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Percutaneous intramedullary supracondylar nailing for fractures of distal femur

Patel K, Kapoor A, Daveshwar R, Golwala P

Med J Malaysia, 2004 May;59 Suppl B:206-7.
PMID: 15468890

A prospective study of 25 patients with supracondylar and intercondylar fracture of the femur was carried out from January 1999 to June 2003 at SSG Hospital, Baroda, India. Twenty-eight percent fractures were open and 72% were closed. Twelve pecent of the fractures had intraarticular extension. AO classification was used to classify the fractures. Eighty-four percent of the fractures were due to high velocity trauma. All the cases were operated by percutaneous supracondylar nailing. No postoperative complication related to fracture treatment was seen. Average follow up was 20.1 months (range 6-40 months). Average age of the patients was 31.5 years. Average time of union was 3.1 months (range 2-4 months). Average knee range of motion was 117 degrees. Even in open injuries, 85.7% had more than 110 infinity range of motion. All patients could return to their pre-injury lifestyle. Rating scale developed by Hospital for Special Surgery was used to quantify the results. Eighty-four percent showed excellent, 8% showed good and 8% showed fair results. Percutaneous supracondylar nailing is thus, an excellent method of treating fractures of distal femur.
A Revised Diagnostic Quantitative RT-PCR for the Detection of Nipah Virus Infection

Patel K, Klena J, Lo MK

Methods Mol Biol, 2023;2682:25-31.
PMID: 37610571 DOI: 10.1007/978-1-0716-3283-3_2

From its discovery in Malaysia in the late 1990s, the spillover of the Nipah virus from its pteropid reservoir into the human population has resulted in sporadic outbreaks of fatal encephalitis and respiratory disease. In this chapter, we revise a previously described quantitative reverse transcription polymerase chain reaction method, which now utilizes degenerate nucleotides at certain positions in the probe and the reverse primer to accommodate the sequence heterogeneity observed within the Nipah henipavirus species.
Fulltext The formyl peptide fMLF primes platelet activation and augments thrombus formation

Salamah MF, Ravishankar D, Vaiyapuri R, Moraes LA, Patel K, Perretti M, et al.

J Thromb Haemost, 2019 Jul;17(7):1120-1133.
PMID: 31033193 DOI: 10.1111/jth.14466

Essentials The role of formyl peptide receptor 1 (FPR1) and its ligand, fMLF, in the regulation of platelet function, hemostasis, and thrombosis is largely unknown. Fpr1-deficient mice and selective inhibitors for FPR1 were used to investigate the function of fMLF and FPR1 in platelets. N-formyl-methionyl-leucyl-phenylalanine primes platelet activation and augments thrombus formation, mainly through FPR1 in platelets. Formyl peptide receptor 1 plays a pivotal role in the regulation of platelet function.
BACKGROUND: Formyl peptide receptors (FPRs) play pivotal roles in the regulation of innate immunity and host defense. The FPRs include three family members: FPR1, FPR2/ALX, and FPR3. The activation of FPR1 by its high-affinity ligand, N-formyl-methionyl-leucyl-phenylalanine (fMLF) (a bacterial chemoattractant peptide), triggers intracellular signaling in immune cells such as neutrophils and exacerbates inflammatory responses to accelerate the clearance of microbial infection. Notably, fMLF has been demonstrated to induce intracellular calcium mobilization and chemotaxis in platelets that are known to play significant roles in the regulation of innate immunity and inflammatory responses. Despite a plethora of research focused on the roles of FPR1 and its ligands such as fMLF on the modulation of immune responses, their impact on the regulation of hemostasis and thrombosis remains unexplored.
OBJECTIVE: To determine the effects of fMLF on the modulation of platelet reactivity, hemostasis, and thrombus formation.
METHODS: Selective inhibitors for FPR1 and Fpr1-deficient mice were used to determine the effects of fMLF and FPR1 on platelets using various platelet functional assays.
RESULTS: N-formyl-methionyl-leucyl-phenylalanine primes platelet activation through inducing distinctive functions and enhances thrombus formation under arterial flow conditions. Moreover, FPR1 regulates normal platelet function as its deficiency in mouse or blockade in human platelets using a pharmacological inhibitor resulted in diminished agonist-induced platelet activation.
CONCLUSION: Since FPR1 plays critical roles in numerous disease conditions, its influence on the modulation of platelet activation and thrombus formation may provide insights into the mechanisms that control platelet-mediated complications under diverse pathological settings.
Fulltext Effect of ultrapure lipopolysaccharides derived from diverse bacterial species on the modulation of platelet activation

Vallance TM, Ravishankar D, Albadawi DAI, Layfield H, Sheard J, Vaiyapuri R, et al.

Sci Rep, 2019 12 03;9(1):18258.
PMID: 31796818 DOI: 10.1038/s41598-019-54617-w

Platelets are small circulating blood cells that play essential roles in the maintenance of haemostasis via blood clotting. However, they also play critical roles in the regulation of innate immune responses. Inflammatory receptors, specifically Toll-like receptor (TLR)-4, have been reported to modify platelet reactivity. A plethora of studies have reported controversial functions of TLR4 in the modulation of platelet function using various chemotypes and preparations of its ligand, lipopolysaccharide (LPS). The method of preparation of LPS may explain these discrepancies however this is not fully understood. Hence, to determine the impact of LPS on platelet activation, we used ultrapure preparations of LPS from Escherichia coli (LPSEC), Salmonella minnesota (LPSSM), and Rhodobacter sphaeroides (LPSRS) and examined their actions under diverse experimental conditions in human platelets. LPSEC did not affect platelet activation markers such as inside-out signalling to integrin αIIbβ3 or P-selectin exposure upon agonist-induced activation in platelet-rich plasma or whole blood whereas LPSSM and LPSRS inhibited platelet activation under specific conditions at supraphysiological concentrations. Overall, our data demonstrate that platelet activation is not largely influenced by any of the ultrapure LPS chemotypes used in this study on their own except under certain conditions.
Isorhapontigenin, a resveratrol analogue selectively inhibits ADP-stimulated platelet activation

Ravishankar D, Albadawi DAI, Chaggar V, Patra PH, Williams HF, Salamah M, et al.

Eur J Pharmacol, 2019 Nov 05;862:172627.
PMID: 31461638 DOI: 10.1016/j.ejphar.2019.172627

Isorhapontigenin is a polyphenolic compound found in Chinese herbs and grapes. It is a methoxylated analogue of a stilbenoid, resveratrol, which is well-known for its various beneficial effects including anti-platelet activity. Isorhapontigenin possesses greater oral bioavailability than resveratrol and has also been identified to possess anti-cancer and anti-inflammatory properties. However, its effects on platelet function have not been reported previously. In this study, we report the effects of isorhapontigenin on the modulation of platelet function. Isorhapontigenin was found to selectively inhibit ADP-induced platelet aggregation with an IC50 of 1.85 μM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100 μM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50 > 100 μM) but inhibited collagen induced platelet aggregation at 50 μM and 100 μM. Isorhapontigenin also inhibited integrin αIIbβ3 mediated inside-out and outside-in signalling and dense granule secretion in ADP-induced platelet activation but interestingly, no effect was observed on α-granule secretion. Isorhapontigenin did not exert any cytotoxicity on platelets at the concentrations of up to 100 μM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85 μM). In addition, the mechanistic studies demonstrated that isorhapontigenin increased cAMP levels and VASP phosphorylation at Ser157 and decreased Akt phosphorylation. This suggests that isorhapontigenin may interfere with cAMP and PI3K signalling pathways that are associated with the P2Y12 receptor. Molecular docking studies emphasised that isorhapontigenin has greater binding affinity to P2Y12 receptor than resveratrol. Our results demonstrate that isorhapontigenin has selective inhibitory effects on ADP-stimulated platelet activation possibly via P2Y12 receptor.
Fulltext Mechanisms underpinning the permanent muscle damage induced by snake venom metalloprotease

Williams HF, Mellows BA, Mitchell R, Sfyri P, Layfield HJ, Salamah M, et al.

PLoS Negl Trop Dis, 2019 01;13(1):e0007041.
PMID: 30695027 DOI: 10.1371/journal.pntd.0007041

Snakebite is a major neglected tropical health issue that affects over 5 million people worldwide resulting in around 1.8 million envenomations and 100,000 deaths each year. Snakebite envenomation also causes innumerable morbidities, specifically loss of limbs as a result of excessive tissue/muscle damage. Snake venom metalloproteases (SVMPs) are a predominant component of viper venoms, and are involved in the degradation of basement membrane proteins (particularly collagen) surrounding the tissues around the bite site. Although their collagenolytic properties have been established, the molecular mechanisms through which SVMPs induce permanent muscle damage are poorly understood. Here, we demonstrate the purification and characterisation of an SVMP from a viper (Crotalus atrox) venom. Mass spectrometry analysis confirmed that this protein is most likely to be a group III metalloprotease (showing high similarity to VAP2A) and has been referred to as CAMP (Crotalus atrox metalloprotease). CAMP displays both collagenolytic and fibrinogenolytic activities and inhibits CRP-XL-induced platelet aggregation. To determine its effects on muscle damage, CAMP was administered into the tibialis anterior muscle of mice and its actions were compared with cardiotoxin I (a three-finger toxin) from an elapid snake (Naja pallida) venom. Extensive immunohistochemistry analyses revealed that CAMP significantly damages skeletal muscles by attacking the collagen scaffold and other important basement membrane proteins, and prevents their regeneration through disrupting the functions of satellite cells. In contrast, cardiotoxin I destroys skeletal muscle by damaging the plasma membrane, but does not impact regeneration due to its inability to affect the extracellular matrix. Overall, this study provides novel insights into the mechanisms through which SVMPs induce permanent muscle damage.
Fulltext Trends of HIV-Related Cancer Mortality between 2001 and 2018: An Observational Analysis

Jani C, Al Omari O, Singh H, Walker A, Patel K, Mouchati C, et al.

Trop Med Infect Dis, 2021 Dec 20;6(4).
PMID: 34941669 DOI: 10.3390/tropicalmed6040213

The burden of AIDS-defining cancers has remained relatively steady for the past two decades, whilst the burden of non-AIDS-defining cancer has increased. Here, we conduct a study to describe mortality trends attributed to HIV-associated cancers in 31 countries. We extracted HIV-related cancer mortality data from 2001 to 2018 from the World Health Organization Mortality Database. We computed age-standardized death rates (ASDRs) per 100,000 population using the World Standard Population. Data were visualized using Locally Weighted Scatterplot Smoothing (LOWESS). Data for females were available for 25 countries. Overall, there has been a decrease in mortality attributed to HIV-associated cancers among most of the countries. In total, 18 out of 31 countries (58.0%) and 14 out of 25 countries (56.0%) showed decreases in male and female mortality, respectively. An increasing mortality trend was observed in many developing countries, such as Malaysia and Thailand, and some developed countries, such as the United Kingdom. Malaysia had the greatest increase in male mortality (+495.0%), and Canada had the greatest decrease (-88.5%). Thailand had the greatest increase in female mortality (+540.0%), and Germany had the greatest decrease (-86.0%). At the endpoint year, South Africa had the highest ASDRs for both males (16.8/100,000) and females (19.2/100,000). The lowest was in Japan for males (0.07/100,000) and Egypt for females (0.028/100,000).
Carbon Monoxide is an Inhibitor of HIF Prolyl Hydroxylase Domain 2

Mbenza NM, Nasarudin N, Vadakkedath PG, Patel K, Ismail AZ, Hanif M, et al.

Chembiochem, 2021 08 03;22(15):2521-2525.
PMID: 34137488 DOI: 10.1002/cbic.202100181

Hypoxia-inducible factor prolyl hydroxylase domain 2 (PHD2) is an important oxygen sensor in animals. By using the CO-releasing molecule-2 (CORM-2) as an in situ CO donor, we demonstrate that CO is an inhibitor of PHD2. This report provides further evidence about the emerging role of CO in oxygen sensing and homeostasis.
Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria: An Open-Label Randomized Controlled Trial CAN KNOW

Grigg MJ, William T, Barber BE, Rajahram GS, Menon J, Schimann E, et al.

Clin Infect Dis, 2018 Jan 06;66(2):229-236.
PMID: 29020373 DOI: 10.1093/cid/cix779

BACKGROUND: Plasmodium knowlesi is reported increasingly across Southeast Asia and is the most common cause of malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria.
METHODS: A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis.
RESULTS: From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events.
CONCLUSIONS: AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia.
CLINICAL TRIALS REGISTRATION: NCT02001012.
Fulltext Age-Related Clinical Spectrum of Plasmodium knowlesi Malaria and Predictors of Severity

Grigg MJ, William T, Barber BE, Rajahram GS, Menon J, Schimann E, et al.

Clin Infect Dis, 2018 Jul 18;67(3):350-359.
PMID: 29873683 DOI: 10.1093/cid/ciy065

BACKGROUND: Plasmodium knowlesi is increasingly reported in Southeast Asia, but prospective studies of its clinical spectrum in children and comparison with autochthonous human-only Plasmodium species are lacking.
METHODS: Over 3.5 years, we prospectively assessed patients of any age with molecularly-confirmed Plasmodium monoinfection presenting to 3 district hospitals in Sabah, Malaysia.
RESULTS: Of 481 knowlesi, 172 vivax, and 96 falciparum malaria cases enrolled, 44 (9%), 71 (41%), and 31 (32%) children aged ≤12 years. Median parasitemia was lower in knowlesi malaria (2480/μL [interquartile range, 538-8481/μL]) than in falciparum (9600/μL; P < .001) and vivax malaria. In P. knowlesi, World Health Organization-defined anemia was present in 82% (95% confidence interval [CI], 67%-92%) of children vs 36% (95% CI, 31%-41%) of adults. Severe knowlesi malaria occurred in 6.4% (95% CI, 3.9%-8.3%) of adults but not in children; the commenst severity criterion was acute kideny injury. No patient had coma. Age, parasitemia, schizont proportion, abdominal pain, and dyspnea were independently associated with severe knowlesi malaria, with parasitemia >15000/μL the best predictor (adjusted odds ratio, 16.1; negative predictive value, 98.5%; P < .001). Two knowlesi-related adult deaths occurred (fatality rate: 4.2/1000 adults).
CONCLUSIONS: Age distribution and parasitemia differed markedly in knowlesi malaria compared to human-only species, with both uncomplicated and severe disease occurring at low parasitemia. Severe knowlesi malaria occurred only in adults; however, anemia was more common in children despite lower parasitemia. Parasitemia independently predicted knowlesi disease severity: Intravenous artesunate is warranted initially for those with parasitemia >15000/μL.
Fulltext Rickettsioses as Major Etiologies of Unrecognized Acute Febrile Illness, Sabah, East Malaysia

Grigg MJ, William T, Clemens EG, Patel K, Chandna A, Wilkes CS, et al.

Emerg Infect Dis, 2020 Jul;26(7):1409-19.
PMID: 32568664 DOI: 10.3201/eid2607.191722

Orientia tsutsugamushi, spotted fever group rickettsioses, and typhus group rickettsioses (TGR) are reemerging causes of acute febrile illness (AFI) in Southeast Asia. To further delineate extent, we enrolled patients >4 weeks of age with nonmalarial AFI in Sabah, Malaysia, during 2013-2015. We confirmed rickettsioses (past or acute, IgG titer >160) in 126/354 (36%) patients. We confirmed acute rickettsioses (paired 4-fold IgG titer rise to >160) in 38/145 (26%) patients: 23 O. tsutsugamushi, 9 spotted fever group, 4 TGR, 1 O. tsutsugamushi/spotted fever group, and 1 O. tsutsugamushi/TGR. PCR results were positive in 11/319 (3%) patients. Confirmed rickettsioses were more common in male adults; agricultural/plantation work and recent forest exposure were risk factors. Dizziness and acute hearing loss but not eschars were reported more often with acute rickettsioses. Only 2 patients were treated with doxycycline. Acute rickettsioses are common (>26%), underrecognized, and untreated etiologies of AFI in East Malaysia; empirical doxycycline treatment should be considered.

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