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Fulltext Cell-based therapy for the treatment of focal articular cartilage lesions: a review of six years od studies in a Malaysian University Medical Centre

Samsudin EZ, Kamarul T

JUMMEC, 2014;17(2):1-11.
MyJurnal

Autologous chondrocyte implantation (ACI) is a significant technique that has gained widespread use for the treatment of focal articular cartilage damage. Since its inception in 2004, the Tissue Engineering Group (TEG) of the Faculty of Medicine, University Malaya has been dedicated to carrying out extensive research on this cell-based therapy. The objective of this report, comprising one clinical case report, six animal studies and one laboratory study, is to summarise and discuss TEG’s key findings. On the whole, we observed that the ACI technique was effective in regenerating hyaline-like cartilage in treated defects. Autologous chondrocytes and mesenchymal stem cells (MSC) were found to produce comparable tissue repair irrespective of the state of MSC differentiation, and the use of alginate-based scaffolding and oral pharmacotherapy (Glucosamine and Chondroitin Sulphate) was shown to enhance ACI-led tissue repair. ACI is suggested to be an efficient therapeutic option for the treatment of articular cartilage defects of the knee.
Advances in stem cells technologies and their commercialization potential

Kamarul T

Expert Rev Clin Pharmacol, 2013 Jul;6(4):363-5.
PMID: 23927663 DOI: 10.1586/17512433.2013.811804

The World Stem Cells & Regenerative Medicine Congress Asia 2013 held in Singapore from 19-21 March 2013 was attended by over 2000 industry attendees and 5000 registered visitors. The focus of the congress was to discuss potential uses of stem cells for various diagnostic and therapeutic applications, their market opportunity and the latest R&D, which would potentially find its way into the market in not too distant future. In addition to the traditional lectures presented by academic and industry experts, there were forums, discussions, posters and exhibits, which provided various platforms for researchers, potential industry partners and even various interest groups to discuss prospective development of the stem cell-related industry.
Fulltext Free radial forearm flap after partial glossectomy for squamous cell carcinoma of the tongue

Chuah, U.C., Kamarul, T., Sara, T.

JUMMEC, 2006;9(2):28-31.
MyJurnal

Squamous cell carcinoma of the tongue is a highly malignant condition and results in high mortality and morbidity in patients despite its early detection (1). Early surgical interventions have been found to reduce mortality but in many reports, tongue reconstructions using live grafts have been found to reduce normal tongue function of speech, swallow and taste. In contrast, our report using free radial forearm flap (FRFF) to reconstruct the defect left over after a radical tongue resection in a 38-year-old gentleman with oral cancer has shown promising results. This type of reconstruction has left the patient with a functional and cosmetically acceptable tongue with minimal alteration in recognizable speech.
N-O, carboxymethyl chitosan enhanced scaffold porosity and biocompatibility under e-beam irradiation at 50 kGy

Lee SY, Kamarul T

Int J Biol Macromol, 2014 Mar;64:115-22.
PMID: 24325858 DOI: 10.1016/j.ijbiomac.2013.11.039

In this study, a chitosan co-polymer scaffold was prepared by mixing poly(vinyl alcohol) (PVA), NO, carboxymethyl chitosan (NOCC) and polyethylene glycol (PEG) solutions to obtain desirable properties for chondrocyte cultivation. Electron beam (e-beam) radiation was used to physically cross-link these polymers at different doses (30 kGy and 50 kGy). The co-polymers were then lyophilized to form macroporous three-dimensional (3-D) matrix. Scaffold morphology, porosity, swelling properties, biocompatibility, expression of glycosaminoglycan (GAG) and type II collagen following the seeding of primary chondrocytes were studied up to 28 days. The results demonstrate that irradiation of e-beam at 50 kGy increased scaffold porosity and pore sizes subsequently enhanced cell attachment and proliferation. Scanning electron microscopy and transmission electron microscopy revealed extensive interconnected microstructure of PVA-PEG-NOCC, demonstrated cellular activities on the scaffolds and their ability to maintain chondrocyte phenotype. In addition, the produced PVA-PEG-NOCC scaffolds showed superior swelling properties, and increased GAG and type II collagen secreted by the seeded chondrocytes. In conclusion, the results suggest that by adding NOCC and irradiation cross-linking at 50 kGy, the physical and biological properties of PVA-PEG blend can be further enhanced thereby making PVA-PEG-NOCC a potential scaffold for chondrocytes.
Fulltext Traumatic hip dislocation in late pregnancy: a case report

Kamarul T, Loh WYC

Med J Malaysia, 2005 Jul;60 Suppl C:114-6.
PMID: 16381296

Hip dislocation in pregnancy is an uncommon injury. We report a case of traumatic hip dislocation in the third trimester of pregnancy to highlight potential problems associated with its treatment. The rationale for choosing the preferred treatment options is discussed.
The comparison between the different generations of autologous chondrocyte implantation with other treatment modalities: a systematic review of clinical trials

Samsudin EZ, Kamarul T

Knee Surg Sports Traumatol Arthrosc, 2016 Dec;24(12):3912-3926.
PMID: 26003481

PURPOSE: This paper aims to review the current evidence for autologous chondrocyte implantation (ACI) generations relative to other treatment modalities, different cell delivery methods and different cell source application.
METHODS: Literature search was performed to identify all level I and II studies reporting the clinical and structural outcome of any ACI generation in human knees using the following medical electronic databases: PubMed, EMBASE, Cochrane Library, CINAHL, SPORTDiscus and NICE healthcare database. The level of evidence, sample size calculation and risk of bias were determined for all included studies to enable quality assessment.
RESULTS: Twenty studies were included in the analysis, reporting on a total of 1094 patients. Of the 20 studies, 13 compared ACI with other treatment modalities, seven compared different ACI cell delivery methods, and one compared different cell source for implantation. Studies included were heterogeneous in baseline design, preventing meta-analysis. Data showed a trend towards similar outcomes when comparing ACI generations with other repair techniques and when comparing different cell delivery methods and cell source selection. Majority of the studies (80 %) were level II evidence, and overall the quality of studies can be rated as average to low, with the absence of power analysis in 65 % studies.
CONCLUSION: At present, there are insufficient data to conclude any superiority of ACI techniques. Considering its two-stage operation and cost, it may be appropriate to reserve ACI for patients with larger defects or those who have had inadequate response to other repair procedures until hard evidence enables specific clinical recommendations be made.
LEVEL OF EVIDENCE: II.
The effect of TGF-beta1 and beta-estradiol on glycosaminoglycan and type II collagen distribution in articular chondrocyte cultures

Ab-Rahim S, Selvaratnam L, Kamarul T

Cell Biol Int, 2008 Jul;32(7):841-7.
PMID: 18479947 DOI: 10.1016/j.cellbi.2008.03.016

Articular cartilage extracellular matrix (ECM) plays a crucial role in regulating chondrocyte functions via cell-matrix interaction, cytoskeletal organization and integrin-mediated signaling. Factors such as interleukins, basic fibroblast growth factor (bFGF), bone morphogenic proteins (BMPs) and insulin-like growth factor (IGF) have been shown to modulate the synthesis of extracellular matrix in vitro. However, the effects of TGF-beta1 and beta-estradiol in ECM regulation require further investigation, although there have been suggestions that these factors do play a positive role. To establish the role of these factors on chondrocytes derived from articular joints, a study was conducted to investigate the effects of TGF-beta1 and beta-estradiol on glycosaminoglycan secretion and type II collagen distribution (two major component of cartilage ECM in vivo). Thus, chondrocyte cultures initiated from rabbit articular cartilage were treated with 10ng/ml of TGF-beta1, 10nM of beta-estradiol or with a combination of both factors. Sulphated glycosaminoglycan (GAG) and type II collagen levels were then measured in both these culture systems. The results revealed that the synthesis of GAG and type II collagen was shown to be enhanced in the TGF-beta1 treated cultures. This increase was also noted when TGF-beta1 and beta-estradiol were both used as culture supplements. However, beta-estradiol alone did not appear to affect GAG or type II collagen deposition. There was also no difference between the amount of collagen type II and GAG being expressed when chondrocyte cultures were treated with TGF-beta1 when compared with cultures treated with combined factors. From this, we conclude that although TGF-beta1 appears to stimulate chondrocyte ECM synthesis, beta-estradiol fails to produce similar effects. The findings of this study confirm that contrary to previous claims, beta-estradiol has little or no effect on chondrocyte ECM synthesis. Furthermore, the use of TGF-beta1 may be useful in future studies looking into biological mechanisms by which ECM synthesis in chondrocyte cultures can be augmented, particularly for clinical application.
Fulltext A Preliminary Study of Human Amniotic Membrane as a Potential Chondrocyte Carrier

Boo, L., Sofiah, S., Selvaratnam, L., Tai, C.C., Pingguan-Murphy, B., Kamarul, T.

Malays Orthop J, 2009;3(2):16-23.
MyJurnal

Purpose:To investigate the feasibilty of using processed human amniotic membrane (HAM) to support the attachment and proliferation of chondrocytes in vitro which it turn can be utilised as a cell delivery vehicle in tissue engineering applications. Methods: Fresh HAM obtained from patients undergoing routine elective ceasarean sections was harvested., processed and dried using either freez drying (FD) or air drying (AD) methods prior to sterilisation by gamma irradiation. Isolated, processed and characterised rabbit autologous chondrolytes were seeded on processsed HAM and cultured for up to three weeks. Cell attachment and proliferation were examined qualitatively using inverted brightfield microcospy. Results: Processed HAM appeared to allow cell attachment when implanted with chrondocytes. Although cells seeded on AD and FD HAM did not appear to attach as strongly as those seeded on glycerol preserved intact human amniotic membrane, these cells to be proliferated in cell culture conditions. Conclusion: Prelimanary results show that processed HAM chondrocyte attachment and proliferation.
Fulltext Tubercular synovitis mimicking rheumatoid nodules

Teo SC, George J, Kamarul T

Med J Malaysia, 2008 Jun;63(2):159-61.
PMID: 18942309 MyJurnal

Tubercular tenosynovitis is an uncommon condition and usually affects the upper limb. We report a case of a patient with Systemic Lupus Erythematosus who presented with wrist swelling. The clinical findings were suggestive of rheumatoid nodules, but the radiographic finding of calcification associated with the nodules and marked erosive changes primarily of the radio-carpal joint with sparing of the metacarpal joints led the radiologist to believe that the nodules may not be rheumatoid nodules. The presence of solid and fluid nature of the nodule and hyperechoic small echogenic foci (matted rice bodies within thickened synovium) on ultrasound suggested the presence of chronic synovitis of tuberculous infection rather than rheumatoid nodule as in our case. We recommend the use of ultrasound to determine the nature of nodular swellings seen clinically in patients with arthropathy.
Fulltext A modified Blatt dorsal capsulodesis in the treatment of dynamic scapholunate instability

Azura L, Ahmad TS, Kamarul T

Med J Malaysia, 2006 Dec;61 Suppl B:51-4.
PMID: 17600993

We report a case of scapholunate dissociation which was initially missed and presented late. A modification of Blatt dorsal capsulodesis performed using dorsal intercarpal ligament (DICL) and extra tunnel appears not only to add to dorsal stability but also address the volar problem as well. This modification may be a better alternative to the current technique of using a single flap.
Fulltext Autologous chondrocyte implantation for knee focal cartilage defects: 3 years' follow-up at the University Malaya Medical Centre

Abbas AA, Mohamad JA, Lydia AL, Selvaratnam L, Razif A, Ab-Rahim S, et al.

JUMMEC, 2014;17(1):8-13.
MyJurnal

Autologous chondrocyte implantation (ACI) is a widely accepted procedure for the treatment of large, fullthickness chondral defects involving various joints, but its use in developing countries is limited because of high cost and failure rates due to limited resources and support systems. Five patients (age
Stability of cervical spine after one-level corpectomy using different numbers of screws and plate systems

Rosli R, Abdul Kadir MR, Kamarul T

Proc Inst Mech Eng H, 2014 Apr;228(4):342-9.
PMID: 24622982 DOI: 10.1177/0954411914527074

Anterior corpectomy and reconstruction using a plate with locking screws are standard procedures for the treatment of cervical spondylotic myelopathy. Although adding more screws to the construct will normally result in improved fixation stability, several issues need to be considered. Past reports have suggested that increasing the number of screws can result in the increase in spinal rigidity, decreased spine mobility, loss of bone and, possibly, screw loosening. In order to overcome this, options to have constrained, semi-constrained or hybrid screw and plate systems were later introduced. The purpose of this study is to compare the stability achieved by four and two screws using different plate systems after one-level corpectomy with placement of cage. A three-dimensional finite-element model of an intact C1-C7 segment was developed from computer tomography data sets, including the cortical bone, soft tissue and simulated corpectomy fusion at C4-C5. A spinal cage and an anterior cervical plate with different numbers of screws and plate systems were constructed to a fit one-level corpectomy of C5. Moment load of 1.0 N m was applied to the superior surface of C1, with C7 was fixed in all degrees of freedom. The kinematic stability of a two-screw plate was found to be statistically equivalent to a four-screw plate for one-level corpectomy. Thus, it can be a better option of fusion and infers comparable stability after one-level anterior cervical corpectomy, instead of a four-screw plate.
Fulltext Recombinant human adiponectin as a potential protein for treating diabetic tendinopathy promotes tenocyte progenitor cells proliferation and tenogenic differentiation in vitro

Rothan HA, Suhaeb AM, Kamarul T

Int J Med Sci, 2013;10(13):1899-906.
PMID: 24324367 DOI: 10.7150/ijms.6774

Adiponectin is an adipocyte-secreting hormone that increases cell sensitivity to insulin. It has been previously demonstrated that this hormone protects against Type II Diabetes and, is found to concurrently promote cell proliferation and differentiation. It is postulated that diabetic patients who suffer from tendinopathy may benefit from using adiponectin, which not only improves the metabolism of diabetic ridden tenocytes but also promotes progenitor cell proliferation and differentiation in tendons. These changes may result in tendon regeneration, which, in diabetic tendinopathy, is difficult to treat. Considering that such findings have yet to be demonstrated, a study was thus conducted using diabetic ridden human tenocyte progenitor cells (TPC) exposed to recombinant adiponectin in vitro. TPC were isolated from tendons of diabetic patients and exposed to 10 μg/ml adiponectin. Cell proliferation rate was investigated at various time points whilst qPCR were used to determine the tenogenic differentiation potential. The results showed that adiponectin significantly reduced blood glucose in animal models. The proliferation rate of adiponectin-treated TPCs was significantly higher at 6, 8 and 10 days as compared to untreated cells (p<0.05). The levels of tenogenic genes expression (collagen I, III, tenomodulin and scleraxis) were also significantly upregulated; whilst the osteogenic (Runx2), chondrogenic (Sox9) and adipogenic (PPARУγ) gene expressions remained unaltered. The results of this study suggest that adiponectin is a potential promoter that not only improves diabetic conditions, but also increases tendon progenitor cell proliferation and differentiation. These features supports the notion that adiponectin may be potentially beneficial in treating diabetic tendinopathy.
Multiple regression analysis of factors influencing dominant hand grip strength in an adult Malaysian population

Hossain MG, Zyroul R, Pereira BP, Kamarul T

J Hand Surg Eur Vol, 2012 Jan;37(1):65-70.
PMID: 21816889 DOI: 10.1177/1753193411414639

Grip strength is an important measure used to monitor the progression of a condition, and to evaluate outcomes of treatment. We assessed how various physical and social factors predict normal grip strength in an adult Malaysian population of mixed Asian ethnicity (254 men, 246 women). Grip strength was recorded using the Jamar dynamometer. The mean grip strength for the dominant hand was 29.8 kg for men and 17.6 kg for women. Multiple regression analysis demonstrated that the dominant hand grip strength was positively associated with height and body mass index, and negatively associated with age for both sexes. Dominant hand grip strength was related to work status for men (p
A preliminary study of the effects of glucosamine sulphate and chondroitin sulphate on surgically treated and untreated focal cartilage damage

Kamarul T, Ab-Rahim S, Tumin M, Selvaratnam L, Ahmad TS

Eur Cell Mater, 2011 Mar 15;21:259-71; discussion 270-1.
PMID: 21409755

The effects of Glucosamine Sulphate (GS) and Chondroitin Sulphate (CS) on the healing of damaged and repaired articular cartilage were investigated. This study was conducted using 18 New Zealand white rabbits as experimental models. Focal cartilage defects, surgically created in the medial femoral condyle, were either treated by means of autologous chondrocyte implantation (ACI) or left untreated as controls. Rabbits were then divided into groups which received either GS+/-CS or no pharmacotherapy. Three rabbits from each group were sacrificed at 12 and 24 weeks post-surgery. Knees dissected from rabbits were then evaluated using gross quantification of repair tissue, glycosaminoglycan (GAG) assays, immunoassays and histological assessments. It was observed that, in contrast to untreated sites, surfaces of the ACI-repaired sites appeared smooth and continuous with the surrounding native cartilage. Histological examination demonstrated a typical hyaline cartilage structure; with proteoglycans, type II collagen and GAGs being highly expressed in repair areas. The improved regeneration of these repair sites was also noted to be significant over time (6 months vs. 3 months) and in GS and GS+CS groups compared to the untreated (without pharmacotherapy) group. Combination of ACI and pharmacotherapy (with glucosamine sulphate alone/ or with chondroitin sulphate) may prove beneficial for healing of damaged cartilage, particularly in relation to focal cartilage defects.
Fulltext A novel and improved method of predicting hand grip strength in the adult Malaysian population

Kamarul T, Ahmad TS, Loh WY

Med J Malaysia, 2006 Dec;61 Suppl B:37-44.
PMID: 17600991

Hand grip strength measurement is a recognized part of hand function assessment. The standard measurement using the Jamar dynamometer and comparing these results to the recommended normal values suggested by the manufacturers of the Jamar was questioned as these values were based on Western population. A study comparing a novel method of predicting grip strength using our software was conducted on 25 normal subjects using the LIDO kinetic workset (Group A and B ). These results were then compared against our predictive software (Group A) and the expected values supplied together with the Jamar Dynamometer (Group B). In another group, 22 normal subjects were tested using the Jamar (Group C and D) and then matched against the predicted values using their recommended chart (Group C). The last group (Group D) was tested using the Jamar but the values attained were compared to the results from our software. In group A, the predictability of our predictive method was 100% (both R & L) as compared to (R = 64%, L = 68%) in group B, (R = 27.3%, L = 59.1%) in group C and (R = 81.8%, L = 86.4%) in group D. The differences between the predictability of both methods were statistically significant. The data collected using both the Jamar and the LIDO kinetic workset correlated well to the data from our software but not to the values suggested by the manufacturers of Jamar. We conclude that our method of predicting hand grip values are superior to that suggested by the manufacturers of dynamometers. The standard reference for hand grip strength provided by the manufacturers is less accurate in predicting the grip strength of our local population.
Hand grip strength in the adult Malaysian population

Kamarul T, Ahmad TS, Loh WY

J Orthop Surg (Hong Kong), 2006 Aug;14(2):172-7.
PMID: 16914783

To measure the hand grip strength of Malaysians aged 18 to 65 years.
The prevention and treatment of hypoadiponectinemia-associated human diseases by up-regulation of plasma adiponectin

Hossain MM, Mukheem A, Kamarul T

Life Sci, 2015 Aug 15;135:55-67.
PMID: 25818192 DOI: 10.1016/j.lfs.2015.03.010

Hypoadiponectinemia is characterized by low plasma adiponectin levels that can be caused by genetic factors, such as single nucleotide polymorphisms (SNPs) and mutations in the adiponectin gene or by visceral fat deposition/obesity. Reports have suggested that hypoadiponectinemia is associated with dyslipidemia, hypertension, hyperuricemia, metabolic syndrome, atherosclerosis, type 2 diabetes mellitus and various cardiovascular diseases. Previous studies have highlighted several potential strategies to up-regulate adiponectin secretion and function, including visceral fat reduction through diet therapy and exercise, administration of exogenous adiponectin, treatment with peroxisome proliferator-activating receptor gamma (PPARγ) agonists (e.g., thiazolidinediones (TZDs)) and ligands (e.g., bezafibrate and fenofibrate) or the blocking of the renin-angiotensin system. Likewise, the up-regulation of the expression and stimulation of adiponectin receptors by using adiponectin receptor agonists would be an effective method to treat obesity-related conditions. Notably, adiponectin is an abundantly expressed bioactive protein that also exhibits a wide spectrum of biological properties, such as insulin-sensitizing, anti-diabetic, anti-inflammatory and anti-atherosclerotic activities. Although targeting adiponectin and its receptors has been useful for treating diabetes and other metabolic-related diseases in experimental studies, current drug development based on adiponectin/adiponectin receptors for clinical applications is scarce, and there is a lack of available clinical trial data. This comprehensive review discusses the strategies that are presently being pursued to harness the potential of adiponectin up-regulation. In addition, we examined the current status of drug development and its potential for clinical applications.
Fulltext Normal anterior cruciate ligament laxity in the Malaysian population

Kamarul T, Razif A, Elina R, Azura M, Chan KY

Malays Orthop J, 2007;1(2):11-16.
MyJurnal

A study to determine average knee laxity in the Malaysian population and how it affects daily living was conducted at the University Malaya Medical Centre between January and April 2004. Fifty two male and 76 female subjects were recruited for this study, all of whom were healthy volunteers with no ambulatory problems. Side to side knee laxity testing was performed using a KT-1000 arthrometer. Significant differences in knee laxity were noted among different races and between sexes. For instance, overall, Chinese and female study participants had higher knee laxity: (left knee, 2.17 mm (SD=1.30) and right knee was 2.88 mm (SD= 1.51)). On average, the difference between knees was 0.70 ± 1.26 mm (less than 1 mm) which is a smaller variation than reported in previous studies which suggested 3 mm. Despite finding knee laxity ranging from 0 to 8mm, no correlations were found between Lysholm, IKDC and Tegner knee outcome scores and the degree of knee laxity. No other predictors such as height, weight and age correlated with levels of knee laxity. We therefore conclude that knee laxity is a common occurrence in the normal population and is therefore not suitable as a sole predictor of knee function and should not be used as the only criteria for surgical intervention.
Study site: Orthopedic clinic, Universiti Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia
Genetically modified mesenchymal stem/stromal cells transfected with adiponectin gene can stably secrete adiponectin

Hossain MM, Murali MR, Kamarul T

Life Sci, 2017 Aug 01;182:50-56.
PMID: 28606849 DOI: 10.1016/j.lfs.2017.06.007

AIMS: Mesenchymal stem/stromal cells (MSCs) hold promises for the treatment of diverse diseases and regeneration of injured tissues. Genetic modification of MSCs through gene delivery might enhance their therapeutic potential. Adiponectin has been appeared as a potential biomarker for predicting various diseases. Plasma adiponectin levels are negatively correlated with various metabolic and vascular diseases and supplementation of exogenous adiponectin ameliorates the diseases. This study aims to develop adiponectin secreting genetically modified MSCs (GM-MSCs) as a potent strategic tool to complement endogenous adiponectin for the treatment of adiponectin deficiency diseases.
MAIN METHODS: Human bone marrow derived MSCs were isolated, expanded in vitro and transfected with adiponectin gene containing plasmid vector. Total RNA was extracted and cDNA was prepared by reverse transcription polymerase chain reaction (RT-PCR). The expression of adiponectin gene and protein in GM-MSCs was analyzed by PCR and Western blotting respectively. The secretion of adiponectin protein from GM-MSCs was analyzed by enzyme-linked immunosorbent assay.
KEY FINDINGS: The expression of adiponectin gene and plasmid DNA was detected in GM-MSCs but not in control group of MSCs. Adiponectin gene expression was detected in GM-MSCs at 2, 7, 14, 21 and 28days after transfection. Western blotting analysis revealed the expression of adiponectin protein only in GM-MSCs. The GM-MSCs stably secreted adiponectin protein into culture media at least for 4weeks.
SIGNIFICANCE: GM-MSCs express and secret adiponectin protein. Therefore, these adiponectin secreting GM-MSCs could be instrumental for the supplementation of adiponectin in the treatment of adiponectin deficiency related diseases.

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