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  1. Luedtke JA, Chanson J, Neam K, Hobin L, Maciel AO, Catenazzi A, et al.
    Nature, 2024 Jan;625(7993):E2.
    PMID: 38040869 DOI: 10.1038/s41586-023-06851-6
  2. Luedtke JA, Chanson J, Neam K, Hobin L, Maciel AO, Catenazzi A, et al.
    Nature, 2023 Oct;622(7982):308-314.
    PMID: 37794184 DOI: 10.1038/s41586-023-06578-4
    Systematic assessments of species extinction risk at regular intervals are necessary for informing conservation action1,2. Ongoing developments in taxonomy, threatening processes and research further underscore the need for reassessment3,4. Here we report the findings of the second Global Amphibian Assessment, evaluating 8,011 species for the International Union for Conservation of Nature Red List of Threatened Species. We find that amphibians are the most threatened vertebrate class (40.7% of species are globally threatened). The updated Red List Index shows that the status of amphibians is deteriorating globally, particularly for salamanders and in the Neotropics. Disease and habitat loss drove 91% of status deteriorations between 1980 and 2004. Ongoing and projected climate change effects are now of increasing concern, driving 39% of status deteriorations since 2004, followed by habitat loss (37%). Although signs of species recoveries incentivize immediate conservation action, scaled-up investment is urgently needed to reverse the current trends.
  3. Zhou J, Azizan EAB, Cabrera CP, Fernandes-Rosa FL, Boulkroun S, Argentesi G, et al.
    Nat Genet, 2021 Sep;53(9):1360-1372.
    PMID: 34385710 DOI: 10.1038/s41588-021-00906-y
    Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.
  4. Wu X, Azizan EAB, Goodchild E, Garg S, Hagiyama M, Cabrera CP, et al.
    Nat Genet, 2023 Jun;55(6):1009-1021.
    PMID: 37291193 DOI: 10.1038/s41588-023-01403-0
    Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.
  5. Shaikh LH, Zhou J, Teo AE, Garg S, Neogi SG, Figg N, et al.
    J Clin Endocrinol Metab, 2015 Jun;100(6):E836-44.
    PMID: 25915569 DOI: 10.1210/jc.2015-1734
    CONTEXT: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosterone production.

    OBJECTIVE: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover.

    DESIGN: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7).

    INTERVENTIONS: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3).

    MAIN OUTCOME MEASURES: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured.

    RESULTS: LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up-regulated. In total, 18 genes associated with the Wnt pathway were greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the noncanonical activator protein-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers.

    CONCLUSION: LGR5 is the most selectively expressed gene in human ZG and reduces aldosterone production and cell number. Such conditions may favor cells whose somatic mutation reverses aldosterone inhibition and cell loss.

  6. Teo AE, Garg S, Shaikh LH, Zhou J, Karet Frankl FE, Gurnell M, et al.
    N Engl J Med, 2015 Oct 08;373(15):1429-36.
    PMID: 26397949 DOI: 10.1056/NEJMoa1504869
    Recent discoveries of somatic mutations permit the recognition of subtypes of aldosterone-producing adenomas with distinct clinical presentations and pathological features. Here we describe three women with hyperaldosteronism, two who presented in pregnancy and one who presented after menopause. Their aldosterone-producing adenomas harbored activating mutations of CTNNB1, encoding β-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR and GNRHR, encoding gonadal receptors, at levels that were more than 100 times as high as the levels in other aldosterone-producing adenomas. The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate toward their common adrenal-gonadal precursor cell type. (Funded by grants from the National Institute for Health Research Cambridge Biomedical Research Centre and others.).
  7. Shin ES, Bang LH, Jun EJ, Her AY, Chung JH, Garg S, et al.
    Cardiol J, 2021;28(4):615-622.
    PMID: 32789835 DOI: 10.5603/CJ.a2020.0105
    Although drug-eluting stents (DES) have become the mainstay of percutaneous coronary intervention, late and very late stent thrombosis remains a concern. Drug-coated balloons (DCB) have the advantage of preserving the anti-restenotic benefits of DES while minimizing potential long-term safety concerns. Currently the two methods to ensure successful DCB treatment of a stenotic lesion are angiography or physiology-guided DCB application. This review will evaluate these two methods based on previous evidence and make suggestions on how to perform DCB treatment more efficiently and safely.
  8. Maqsood K, Ali A, Ilyas SU, Garg S, Danish M, Abdulrahman A, et al.
    Chemosphere, 2022 Jan;286(Pt 2):131690.
    PMID: 34352553 DOI: 10.1016/j.chemosphere.2021.131690
    The experimental determination of thermophysical properties of nanofluid (NF) is time-consuming and costly, leading to the use of soft computing methods such as response surface methodology (RSM) and artificial neural network (ANN) to estimate these properties. The present study involves modelling and optimization of thermal conductivity and viscosity of NF, which comprises multi-walled carbon nanotubes (MWCNTs) and thermal oil. The modelling is performed to predict the thermal conductivity and viscosity of NF by using Response Surface Methodology (RSM) and Artificial Neural Network (ANN). Both models were tested and validated, which showed promising results. In addition, a detailed optimization study was conducted to investigate the optimum thermal conductivity and viscosity by varying temperature and NF weight per cent. Four case studies were explored using different objective functions based on NF application in various industries. The first case study aimed to maximize thermal conductivity (0.15985 W/m oC) while minimizing viscosity (0.03501 Pa s) obtained at 57.86 °C and 0.85 NF wt%. The goal of the second case study was to minimize thermal conductivity (0.13949 W/m °C) and viscosity (0.02526 Pa s) obtained at 55.88 °C and 0.15 NF wt%. The third case study targeted maximizing thermal conductivity (0.15797 W/m °C) and viscosity (0.07611 Pa s), and the optimum temperature and NF wt% were 30.64 °C and 0.0.85,' respectively. The last case study explored the minimum thermal conductivity (0.13735) and maximum viscosity (0.05263 Pa s) obtained at 30.64 °C and 0.15 NF wt%.
  9. Xie CB, Shaikh LH, Garg S, Tanriver G, Teo AE, Zhou J, et al.
    Sci Rep, 2016 Apr 21;6:24697.
    PMID: 27098837 DOI: 10.1038/srep24697
    Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) CaV1.3. Using a novel antagonist of CaV1.3, compound 8, we investigated the role of CaV1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, CaV1.2, over CaV1.3. In H295R cells transfected with wild-type or mutant CaV1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 μM of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 μM). Selective CaV1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of CaV1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of CaV1.3.
  10. Lyn LY, Sze HW, Rajendran A, Adinarayana G, Dua K, Garg S
    Acta Pharm, 2011 Dec;61(4):391-402.
    PMID: 22202198 DOI: 10.2478/v10007-011-0037-z
    Piroxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility which exhibits polymorphism. The present study was carried out to develop polymorphs of piroxicam with enhanced solubility and dissolution rate by the crystal modification technique using different solvent mixtures prepared with PEG 4000 and PVP K30. Physicochemical characteristics of the modified crystal forms of piroxicam were investigated by X-ray powder diffractometry, FT-IR spectrophotometry and differential scanning calorimetry. Dissolution and solubility profiles of each modified crystal form were studied and compared with pure piroxicam. Solvent evaporation method (method I) produced both needle and cubic shaped crystals. Slow crystallization from ethanol with addition of PEG 4000 or PVP K30 at room temperature (method II) produced cubic crystal forms. Needle forms produced by method I improved dissolution but not solubility. Cubic crystals produced by method I had a dissolution profile similar to that of untreated piroxicam but showed better solubility than untreated piroxicam. Cubic shaped crystals produced by method II showed improved dissolution, without a significant change in solubility. Based on the XRPD results, modified piroxicam crystals obtained by method I from acetone/benzene were cube shaped, which correlates well with the FTIR spectrum; modified needle forms obtained from ethanol/methanol and ethanol/acetone showed a slight shift of FTIR peak that may be attributed to differences in the internal structure or conformation.
  11. Gorajana A, Ying CC, Shuang Y, Fong P, Tan Z, Gupta J, et al.
    Curr Drug Deliv, 2013 Jun;10(3):309-16.
    PMID: 23360246
    Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility. Solid dispersions were prepared by solvent and fusion methods. Dapivirine release from the solid dispersion system was determined by conducting in-vitro dissolution studies. The physicochemical characteristics of the drug and its formulation were studied using Differential Scanning Calorimetry (DSC), powder X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). A significant improvement in drug dissolution rate was observed with the solid dispersion systems. XRD, SEM and DSC results indicated the transformation of pure Dapivirine which exists in crystalline form into an amorphous form in selected solid dispersion formulations. FTIR and HPLC analysis confirmed the absence of drug-excipient interactions. Solid dispersion systems can be used to improve the dissolution rate of Dapivirine. This improvement could be attributed to the reduction or absence of drug crystallinity, existence of drug particles in an amorphous form and improved wettability of the drug.
  12. Alhadi F, Hamidy A, Farajallah A, Munir M, Atmaja VY, Garg S, et al.
    Zootaxa, 2019 Jun 04;4613(1):zootaxa.4613.1.5.
    PMID: 31716427 DOI: 10.11646/zootaxa.4613.1.5
    Micryletta inornata (Boulenger 1890), the type species of the genus Micryletta, was originally described from the island of Sumatra in Indonesia. Subsequently, this species has been widely reported from Sundaland (Sumatra and Malay Peninsula), Indo-China, Northeast India and South Andaman, up to southern China and Taiwan. However, since the original description there has been no further report of this species from the type locality or the island. During a herpetofaunal survey in Sumatra, several specimens that are morphologically concordant with the original description and the syntypes of M. inornata were found, and thus the species was rediscovered after 125 years. Here, we provide a redescription of the species based on the freshly collected specimens, along with a detailed morphological and molecular comparison with known congeners. Further, using molecular data from the mitochondrial 16S rRNA gene, our study recovered the Sumatran M. inornata as a phylogenetically distinct lineage from all other populations previously referred to this species. This confirms that all known Micryletta 'inornata' populations from regions outside Sumatra constitute several other lineages representing either new species or previously available names currently considered as synonyms, consequently requiring taxonomic validation in the future.
  13. Lim SM, Pang ZW, Tan HY, Shaikh M, Adinarayana G, Garg S
    Drug Dev Ind Pharm, 2015;41(11):1847-55.
    PMID: 25721984 DOI: 10.3109/03639045.2015.1014818
    Poor biopharmaceutical properties and toxicities associated with the intravenous formulation of docetaxel (DTX) necessitate the exploration of an alternate oral route of delivery.
  14. Choudhury H, Pandey M, Saravanan V, Mun ATY, Bhattamisra SK, Parikh A, et al.
    Biomater Adv, 2023 Oct;153:213556.
    PMID: 37478770 DOI: 10.1016/j.bioadv.2023.213556
    Cancer at the lower end of the digestive tract, colorectal cancer (CRC), starts with asymptomatic polyps, which can be diagnosed as cancer at a later stage. It is the fourth leading cause of malignancy-associated mortality worldwide. Despite progress in conventional treatment strategies, the possibility to overcome the mortality and morbidity issues with the enhancement of the lifespan of CRC patients is limited. With the advent of nanocarrier-based drug delivery systems, a promising revolution has been made in diagnosis, treatment, and theranostic purposes for cancer management. Herein, we reviewed the progress of miniaturized nanocarriers, such as liposomes, niosomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles, employed in passive and active targeting and their role in theranostic applications in CRC. With this novel scope, the diagnosis and treatment of CRC have proceeded to the forefront of innovation, where specific characteristics of the nanocarriers, such as processability, flexibility in developing precise architecture, improved circulation, site-specific delivery, and rapid response, facilitate the management of cancer patients. Furthermore, surface-engineered technologies for the nanocarriers could involve receptor-mediated deliveries towards the overexpressed receptors on the CRC microenvironment. Moreover, the potential of clinical translation of these targeted miniaturized formulations as well as the possible limitations and barriers that could impact this translation into clinical practice were highlighted. The advancement of these newest developments in clinical research and progress into the commercialization stage gives hope for a better tomorrow.
  15. Koh PT, Chuah JN, Talekar M, Gorajana A, Garg S
    Indian J Pharm Sci, 2013 May;75(3):291-301.
    PMID: 24082345 DOI: 10.4103/0250-474X.117434
    The aim of this study was to enhance the dissolution rate of efavirenz using solid dispersion systems (binary and ternary). A comparison between solvent and fusion method was also investigated. Solid dispersions of efavirenz were prepared using polyethylene glycol 8000, polyvinylpyrrolidone K30 alone and combination of both. Tween 80 was incorporated to obtain a ternary solid dispersion system. Dissolution tests were conducted and evaluated on the basis of cumulative percentage drug release and dissolution efficiency. Physicochemical characterizations of the solid dispersions were carried out using differential scanning calorimetric, powder X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy. Dissolution was remarkably improved in both systems compared to pure efavirenz (P<0.05). An optimum ratio was identified at a drug:polymer of 1:10. Incorporation of Tween 80 to 1:10 formulations formed using solvent method showed further improvement in the dissolution rate. Physicochemical characterization results suggested that efavirenz existed in the amorphous form in all the solid dispersion systems providing evidence of improvement in dissolution. No statistically significant difference (P>0.05) in dissolution was observed between the two methods. Binary and ternary solid dispersion systems both have showed a significant improvement in the dissolution rate of efavirenz. Formulations with only polyvinylpyrrolidone K30 showed best dissolution profile and 1:10 was identified as an optimum drug-polymer weight ratio.
  16. Sharma A, Jindal S, Narula MS, Garg S, Sethi A
    Malays Orthop J, 2017 Mar;11(1):74-76.
    PMID: 28435581 DOI: 10.5704/MOJ.1703.011
    The incidence of bilateral gleno-humeral joint dislocation is rare, is almost always posterior and is usually caused by sports injuries, epileptic seizures, electrical shock, or electroconvulsive therapy. Bilateral fracture-dislocation is even rarer, with a few cases reported in the literature. We report an unusual case with dislocation of the both glenohumeral joints in opposite direction after a seizure episode, with fracture of greater tuberosity on one side and of the lesser tuberosity on the contralateral side. Although there have been a few reports of bilateral asymmetric fracture dislocations of the shoulder in the past, an injury pattern resembling our case has, to the best of our knowledge, not been described in the literature so far. This report includes a detailed discussion regarding the mechanism of injury in a case of asymmetrical dislocation following a seizure episode. At final follow-up, the patient had healed fractures, painless near normal range of motion with no redislocations.
  17. Krishna A, Garg S, Gupta S, Bansal H
    Malays Orthop J, 2021 Jul;15(2):143-150.
    PMID: 34429835 DOI: 10.5704/MOJ.2107.021
    Introduction: To evaluate the trends of C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) in the first three weeks after uncomplicated total hip (THR) and total knee (TKR) arthroplasty/replacement in the Indian population and to compare it with available literature.

    Materials and methods: A total of 90 patients were enrolled for this prospective study, of which 30 were unilateral THR, 30 were unilateral TKR (U/L TKR) and 30 were simultaneous bilateral TKR (B/L TKR). Serum CRP and ESR were measured on the day before surgery and post-operatively on day 1st, 2nd, 3rd, 7th, 12th, and at the end of 3rd week.

    Results: CRP showed a peak at day 2nd with normalisation to pre-operative value by the end of 3rd week. While ESR showed a peak on day 3rd and continued to remain elevated even at end of 3rd week post-operatively. Both mean CRP and ESR values were higher in THR patients followed by in B/L TKR and then in U/L TKR patients.

    Conclusion: CRP persists to be the best acute phase reactant in the early post-operative phase with a relatively typical pattern as compared to ESR. CRP values peak at post-operative day 2nd and then show a gradual decline. However, its normalisation to pre-operative baseline values may vary among different groups of population.

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