were CD34 negative HLA-DR negative and 52 cases (6.34%) were CD34 positive HLA-DR negative. The median age at diagnosis was higher in CD34 negative HLA-DR negative AML than in CD34 positive HLA-DR negative AML group (38 years vs. 12 years, p 0.001). DIC rate was higher in CD34 negative HLA-DR negative group than the other group (p 0.001). Median total leucocyte count was higher with higher blast count in peripheral blood and bone marrow in CD34 negative HLA-DR negative AML cases than the other group (p 0.05). CD34 negative HLA-DR negative AML was more associated with normal karyotype (96.2% vs. 38.5%; p 0.001), NPM1 mutation (67.8% vs. 8.3%; p 0.001) and FLT-ITD mutation (37.3% vs. 13.9%; p 0.05). In CD34 negative HLA-DR negative group, 16 cases had co-occurrence of NPM1 and FLT3-ITD mutations, whereas no case of CD34 positive HLA-DR negative group had such dual mutation positivity. There was poor median overall survival [3.8 months (95%CI: 2.3-7.8 months) vs. 20.4 months (95% CI: 12.8-25.7 months); p = 0.0148] in CD34 positive HLA-DR negative AML than CD34 negative HLA-DR negative AML cases.We found that the CD34 negative HLADR negative non APL AML is highly associated with NPM1 and FLT3-ITD mutation, older age at diagnosis, DIC, higher total leucocyte count, higher blast counts and normal karyotype in comparison to CD34 positive HLA-DR negative AML group. Co-occurrence of NPM1 and FLT3-ITD mutation was also exclusively seen in CD34 negative HLA-DR negative group. There was poor overall survival in CD34 positive HLA-DR negative AML than CD34 negative HLA-DR negative AML cases.

To gain insights into the idiosyncrasies of CD34 + enriched leukemic stem cells, we investigated the nature and extent of transcriptional heterogeneity by single-cell sequencing in pediatric AML. Whole transcriptome analysis of 28,029 AML single cells was performed using the nanowell cartridge-based barcoding technology. Integrated transcriptional analysis identified unique leukemic stem cell clusters of each patient and intra-patient heterogeneity was revealed by multiple LSC-enriched clusters differing in their cell cycle processes and BCL2 expression. All LSC-enriched clusters exhibited gene expression profile of dormancy and self-renewal. Upregulation of genes involved in non-coding RNA processing and ribonucleoprotein assembly were observed in LSC-enriched clusters relative to HSC. The genes involved in regulation of apoptotic processes, response to cytokine stimulus, and negative regulation of transcription were upregulated in LSC-enriched clusters as compared to the blasts. Validation of top altered genes in LSC-enriched clusters confirmed upregulation of TCF7L2, JUP, ARHGAP25, LPAR6, and PRDX1 genes, and serine/threonine kinases (STK24, STK26). Upregulation of LPAR6 showed trend towards MRD positive status (Odds ratio = 0.126; 95% CI = 0.0144-1.10; p = 0.067) and increased expression of STK26 significantly correlated with higher RFS (HR = 0.231; 95% CI = 0.0506-1.052; p = 0.04). Our findings addressed the inter- and intra-patient diversity within AML LSC and potential signaling and chemoresistance-associated targets that warrant investigation in larger cohort that may guide precision medicine in the near future.

CD123 is overexpressed in many hematologic malignancies and found to be useful in characterizing leukemic blasts of both acute myeloid leukemia (AML) and B-acute lymphoblastic leukemia (B-ALL). CD123 has been recently found to be a marker of leukemic stem cells, and its utility to measure residual disease and potential role in disease relapse is under evaluation.Herein, we have evaluated the expression of CD123 in 757 samples of acute leukemia including 479 treatment-naive and 278 follow-up samples and compared with post-induction morphologic complete remission and measurable residual disease (MRD) status. Multiparametric flow cytometry was used for assessment of CD123 expression and immunophenotypic characterization of leukemic blasts at diagnostic and MRD assessment time points.Using variable cutoffs of 5%, 10%, and 20% to define a case as CD123-positive, expression of CD123 was observed in 75.6%, 66.2%, and 50% of AML and 88.6%, 81.8%, and 75% of B-ALL, respectively. Of 11 patients, 7 (63.63%) had mixed phenotype acute leukemia, but none of the 12 patients with T-acute lymphoblastic leukemia showed positivity for CD123. CD123 expression at diagnosis was associated with post-induction MRD-positive status in both B-ALL (P .001) and AML (P = .001). We also evaluated the utility of CD123 as a leukemia-associated aberrant immunophenotype and found it to be useful in both patients with AML (baseline, 50.6%; follow-up, 53%) and B-ALL (baseline, 75%; follow-up, 73.07%).In conclusion, CD123 may be considered as a cardinal marker for residual disease assessment and response evaluation in AML and B-ALL.

Isolated epididymal torsion is a very rare cause of an acute scrotum. Anomalies of the epididymis are more commonly encountered with undescended testicles and can predispose to epididymal torsion. Management is similar to that of testicular torsion. We report the case of a 3-year-old boy who presented with an acute scrotum. Immediate surgical exploration revealed an isolated epididymal torsion in an undescended testis, only the second of its kind to be reported so far. The epididymis and testis were salvaged and the testis was fixed in the scrotum. There are multiple learning points from this case report. Firstly, that epididymal torsion is a diagnosis to be considered when exploring an acute scrotum. Secondly, that epididymal torsion even an undescended testis can result in clinical symptoms of an acute scrotum. And finally, that epididymal anomalies encountered during surgery should be tackled appropriately, to prevent retorsion.

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism. Scientific evidences suggest that high iron storage may play a role in pathogenesis of type 2 diabetes. Excess iron accumulation induces organ damage due to the overproduction of ROS through Fenton reaction. Thus, the aim of this study was to find out the relation between serum iron, total iron binding capacity (TIBC) and oxidative stress (OS) with glycosylated haemoglobin (HbA1c) in type 2 diabetes mellitus patients. The study consisted of 90 subjects, which were divided into 3 different groups; Group 1 compromised of 30 healthy individuals, Group 2 included 30 T2DM patients with normal glycemic control and Group 3 included 30 T2DM patients with poor glycemic control. Blood samples were collected from the three groups and fasting plasma glucose (FPG), post-prandial plasma glucose (PPPG), HbA1c, Iron, TIBC, Hemoglobin (HB), Malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) levels were analysed. We found, that mean levels of FPG, PPPG, HbA1c, Iron and MDA were significantly higher (p < 0.05) and mean levels of TIBC, SOD and CAT were significantly decreased (p < 0.05) in group 3 as compared to group 2 and group 1. There was no significant difference (p > 0.05) observed in iron, TIBC and Hb levels between group 1 and group 2. We found a significant positive correlation of Iron and MDA with HbA1c and significant negative correlation of TIBC, SOD and CAT with HbA1c in group 3. In our study we found significant positive correlation of HbA1c with MDA and iron that indicates poor glycemic control leads to increased glycation of haemoglobin and other heme containing proteins. It causes more release of iron that leading to production of oxidative stress and thereby it might plays significant role in early appearance of diabetic complications.

Immunophenotypic profile and post-therapy alteration in antigenic expression were evaluated in normal, reactive, and aberrant plasma cells (NPC, RPC, and APC) for impact on measurable residual disease (MRD) assessment in multiple myeloma (MM).Samples from non-MM staging marrow (n = 30), Hodgkin's lymphoma (n = 30) and MM (n = 724) were prospectively evaluated for expression profiles of NPC, RPC, and APC using antigens recommended in consensus guidelines.Polyclonal NPC-RPC demonstrated aberrations for all antigens evaluated with a higher frequency of aberrancies in post-therapy samples compared to treatment naïve samples (p 0.001%). Immunomodulation in APC was observed in 79% of post-therapy samples with a change in expression of 1, 2, and ≥3 antigens in 19.9%, 15.6%, and 43.5% samples, respectively. In 13.4% of samples, APC showed no aberrancy and aberrant status was assigned based on cytoplasmic light chain restriction (cyLCR) alone. 9% samples with an admixture of NPC and APC displayed normal cytoplasmic kappa to lambda ratio (cyKLR) when the percentage of APC of total PC (neoplastic plasma cell index, NPCI), was below 25% and 50% for kappa and lambda restricted cases, respectively.The panorama and high frequency of antigenic aberrations on polyclonal PC signify the importance of MRD assay validation on a large cohort under normal and reactive conditions. Frequent Immunophenotypic shifts in APC re-confirm the redundancy of baseline immunophenotype for MRD evaluation. Small clones of APC may be missed by assessment of cyKLR alone and therefore, surface marker aberrancy supported by cyLCR is required for definitive assignment of residual APC.

Endothelial colony forming cells (ECFCs) participate in neovascularization. Endothelial nitric oxide synthase (eNOS) derived NO· helps in homing of endothelial progenitor cells (EPCs) at the site of vascular injury. The enzyme cofactor tetrahydrobiopterin (BH4) stabilizes the catalytic active state of eNOS. Association of intracellular ECFCs biopterins and ratio of reduced to oxidized biopterin (BH4:BH2) with circulatory EPCs and ECFCs functionality have not been studied. We investigated ECFCs biopterin levels and its association with circulatory EPCs as well as ECFCs proliferative potential in terms of day of appearance in culture. Circulatory EPCs were enumerated by flowcytometry in 53 coronary artery disease (CAD) patients and 42 controls. ECFCs were cultured, characterized, and biopterin levels assessed by high performance liquid chromatography. Appearance of ECFCs’ colony and their number were recorded. Circulatory EPCs were significantly lower in CAD and ECFCs appeared in 56% and 33% of CAD and control subjects, respectively. Intracellular BH4 and BH4:BH2 were significantly reduced in CAD. BH4:BH2 was positively correlated with circulatory EPCs (p = 0.01), and negatively with day of appearance of ECFCs (p = 0.04). Circulatory EPCs negatively correlated with ECFCs appearance (p = 0.02). These findings suggest the role of biopterins in maintaining circulatory EPCs and functional integrity of ECFCs.

Troxerutin (TXR) is a phytochemical reported to possess anti-inflammatory and hepatoprotective effects. In this study, we aimed to exploit the antiarthritic properties of TXR using an adjuvant-induced arthritic (AIA) rat model. AIA-induced rats showed the highest arthritis score at the disease onset and by oral administration of TXR (50, 100, and 200 mg/kg body weight), reduced to basal level in a dose-dependent manner. Isobaric tags for relative and absolute quantitative (iTRAQ) proteomics tool were employed to identify deregulated joint homogenate proteins in AIA and TXR-treated rats to decipher the probable mechanism of TXR action in arthritis. iTRAQ analysis identified a set of 434 proteins with 65 deregulated proteins (log2 case/control≥1.5) in AIA. Expressions of a set of important proteins (AAT, T-kininogen, vimentin, desmin, and nucleophosmin) that could classify AIA from the healthy ones were validated using Western blot analysis. The Western blot data corroborated proteomics findings. In silico protein–protein interaction study of tissue-proteome revealed that complement component 9 (C9), the major building blocks of the membrane attack complex (MAC) responsible for sterile inflammation, get perturbed in AIA. Our dosimetry study suggests that a TXR dose of 200 mg/kg body weight for 15 days is sufficient to bring the arthritis score to basal levels in AIA rats. We have shown the importance of TXR as an antiarthritic agent in the AIA model and after additional investigation, its arthritic ameliorating properties could be exploited for clinical usability.

In the present era, emergence of next generation sequencing approaches has revolutionized the field of gut microbiome study. However, the adopted DNA extraction step used in metagenomics experiments and its efficiency may play a critical role in their reproducibility and outcome. In this study, fecal samples from active and non-tuberculosis subjects (ATB/NTB, n=7) were used. Fecal samples of a subgroup of these subjects were subjected to Mechanical enzymatic lysis (MEL) and Phenol: Chloroform: Isoamyl Alcohol (PCIA) methods of DNA extraction and a third-generation sequencing platform i.e. MinION was employed for microbiome profiling. Findings of this study demonstrated that DNA extraction method significantly impacts the DNA yield and microbial diversity. Irrespective of the adopted method of DNA extraction, ATB patients showed altered microbial diversity compared to NTB controls. Also, the fecal microbial diversity details are better captured in samples processed by MEL method and may be suitable to be adopted for high-throughput gut microbiome studies.

Tuberculosis (TB) patients present dysregulated immunity, iron metabolism and anaemia of inflammation. In this study, circulatory cytokines, trace metals, and iron-related proteins (hepcidin, ferroportin, transferrin, DMT1, Nramp1, ferritin, ceruloplasmin, hemojuvelin, aconitase, transferring receptor) were monitored in case (active tuberculosis patients: ATB) and control (non-tuberculosis: NTB and healthy) study populations (n=72, male, 42.94 mean age (16-83)). Using serum elemental and cytokine levels, a partial least square discriminate analysis model (PLS-DA) was built and variables with a VIP score of >0.6 were selected as important markers. A biosignature of IL-13, IL-12(p70), IFN-γ, IL-10, IL-5, IL-18, IL-4, Selenium, and Aluminium clustered ATB away from controls. Interestingly, low iron and selenium levels, while high copper and aluminum levels were observed in ATB subjects. All the important serum cytokines were positively correlated in ATB subjects. A low abundance of transferrin, ferroportin, and hemojuvelin, while higher ferritin and ceruloplasmin levels explained an altered iron metabolism in ATB subjects which partially resolved upon completion of treatment. Further, the identified biosignature in TB patients, that explained anemia of inflammation, along with perturbed iron homeostasis could be useful targets for the development of host-directed adjunct therapeutics.

A novel method to construct dynamic inversion compensation is proposed for feedforward tracking control. In contrast to common approaches involving parametric system identification followed by inversion synthesis, in this article we apply iterative learning control to track an impulse signal, where the converged control input is directly used to construct the inverse filter. The method is applicable to multivariable systems without a diagonalization process. The proposed method is implemented on a linear motor and an active magnetic bearing system, respectively. The experimental results are presented to demonstrate the feedforward tracking performance.

Background: Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by alveolar accumulation of surfactant material with reduced lung function and resulting hypoxemia. It is characterized by a variable clinical course, and whole lung lavage (WLL) is the standard treatment. Herein, we report our multicentric experience of management of primary PAP. Materials and Methods: This retrospective study included patients with PAP managed at various armed forces respiratory centers from 2009 to 2019. The diagnosis of primary PAP was based on histopathologic confirmation on transbronchial lung biopsy or open lung biopsy and absence of causes of secondary PAP. We analyzed the response to WLL in these patients as well as the safety of the procedure. Results: During the above-specified period, ten patients with a diagnosis of PAP were admitted to various armed forces respiratory centers. The median age of the patients was 34.5 years (range 23–59); there were nine males (90%). The mean duration (± standard deviation) of symptoms was 10.8 (±2.70) months. For management, WLL was done for eight patients with a median volume of 23.5 L (range 18–45) per patient. All the patients showed significant symptomatic response as well as improvement in physiological parameters with no major complications. The median follow-up of all patients was 18 (range 5–44) months. Conclusions: WLL is a safe, effective therapy in an experienced setting in patients with PAP and provides long-lasting benefits.

This paper presents a novel adaptive feedforward control (AFC) method for rejecting sinusoidal disturbances with known frequencies acting on multi-input-multi-output (MIMO) discrete time linear systems based on the H-infinity synthesis. First, the gradient AFC (GAFC) for MIMO systems is reviewed, and the linear time invariant (LTI) equivalent form of the GAFC is approximated for stability analysis. For single-input-single-output (SISO) systems, this paper shows small adaptation gains guarantee the stability of GAFC for any disturbance frequency. Then inspired by the stability of SISO GAFC, the inversion based AFC (IAFC) is proposed for MIMO systems. In this method, the GAFC is compensated by an H-infinity model matching filter, which renders nearly decoupled systems with fixed time delays. The LTI analysis, simulation study and experimental results from an open-loop unstable MIMO Active Magnetic Bearing Spindle (AMBS) are presented to demonstrate the stability and effectiveness of the proposed IAFC in rejecting narrow-band disturbances.

The widespread availability and use of modern synthetic therapeutic agents have led to a massive decline in ethnomedical therapies. However, these synthetic agents often possess toxicity leading to various adverse effects. For instance, anti-tubercular treatment (ATT) is toxic, lengthy, and severely impairs host immunity, resulting in posttreatment vulnerability to reinfection and reactivation of tuberculosis (TB). Incomplete ATT enhances the risk for the generation of multidrug- or extensively drug-resistant (MDR or XDR, respectively) variants of Mycobacterium tuberculosis (M. tb), the TB-causing microbe. Therefore, a new therapeutic approach that minimizes these risks is urgently needed to combat this deadly disease and prevent future TB epidemics. Previously, we have shown that the phytochemical bergenin induces T helper 1 (Th1)– and Th17 cell–based protective immune responses and potently inhibits mycobacterial growth in a murine model of M. tb infection, suggesting bergenin as a potential adjunct agent to TB therapy. Here, we combined ATT therapy with bergenin and found that this combination reduces immune impairment and the length of treatment in mice. We observed that co-treatment with the anti-TB drug isoniazid and bergenin produces additive effects and significantly reduces bacterial loads compared with isoniazid treatment alone. The bergenin co-treatment also reduced isoniazid-induced immune impairment; promoted long-lasting, antigen-specific central memory T cell responses; and acted as a self-propelled vaccine. Of note, bergenin treatment significantly reduced the bacterial burden of a multidrug-resistant TB strain. These observations suggest that bergenin is a potent immunomodulatory agent that could be further explored as a potential adjunct to TB therapy.