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Secondary acute myeloid leukemia after etoposide therapy for haemophagocytic lymphohistiocytosis

RamaChandran S, Ariffin H

Pediatr Blood Cancer, 2009 Sep;53(3):488-90.
PMID: 19434733 DOI: 10.1002/pbc.22063

Haemophagocytic lymphohistiocytosis (HLH) is an uncommon disease with a high fatality rate. Etoposide is an important component of current HLH treatment regimes. Two patients with HLH developed etoposide-related secondary acute myeloid leukemia (sAML) following therapy for HLH. Etoposide, an epipodophyllotoxin, is a topoisomerase II inhibitor that interacts with DNA to potentiate leukaemogenesis. The risk of developing sAML is estimated to be between 1% and 5%, 2-20 years after exposure to etoposide but may also be related to cumulative drug doses, treatment schedules, host factors and co-administration of other antineoplastic agents.
Fulltext The prevalence of sexually transmitted diseases among prostitutes in Malaysia

Ramachandran S, Ngeow YF

Genitourin Med, 1990 Oct;66(5):334-6.
PMID: 2245980 DOI: 10.1136/sti.66.5.334

The prevalence of sexually transmitted diseases was determined among 370 prostitutes in Kuala Lumpur, Malaysia. Chlamydial cervicitis (26.5%) was detected more frequently than gonorrhoea (14.25%) and was associated more often with pelvic inflammatory disease. Concurrent infections and asymptomatic infections were common. Seropositivity to hepatitis B and syphilis were 66.3% and 13.6% respectively. Women under 20 years of age had significantly higher rates of infection with Chlamydia trachomatis and hepatitis B virus than older women.
Study site: private clinic, Kuala Lumpur, Malaysia
Effect of copper and cadmium on three Malaysian tropical estuarine invertebrate larvae

Ramachandran S, Patel TR, Colbo MH

Ecotoxicol Environ Saf, 1997 Mar;36(2):183-8.
PMID: 9126437

Three species of tropical estuarine invertebrates were exposed to copper sulfate and cadmium chloride to investigate their potential as test specimens for sediment toxicity assays in the South-east Asian regions. The larvae of the reef sea urchin (Diadema setosum), the oyster (Crassostrea iradalei), and the mud crab (Scylla seratta Forskall) were used in the 48-hr assays with copper and cadmium as reference toxicants. In addition the sea urchin were tested for end point measurements at different stages of the larval development and a 60-min sperm bioassay. The study revealed that the sea urchin first cleavage, which is an assay end point and which takes place about 1 hr after fertilization, was the most sensitive stage for both toxicants, with copper being more toxic than cadmium. Sensitivity comparisons between the three invertebrate larvae revealed the mud crab zoea larvae to be most sensitive for cadmium with an LC50 value of 0.078 microgram/ml, while the sea urchin was more sensitive for copper, with EC50 values of 0.01 microgram/ml at the first cleavage stage and 0.04 microgram/ml at the pluteus larva stage. All the invertebrates tested gave responses that made them suitable test organisms for metal bioassays in the tropical estuarine environment.
Treatment of gonorrhea with sulbactam/ampicillin

Ngeow YF, Ramachandran S, Cheong YM

Sex Transm Dis, 1991 7 1;18(3):192-4.
PMID: 1948519

Between January and August, 1989, 36 men and 28 women with uncomplicated lower genital tract infections by Neisseria gonorrhoeae were given single intramuscular injections of sulbactam (500 mg)/ampicillin (1000 mg) together with 1 g oral probenecid. Cure rates that were obtained were 100% for women, 97.2% for men, 100% for patients with penicillinase-producing Neisseria gonorrhoeae (PPNG), and 98.4% for patients with non-PPNG. No serious side effects were encountered, and patient acceptance of the drug was good. A high proportion of patients had concurrent chlamydial infection. Sulbactam/ampicillin was found to be effective against gonococcal urethritis and cervicitis by both PPNG and non-PPNG but have little effect on concomitant chlamydial infections, especially in women.
Prevalence of chlamydial antibody in Malaysians

Ngeow YF, Rachagan SP, Ramachandran S

J Clin Pathol, 1990 May;43(5):400-2.
PMID: 2196283

A single antigen indirect immunofluorescence test was used to screen for chlamydial antibody among Malaysian infants, children, sexually active adults and prostitutes. Of 794 serum samples tested, 361 (45.5%) were positive. Seropositivity increased with age and sexual activity and ranged from 10 to 16% among children under 10 years old to 94.4% among prostitutes. Pregnant women and female adolescents showed a higher antibody prevalence than nonpregnant and older women. Six (13%) infants under 6 months of age were positive for chlamydial IgM.
Detection of Chlamydia trachomatis in urine samples by polymerase chain reaction and enzyme immunoassay

Ngeow YF, Hema V, Zakaria M, Lee CH, Ramachandran S

Malays J Pathol, 1997 Dec;19(2):127-32.
PMID: 10879253

First-void urine samples collected from sexually transmitted diseases (STD) clinic patients were examined by a nested polymerase chain reaction (PCR) and a commercial enzyme immunoassay (IDEIA Chlamydia) for the diagnosis of Chlamydia trachomatis urethritis or cervicitis. The primers for the PCR amplified a target in the major outer membrane protein (MOMP) gene in C trachomatis while the IDEIA detected genus-specific chlamydial lipopolysaccharide. Discrepant results were resolved by retesting urine specimens with a second (plasmid-based) PCR and taking urethral or endocervical swab results into consideration. For 231 men (chlamydial prevalence 20.4%), the sensitivity, specificity, positive and negative predictive values were 59.6%, 99.5%, 96.6% and 90.6% for urine IDEIA, 68.1%, 99.5%, 97% and 92.4% for urethral swab IDEIA and 97.9%, 99.5%, 97.9% and 99.5% for urine PCR. The corresponding rates for 66 women (chlamydial prevalence 54.6%) were 19.4%, 100%, 100% and 50.8% for urine IDEIA, 86.1%, 96.7%, 96.9% and 85.3% for endocervical swab IDEIA and 91.7%, 93.3%, 94.3% and 90.3% for urine PCR. Hence, in a high prevalence population, the urine IDEIA was a suitable alternative to the male urethral swab IDEIA but significantly less sensitive than the endocervical swab IDEIA. The urine PCR was, however, much more sensitive than the urine IDEIA for both men and women and could replace the endocervical swab IDEIA for the diagnosis of chlamydial cervicitis.
Screening for hemoglobinopathies among patients in a government hospital and health clinics in Perlis, Malaysia

Chin YM, Esa E, Mohd Yacob A, Ramachandran S, Zakaria Z

Journal of Medical Science & Technology, 2014;3(2):82-86.

The hemoglobinopathies include all genetic diseases of hemoglobin (Hb) and fall into two main groups: the thalassemias and structural hemoglobin variants (abnormal hemoglobins). Thalassemia is a public health problem in Malaysia. About 4.5% of the Malays and Chinese are β-thalassemia carriers. We performed hemoglobin analysis on a total of 499 patients from a Government Hospital and Health Clinics in the state of Perlis, Malaysia. About 91.4% of the patients were Malays. All patients had microcytic hypochromic anemia except for a few who went for thalassemia screening. Female patients outnumbered male patients in the ratio of 3.5:1. About 75.7% of the female patients were of childbearing age (17 - 40 years) and a majority of them were there for their antenatal checkup. Using our screen tests (full blood count, high performance liquid chromatography (HPLC), and agarose gel electrophoresis), the common hemoglobinopathies detected were HbE trait (19.3%), β-thalassemia trait (14.6%), HbH disease (1.8%), Hb Constant Spring (1.6%), Homozygous HbE (1.4%), and HbE- β-thalassemia (1.4%). Thalassemia is preventable through screening and education programmes, and prenatal diagnosis. Thalassemia screening is provided free of charge at various government hospitals and health clinics throughout the country.
Key words: Hemoglobinopathies screening, β-thalassemia trait, HbE trait, Thalassemic diseases
Review of inhalable nanoparticles for the pulmonary delivery of anti-tuberculosis drugs

Ramachandran S, Prakash P, Mohtar N, Kumar KS, Parumasivam T

Pharm Dev Technol, 2023 Dec;28(10):978-991.
PMID: 37937865 DOI: 10.1080/10837450.2023.2279691

Tuberculosis is an airborne disease caused by the pathogen, Mycobacterium tuberculosis, which predominantly affects the lungs. World Health Organization (WHO) has reported that about 85% of TB patients are cured with the existing 6-month antibiotic regimen. However, the lengthy oral administration of high-dose anti-TB drugs is associated with significant side effects and leads to drug resistance cases. Alternatively, reformulating existing anti-tubercular drugs into inhalable nanoparticulate systems is a promising strategy to overcome the challenges associated with oral treatment as they could enhance drug retention in the pulmonary region to achieve an optimal drug concentration in the infected lungs. Hence, this review provides an overview of the literature on inhalable nano-formulations for the delivery of anti-TB drugs, including their formulation techniques and preclinical evaluations between the years 2000 and 2020, gathered from electronic journals via online search engines such as Google Scholar and PubMed. Previous in vitro and in vivo studies highlighted that the nano-size, low toxicity, and high efficacy were among the factors influencing the fate of nanoparticulate system upon deposition in the lungs. Although many preclinical studies have shown that inhalable nanoparticles increased therapeutic efficacy and minimised adverse drug reactions when delivered through the pulmonary route, none of them has progressed into clinical trials to date. This could be attributed to the high cost of inhaled regimes due to the expensive production and characterisation of the nanoparticles as well as the need for an inhalation device as compared to the oral treatment. Another barrier could be the lack of medical acceptance due to insufficient number of trained staff to educate the patients on the correct usage of the inhalation device. Hence, these barriers should be addressed satisfactorily to make the inhaled nanoparticles regimen a reality for the treatment of TB.
Fulltext Role of Cytokines and Chemokines in NSCLC Immune Navigation and Proliferation

Ramachandran S, Verma AK, Dev K, Goyal Y, Bhatt D, Alsahli MA, et al.

Oxid Med Cell Longev, 2021;2021:5563746.
PMID: 34336101 DOI: 10.1155/2021/5563746

With over a million deaths every year around the world, lung cancer is found to be the most recurrent cancer among all types. Nonsmall cell lung carcinoma (NSCLC) amounts to about 85% of the entire cases. The other 15% owes it to small cell lung carcinoma (SCLC). Despite decades of research, the prognosis for NSCLC patients is poorly understood with treatment options limited. First, this article emphasises on the part that tumour microenvironment (TME) and its constituents play in lung cancer progression. This review also highlights the inflammatory (pro- or anti-) roles of different cytokines (ILs, TGF-β, and TNF-α) and chemokine (CC, CXC, C, and CX3C) families in the lung TME, provoking tumour growth and subsequent metastasis. The write-up also pinpoints recent developments in the field of chemokine biology. Additionally, it covers the role of extracellular vesicles (EVs), as alternate carriers of cytokines and chemokines. This allows the cytokines/chemokines to modulate the EVs for their secretion, trafficking, and aid in cancer proliferation. In the end, this review also stresses on the role of these factors as prognostic biomarkers for lung immunotherapy, apart from focusing on inflammatory actions of these chemoattractants.
Fulltext Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis

Hudson J, Cruickshank M, Quinton R, Aucott L, Aceves-Martins M, Gillies K, et al.

Lancet Healthy Longev, 2022 Jun;3(6):e381-e393.
PMID: 35711614 DOI: 10.1016/S2666-7568(22)00096-4

BACKGROUND: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD.
METHODS: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005.
FINDINGS: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk.
INTERPRETATION: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone.
FUNDING: National Institute for Health Research Health Technology Assessment Programme.
Fulltext Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis

Hudson J, Cruickshank M, Quinton R, Aucott L, Wu F, Grossmann M, et al.

Lancet Healthy Longev, 2023 Oct;4(10):e561-e572.
PMID: 37804846 DOI: 10.1016/S2666-7568(23)00169-1

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment.
METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005.
FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory).
INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity.
FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.
Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Zheng SL, Henry A, Cannie D, Lee M, Miller D, McGurk KA, et al.

Nat Genet, 2024 Nov 21.
PMID: 39572783 DOI: 10.1038/s41588-024-01952-y

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.

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