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Fulltext Needle Aspiration and Cytology for Suspected Osteoarticular Tuberculosis in Children

Agarwal A, Singh S, Agarwal S, Gupta S

Malays Orthop J, 2018 Nov;12(3):31-37.
PMID: 30555644 DOI: 10.5704/MOJ.1811.007

Introduction: Early diagnosis of osteoarticular tuberculosis (OATB) is essential to prevent significant functional disability. There is no single test for diagnosis. Despite an array of investigations available, definitive diagnosis at early stage before starting antitubercular drugs is still a challenge. Materials and Methods: A cross sectional study was carried out between February 2016 and October 2017. All children less than 18 years of age with suspected osteoarticular tuberculosis were included. The cases were subjected to simple needle aspiration from whichever site was accessible. Multiple sample aspirations were done at site of involvement. Smears were prepared from the aspirated material. Results: Ziehl-Neelsen staining for Acid Fast Bacilli (AFB) showed deep pink red rods under light microscopy. Features suggestive of tuberculosis can be seen by May-Grünwald-Giemsa (MGG) staining. Auramine-O staining method of detecting AFB under fluorescent microscope shows the bacilli as greenish yellow slender curved rods in dark background. Fluorescent microscopy has higher sensitivity and comparable specificity. In our study, microbiological confirmation of OATB could be done in 100% cases where the lesion could be accessed for aspiration. The molecular techniques are relatively more expensive and not available everywhere. Conclusion: Meticulous search for AFB in a well stained smear using three different staining methods provides a direct evidence of infection over costly imaging especially in poor patients seen in resource limited settings.
Fulltext Wellen's syndrome: Challenges in diagnosis

Agarwal A, Vyas S, Kumar R

Malays Fam Physician, 2015;10(3):35-7.
PMID: 27570607

Wellen's syndrome is a pre-infarction stage of coronary artery disease characterised by predefined clinical and electrocardiographic (ECG) criteria of a subgroup of patients with myocardial ischaemia. Early recognition and appropriate intervention of this syndrome carry significant diagnostic and prognostic value. We report this unusual syndrome in an elderly man who presented with recurrent angina and characteristic ECG changes as T-waves inversion in the precordial leads, especially in V2-V6 during pain-free periods and ECG obtained during episodes of pain demonstrating upright T-waves with possible elevated ST segments from V1-V4. Cardiac enzymes were positive and coronary angiography revealed critical stenosis in the proximal left anterior descending artery. It is important to timely identify this condition and intervene appropriately as these patients may develop extensive myocardial infarction that carries a significant morbidity and mortality.
Oxidative stress and sperm function: A systematic review on evaluation and management

Dutta S, Majzoub A, Agarwal A

Arab J Urol, 2019;17(2):87-97.
PMID: 31285919 DOI: 10.1080/2090598X.2019.1599624

Objective: To review and present the most distinct concepts on the association of reactive oxygen species (ROS) with male reproduction. Methods: The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines were used to search PubMed, Medline, EMBASE, and the Cochrane electronic databases for studies investigating the role of oxidative stress (OS) on sperm function. Results: The literature search yielded 1857 studies, of which 1791 articles were excluded because of irrelevance of data, non-English language, non-human nature or because they were case reports or commentaries. All included studies were reviews (46), meta-analyses (one), original research studies (18) and guideline articles (one). The studies were published between 1984 and 2018. Under normal physiological conditions, ROS are vital for sperm maturation, hyperactivation, capacitation, acrosome reaction, as well as fertilisation. However, a number of endogenous and exogenous causes may induce supra-physiological levels of ROS resulting in lipid peroxidation, sperm DNA fragmentation and apoptosis, and consequently infertility. Several laboratory testing methods can be used in infertile men to diagnose OS. Treatment usually involves antioxidant supplementation and, when possible, elimination of the causative factor. Conclusion: OS is an important cause of male factor infertility. Its assessment provides essential information that can guide treatment strategies aimed at improving the male's reproductive potential. Abbreviations: bp: base-pair; CAT: catalase; LPO: lipid peroxidation; MDA: malondialdehyde; MiOXSYS: Male Infertility Oxidative System; mtDNA: mitochondrial DNA; NAD(PH): nicotinamide adenine dinucleotide (phosphate); NO: nitric oxide; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; ORP: oxidation-reduction potential; OS: oxidative stress; PKA: protein kinase A; PLA2: phospholipase A2; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PUFA: poly-unsaturated fatty acid; ROS: reactive oxygen species; SOD: superoxide dismutase; TAC: total antioxidant capacity; TBA: thiobarbituric acid.
Fulltext Insights into an Award-Winning Summer Internship Program: The First Six Years

Kashou A, Durairajanayagam D, Agarwal A

World J Mens Health, 2016 Apr;34(1):9-19.
PMID: 27169124 DOI: 10.5534/wjmh.2016.34.1.9

Since its inception in 2008, the American Center for Reproductive Medicine's summer internship program in reproductive research and writing has trained 114 students from 23 states within the United States and 10 countries worldwide. Its fundamental goal is to inspire pre-medical and medical students to embrace a career as a physician-scientist. During this intensive course, established scientists and clinicians train interns in the essential principles and fundamental concepts of bench research and scientific writing. Over the first six years (2008~2013), interns have collectively published 98 research articles and performed 12 bench research projects on current and emerging topics in reproductive medicine. Interns have also developed and honed valuable soft skills including time management, communication and presentation skills, as well as life values, which all enhance personal and professional satisfaction. Program graduates are able to recognize the value of medical research and its potential to impact patient care and gain insight into their own career pathway. Between 2011 and 2014, the internship program was thrice awarded a Scholarship in Teaching Award by Case Western Reserve School of Medicine for its innovative teaching approach and positive impact on medical education and student careers. This report highlights the demographics, logistics, implementation, feedback, and results of the first six years of the American Center for Reproductive Medicine's summer internship program at Cleveland Clinic (Cleveland, OH, USA). This may be helpful to other research and academic institutions considering implementing a similar program. In addition, it creates awareness among potential physician-scientists of what the world of research has to offer in both scientific writing and bench research. Finally, it may stimulate further discussion regarding narrowing the gap between physicians and scientists and refinement of the current program.
Comparative analysis of tests used to assess sperm chromatin integrity and DNA fragmentation

Dutta S, Henkel R, Agarwal A

Andrologia, 2021 Mar;53(2):e13718.
PMID: 32628294 DOI: 10.1111/and.13718

Male infertility has a complex etiology, and many times, the cause is unknown. While routine semen analysis provides an overview of basic semen parameters, such as sperm concentration, motility, viability and morphology, a significant overlap of these parameters has been reported in fertile and infertile men. Moreover, conventional semen parameters do not reveal the cellular or molecular mechanisms of sperm dysfunctions leading to infertility. Therefore, sperm functional parameters, including sperm chromatin integrity, are evaluated to provide information on subtle sperm defects that are not routinely identified. Incomplete or defective sperm chromatin condensation increases the susceptibility of the sperm DNA to oxidative damage or other factors. To evaluate sperm chromatin integrity, different methods with varying degrees of diagnostic and prognostic capabilities are available. Among these assays, SCSA, TUNEL and SCD assays are most commonly used. While these assays rather evaluate the DNA directly for damages, the aniline blue and chromomycin A3 stains test for the quality of chromatin condensation. Thus, this review discusses and compares different methods used to evaluate sperm chromatin integrity and condensation, and their inclusion in the routine evaluation of the male infertility.
Afterword: An update on clinical utility and diagnostic value of various andrological techniques

Durairajanayagam D, Agarwal A, Baskaran S, Vij S

Andrologia, 2021 Mar;53(2):e13819.
PMID: 33620116 DOI: 10.1111/and.13819
Obesity and male infertility: Mechanisms and management

Leisegang K, Sengupta P, Agarwal A, Henkel R

Andrologia, 2021 Feb;53(1):e13617.
PMID: 32399992 DOI: 10.1111/and.13617

Obesity is considered a global health problem affecting more than a third of the population. Complications of obesity include cardiovascular diseases, type 2 diabetes mellitus, malignancy (including prostatic cancer), neurodegeneration and accelerated ageing. In males, these further include erectile dysfunction, poor semen quality and subclinical prostatitis. Although poorly understood, important mediators of obesity that may influence the male reproductive system include hyperinsulinemia, hyperleptinemia, chronic inflammation and oxidative stress. Obesity is known to disrupt male fertility and the reproduction potential, particularly through alteration in the hypothalamic-pituitary-gonadal axis, disruption of testicular steroidogenesis and metabolic dysregulation, including insulin, cytokines and adipokines. Importantly, obesity and its underlying mediators result in a negative impact on semen parameters, including sperm concentration, motility, viability and normal morphology. Moreover, obesity inhibits chromatin condensation, DNA fragmentation, increases apoptosis and epigenetic changes that can be transferred to the offspring. This review discusses the impact of obesity on the male reproductive system and fertility, including associated mechanisms. Furthermore, weight management strategies, lifestyle changes, prescription medication, and complementary and alternative medicine in the management of obesity-induced subfertility is discussed.
Causes and consequences of sperm mitochondrial dysfunction

Durairajanayagam D, Singh D, Agarwal A, Henkel R

Andrologia, 2021 Feb;53(1):e13666.
PMID: 32510691 DOI: 10.1111/and.13666

Mitochondria have multiple functions, including synthesis of adenine triphosphate, production of reactive oxygen species, calcium signalling, thermogenesis and apoptosis. Mitochondria have a significant contribution in regulating the various physiological aspects of reproductive function, from spermatogenesis up to fertilisation. Mitochondrial functionality and intact mitochondrial membrane potential are a pre-requisite for sperm motility, hyperactivation, capacitation, acrosin activity, acrosome reaction and DNA integrity. Optimal mitochondrial activity is therefore crucial for human sperm function and semen quality. However, the precise role of mitochondria in spermatozoa remains to be fully explored. Defects in sperm mitochondrial function severely impair the maintenance of energy production required for sperm motility and may be an underlying cause of asthenozoospermia. Sperm mtDNA is susceptible to oxidative damage and mutations that could compromise sperm function leading to infertility. Males with abnormal semen parameters have increased mtDNA copy number and reduced mtDNA integrity. This review discusses the role of mitochondria in sperm function, along with the causes and impact of its dysfunction on male fertility. Greater understanding of sperm mitochondrial function and its correlation with sperm quality could provide further insights into their contribution in the assessment of the infertile male.
An update on clinical utility and diagnostic value of various andrological techniques

Baskaran S, Agarwal A, Durairajanayagam D, Vij S

Andrologia, 2021 Mar;53(2):e13783.
PMID: 33620115 DOI: 10.1111/and.13783
The impact of COVID-19 on the male reproductive tract and fertility: A systematic review

Sengupta P, Leisegang K, Agarwal A

Arab J Urol, 2021;19(3):423-436.
PMID: 34552795 DOI: 10.1080/2090598X.2021.1955554

Objective: The COVID-19 pandemic, caused by the acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), remains an ongoing public health challenge. Although males are affected slightly more than females, the impact of SARS-COV-2 on male reproductive system remains unclear. This systematic review aims to provide a concise update on the effects of COVID-19 on male reproductive health, including the presence of viral RNA in semen, and the impact on semen quality, testicular histology, testicular pain and male reproductive hormones. The global health is fronting an immediate as well as impending threat from the novel coronavirus (SARS-CoV-2) causing coronavirus disease (COVID-19), that inflicts more males than females. Evidence suggest that male reproductive system is susceptible to this viral infection. However, there are still several pertinent queries that remain to be fully explained regarding the mechanism in testicular SARS-CoV-2 dynamics and the exact mode of its actions. Thus, the present systematic review aims to provide a concise update on the effects of coronavirus disease 2019 (COVID-19) on male reproduction..
Methods: A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines searching the PubMed database. Eligibility for inclusion were original human studies evaluating the impact of COVID-19 on male reproductive health. Specific outcomes required for inclusion were at least one of the following: i) seminal detection of mRNA virus, or evaluation of ii) semen analysis, iii) testicular histology or ultrasonography, iv) testicular clinical symptoms and/or v) male reproductive hormones in COVID-19-positive patients.
Results: Of 553 retrieved articles, 25 met the inclusion criteria. This included studies primarily investigating the presence of viral RNA in semen (n = 12), semen quality (n = 2), testicular histology (n = 5), testicular pain (n = 2) and male reproductive hormones (n= 4). Results show little evidence for the presence of viral RNA in semen, although COVID-19 seems to affect seminal parameters, induce orchitis, and cause hypogonadism. Mortality cases suggest severe histological disruption of testicular architecture, probably due to a systemic and local reproductive tract inflammatory response and oxidative stress-induced damage.
Conclusions: Clinical evaluation of the male reproductive tract, seminal parameters and reproductive hormones is recommended in patients with current or a history of COVID-19, particularly in males undergoing fertility treatment. Any long-term negative impact on male reproduction remains unexplored and an important future consideration.
Fulltext Vitrification of Blastocyst Murine embryos affects PI3K pathway by modulating the expression of XIAP and S6K1 proteins

Mohd Fazirul, M., Sharaniza, A.R., Norhazlin, J.M.Y., Wan Hafizah, W.J., Razif, D., Froemming, G.R.A., et al.

Pertanika Journal of Science & Technology, 2017;25(108):187-198.
MyJurnal

Cryopreservation by vitrification has been widely used in Assisted Reproductive Technology (ART) to preserve embryos for an extended period of time. However, the effect of vitrification on development of the embryos is lacking. Therefore, understanding on vitrification effects on embryonic proteins, especially those involved in preimplantation development is crucial to provide high quality embryos for further usage. In this study, XIAP and S6K1 protein expressions following vitrification was investigated, since they have been implicated in diverse cellular processes including cell growth, migration, proliferation, differentiation, survival and development of preimplantation embryos via the PI3K pathway. Embryos were obtained from superovulated female ICR mice which were mated with fertile males. The embryos were harvested at the 2-cell stage and cultured until blastocyst stage. Blastocysts were then vitrified in ESF40 cryoprotectant. Western blot was carried out to determine the expression of XIAP and S6K1 proteins. The results showed the expression of XIAP and S6K1 significantly decreased in vitrified blastocyst compared to the control. This indicates that blastocyst vitrification may impact developmental competence through the activation of apoptotic pathways.
Geographical differences in semen characteristics: Comparing semen parameters of infertile men of the United States and Iraq

Palani A, Sengupta P, Agarwal A, Henkel R

Andrologia, 2020 Apr;52(3):e13519.
PMID: 32003032 DOI: 10.1111/and.13519

The declining trend of male fecundity is a major global health and social concern. Among numerous other confounding factors, variations in male fertility parameters in different regions have repeatedly been suggested to be influenced by geographic locations. The impact of overall lifestyle, behavioural patterns, ethnicity, work stress and associated factors upon health differ greatly between developed and developing countries. These factors, individually or in combination, affect male reproductive functions ensuing the discrepancies in semen qualities in connection with geographic variations. However, reports comparing semen characteristics between developed and developing countries are sparse. The present study finds its novelty in presenting a comparison in semen parameters of infertile men in the United States (n = 76) that fairly represents the population of a highly developed region and Iraq (n = 102), the representative of male populations of a developing region. Samples were collected and analysed according to WHO (WHO laboratory manual for the examination and processing of human semen, WHO; 2010) criteria by means of the Mann-Whitney test. The US population demonstrated lower sperm concentration, total count, and total and progressive sperm motility with a higher seminal total antioxidant capacity (TAC) as compared to the Iraqi population. This report encourages further investigations concerning the confounding factors leading to such alterations in semen qualities between these two geographic areas.
Fulltext Role of L-carnitine in female infertility

Agarwal A, Sengupta P, Durairajanayagam D

Reprod Biol Endocrinol, 2018 Jan 26;16(1):5.
PMID: 29373970 DOI: 10.1186/s12958-018-0323-4

BACKGROUND: L-carnitine (LC), and its acetylated form, acetyl L-carnitine (ALC), have immense functional capabilities to regulate the oxidative and metabolic status of the female reproductive system. The vulnerability of this system to free radicals demand for advanced strategies to combat them. For this purpose, the 'quasi vitamins' LC and ALC can be used either individually, or in combination with each other or with other antioxidants.
MAIN BODY: This review (a) summarizes the effects of carnitines on female fertility along with the findings from various in vivo and in vitro studies involving human, animal and assisted reproductive technology, and (b) proposes their mechanism of actions in improving female fertility through their integrated actions on reducing cellular stress, maintaining hormonal balance and enhancing energy production. They reportedly aid β-oxidation in oocytes, maintain its cell membrane stability by acetylation of phospholipids and amphiphilic actions, prevent free radical-induced DNA damage and also stabilize acetyl Co-A/Co-A ratio for adequate acetyl storage as energy supply to maintain the robustness of reproductive cells.
CONCLUSION: While both LC and ALC have their applications in improving female fertility, ALC is preferred for its better antioxidant properties and LC for amelioration of energy supply to the cells. These beneficial effects show great promise in its application as a treatment option for women facing infertility disorders.
Proteomics, oxidative stress and male infertility

Agarwal A, Durairajanayagam D, Halabi J, Peng J, Vazquez-Levin M

Reprod Biomed Online, 2014 Jul;29(1):32-58.
PMID: 24813754 DOI: 10.1016/j.rbmo.2014.02.013

Oxidative stress has been established as one of the main causes of male infertility and has been implicated in many diseases associated with infertile men. It results from high concentrations of free radicals and suppressed antioxidant potential, which may alter protein expression in seminal plasma and/or spermatozoa. In recent years, proteomic analyses have been performed to characterize the protein profiles of seminal ejaculate from men with different clinical conditions, such as high oxidative stress. The aim of the present review is to summarize current findings on proteomic studies performed in men with high oxidative stress compared with those with physiological concentrations of free radicals, to better understand the aetiology of oxidative stress-induced male infertility. Each of these studies has suggested candidate biomarkers of oxidative stress, among them are DJ-1, PIP, lactotransferrin and peroxiredoxin. Changes in protein concentrations in seminal plasma samples with oxidative stress conditions were related to stress responses and to regulatory pathways, while alterations in sperm proteins were mostly associated to metabolic responses (carbohydrate metabolism) and stress responses. Future studies should include assessment of post-translational modifications in the spermatozoa as well as in seminal plasma proteomes of men diagnosed with idiopathic infertility. Oxidative stress, which occurs due to a state of imbalance between free radicals and antioxidants, has been implicated in most cases of male infertility. Cells that are in a state of oxidative stress are more likely to have altered protein expression. The aim of this review is to better understand the causes of oxidative stress-induced male infertility. To achieve this, we assessed proteomic studies performed on the seminal plasma and spermatozoa of men with high levels of oxidative stress due to various clinical conditions and compared them with men who had physiological concentrations of free radicals. A variety of sperm and seminal plasma proteins were found to be expressed either in abundance (over-expressed) or in a lesser amount (underexpressed), while other proteins were found to be unique either to men with oxidative stress or to men with a balanced ratio of antioxidants/free radicals. Each study included in this review suggested several proteins that could possibly act as biomarkers of oxidative stress-induced male infertility, such as protein DJ-1, PIP, lactotransferrin and peroxiredoxin. Pathway analysis performed in these studies revealed that the changes in seminal plasma proteins in men with oxidative stress could be attributed to stress responses and regulatory pathways, while changes in sperm proteins were linked to stress responses and metabolic responses. Subsequent studies could look into post-translational modifications in the protein profile of men with idiopathic infertility. We hope that the information in this review will contribute to a better understanding of the main causes of idiopathic male infertility.
Afterword to an update on male infertility: Factors, mechanisms, and interventions

Durairajanayagam D, Agarwal A, Baskaran S, Ko E, Ramasamy R

Andrologia, 2021 Feb;53(1):e13752.
PMID: 33484502 DOI: 10.1111/and.13752
An update on male infertility: Factors, mechanisms, and interventions

Ko E, Ramasamy R, Durairajanayagam D, Baskaran S, Agarwal A

Andrologia, 2021 02;53(1):e13741.
PMID: 33135797 DOI: 10.1111/and.13741
Differential proteomic profiling of spermatozoal proteins of infertile men with unilateral or bilateral varicocele

Agarwal A, Sharma R, Durairajanayagam D, Cui Z, Ayaz A, Gupta S, et al.

Urology, 2015 Mar;85(3):580-8.
PMID: 25733269 DOI: 10.1016/j.urology.2014.11.030

To compare the sperm protein profile between infertile men with unilateral varicocele and infertile men with bilateral varicocele.
Fulltext Microtubular Dysfunction and Male Infertility

Gunes S, Sengupta P, Henkel R, Alguraigari A, Sinigaglia MM, Kayal M, et al.

World J Mens Health, 2020 Jan;38(1):9-23.
PMID: 30350487 DOI: 10.5534/wjmh.180066

Microtubules are the prime component of the cytoskeleton along with microfilaments. Being vital for organelle transport and cellular divisions during spermatogenesis and sperm motility process, microtubules ascertain functional capacity of sperm. Also, microtubule based structures such as axoneme and manchette are crucial for sperm head and tail formation. This review (a) presents a concise, yet detailed structural overview of the microtubules, (b) analyses the role of microtubule structures in various male reproductive functions, and (c) presents the association of microtubular dysfunctions with male infertility. Considering the immense importance of microtubule structures in the formation and maintenance of physiological functions of sperm cells, this review serves as a scientific trigger in stimulating further male infertility research in this direction.
Role of Withania somnifera (Ashwagandha) in the management of male infertility

Sengupta P, Agarwal A, Pogrebetskaya M, Roychoudhury S, Durairajanayagam D, Henkel R

Reprod Biomed Online, 2018 Mar;36(3):311-326.
PMID: 29277366 DOI: 10.1016/j.rbmo.2017.11.007

To manage male infertility caused by hormonal imbalance, infections and other predicaments, multifarious treatment strategies are emerging worldwide. Contemporary treatments, such as assisted reproductive techniques, are costly with low success rates of only 10-30%; however, herbal remedies are gaining more attention as an alternative or supplementary therapeutic modality for male infertility. The beneficial effects induced by oral intake of the roots of a small evergreen shrub, Withania sominifera (Ashwagandha) on semen quality of infertile men have previously been studied. Oral intake of Ashwagandha roots has been found to inhibit lipid peroxidation, improve sperm count and motility, and regulate reproductive hormone levels. The molecular mechanisms of these effects, however, are yet to be unveiled. In this review, we will discuss the role of herbal medicines in male infertility; provide a detailed analysis of various human and animal studies involving Withania somnifera; describe a proposed direct oxidative mechanism involving mitigation of oxidative stress as well as an indirect mechanism consisting of a gamma-aminobutyric acid-like-mimetic pathway ameliorating hormonal balance through crosstalk among different endocrine glands to improve male fertility; and how Withania somnifera supplementation mitigates risk factor-induced male infertility as well as ameliorates male fertility.
Somatic-Immune Cells Crosstalk In-The-Making of Testicular Immune Privilege

Dutta S, Sandhu N, Sengupta P, Alves MG, Henkel R, Agarwal A

Reprod Sci, 2021 Sep 27.
PMID: 34580844 DOI: 10.1007/s43032-021-00721-0

Immunological infertility contributes significantly to the etiology of idiopathic male infertility. Shielding the spermatogenic cells from systemic immune responses is fundamental to secure normal production of spermatozoa. The body's immune system is tuned with the host self-components since the early postnatal period, while sperm first develops during puberty, thus rendering spermatogenic proteins as 'non-self' or 'antigenic.' Development of antibodies to these antigens elicits autoimmune responses affecting sperm motility, functions, and fertility. Therefore, the testes need to establish a specialized immune-privileged microenvironment to protect the allogenic germ cells by orchestration of various testicular cells and resident immune cells. This is achieved through sequestration of antigenic germ cells by blood-testis barrier and actions of various endocrine, paracrine, immune-suppressive, and immunomodulatory mechanisms. The various mechanisms are very complex and need conceptual integration to disclose the exact physiological scenario, and to facilitate detection and management of immunogenic infertility caused by disruption of testicular immune regulation. The present review aims to (a) discuss the components of testicular immune privilege; (b) explain testicular somatic and immune cell interactions in establishing and maintaining the testicular immune micro-environment; and (c) illustrate the integration of multiple mechanisms involved in the control of immune privilege of the testis.

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