Definite stent thrombosis among Malaysian population: predictors and insights of mechanisms from intracoronary imaging.

Med J Malaysia. 2020 Sep;75(5):472-478

Authors: Lim KC, Yap LB, Amin AN

Abstract
INTRODUCTION: Stent thrombosis (ST) is an uncommon, but significant complication following angioplasty. We aimed to examine the predictors, clinical outcomes and mechanism of definite ST cases among patients who underwent percutaneous coronary intervention (PCI).
METHODS: This was a retrospective observational registry of 14,935 patients from the year 2011 till 2015. Clinical characteristics, clinical outcome and intracoronary imaging data were recorded in all the patients. The SPSS Statistic version 24 was used for statistical analysis. The Cox regression hazard model was used to report calculate the hazard ratio (HR) with a 95% confidence interval (95%CI). Independent predictors of ST were identified by univariate logistic regression analysis. Variables that showed a statistically significant effect in univariate analyses were entered in a multivariate Cox proportional hazards model. A p-value<0.05 was regarded as significant.
RESULTS: The incidence of definite ST was 0.25% (37 out of 14935 patients). 75% of ST group patients presented with ST elevation myocardial infarction (75% vs. 19.8%, p<0.01). There was higher mortality among patients with ST when compared to the group without ST (Hazard Ratio, HR=10.69, 95%CI: 1.13, 100). Two independent predictors of ST were 1) previous history of acute myocardial infarction (HR=2.36, 95%CI: 1.19, 4.70) and 2) PCI in the context of acute coronary syndrome when compared to elective PCI (HR=37, 95%CI: 15.7, 91.5). Examination of 19 ST cases with intracoronary imaging identified nine cases (47%) of underexpanded stents and five cases (26%) of malopposition of stents.
CONCLUSIONS: ST is associated with high mortality. PCI in acute coronary syndrome setting and a previous history of acute myocardial infarction were significant predictors for ST. Intracoronary imaging identified stent underexpansion and malopposition as common reasons for ST. In cases where the risk of ST is high, the use of intracoronary imaging guided PCI is recommended.

PMID: 32918412 [PubMed - in process]

A Rare Case of Acute Hemorrhagic Leukoencephalitis in a COVID-19 Patient.

J Neurol Sci. 2020 Jul 15;416:117035

Authors: Yong MH, Chan YFZ, Liu J, Sanamandra SK, Kheok SW, Lim KC, Sewa DW

PMID: 32738478 [PubMed - as supplied by publisher]

Cryptic asymptomatic parasellar high signal on time-of-flight MR angiography: how to resolve the clinical conundrum.

Neuroradiology. 2020 Jul 26;:

Authors: Lim KC, Raj S, Kee TP, Sim S, Ho Mien I, Ho JXM, McAdory LE, Lim WEH, Chan LL

Abstract
PURPOSE: Hyperintense parasellar signal on time-of-flight MR angiography (TOF-MRA) in asymptomatic patients may be due to a variety of nonpathological causes and mimic parasellar high flow signal in pathological arteriovenous shunts at the cavernous sinus (CSAVS). This creates a clinical conundrum between diagnosing an aggressive yet asymptomatic CSAVS subtype against exposing patients without CSAVS to potential complications of an invasive angiographic evaluation. We reviewed common nonpathological causes of hyperintense parasellar signal and contrast their imaging features against those of pathological CSAVS and proposed a systemic approach to resolve such conundrum.
METHODS: The anatomy of the cavernous sinus (CS) and causes of nonpathological parasellar hyperintense TOF-MRA signal are described and explained with case reviews, illustrations, and reference to published literature where appropriate. Imaging features of proven CSAVS are juxtaposed to aid in radiological differentiation. An algorithm is proposed to manage patients with such incidental TOF-MRA findings.
RESULTS: The margins, contour, extent, intensity, and stippling appearance aid in evaluation of pathological versus incidental TOF-MRA parasellar signal, and differentiation of CSAVS from nonpathological causes. Pertinent radiological features are summarized in a table. For unresolved cases suspected for CSAVS, further evaluation with dynamic time-resolved contrast-enhanced MRA is proposed and depicted in a decision tree flow chart.
CONCLUSION: Familiarity with the differentiating radiological features and a systematic management workflow could aid in resolving the clinical conundrum of findings of cryptic asymptomatic parasellar TOF-MRA high signal, while facilitating timely detection of the asymptomatic CSAVS.

PMID: 32715357 [PubMed - as supplied by publisher]

The endosymbiont Wolbachia rebounds following antibiotic treatment.

PLoS Pathog. 2020 07;16(7):e1008623

Authors: Gunderson EL, Vogel I, Chappell L, Bulman CA, Lim KC, Luo M, Whitman JD, Franklin C, Choi YJ, Lefoulon E, Clark T, Beerntsen B, Slatko B, Mitreva M, Sullivan W, Sakanari JA

Abstract
Antibiotic treatment has emerged as a promising strategy to sterilize and kill filarial nematodes due to their dependence on their endosymbiotic bacteria, Wolbachia. Several studies have shown that novel and FDA-approved antibiotics are efficacious at depleting the filarial nematodes of their endosymbiont, thus reducing female fecundity. However, it remains unclear if antibiotics can permanently deplete Wolbachia and cause sterility for the lifespan of the adult worms. Concerns about resistance arising from mass drug administration necessitate a careful exploration of potential Wolbachia recrudescence. In the present study, we investigated the long-term effects of the FDA-approved antibiotic, rifampicin, in the Brugia pahangi jird model of infection. Initially, rifampicin treatment depleted Wolbachia in adult worms and simultaneously impaired female worm fecundity. However, during an 8-month washout period, Wolbachia titers rebounded and embryogenesis returned to normal. Genome sequence analyses of Wolbachia revealed that despite the population bottleneck and recovery, no genetic changes occurred that could account for the rebound. Clusters of densely packed Wolbachia within the worm's ovarian tissues were observed by confocal microscopy and remained in worms treated with rifampicin, suggesting that they may serve as privileged sites that allow Wolbachia to persist in worms while treated with antibiotic. To our knowledge, these clusters have not been previously described and may be the source of the Wolbachia rebound.

PMID: 32639986 [PubMed - indexed for MEDLINE]

Astrocyte-Derived Exosomes in an iPSC Model of Bipolar Disorder.

Adv Neurobiol. 2020;25:219-235

Authors: Attili D, Schill DJ, DeLong CJ, Lim KC, Jiang G, Campbell KF, Walker K, Laszczyk A, McInnis MG, O'Shea KS

Abstract
Bipolar I Disorder (BP) is a serious, recurrent mood disorder that is characterized by alternating episodes of mania and depression. To begin to identify novel approaches and pathways involved in BP, we have obtained skin samples from BP patients and undiagnosed control (C) individuals, reprogrammed them to form induced pluripotent stem cells (iPSC), and then differentiated the stem cells into astrocytes. RNAs from BP and C astrocytes were extracted and RNAseq analysis carried out. 501 differentially expressed genes were identified, including genes for cytoskeletal elements, extracellular matrix, signaling pathways, neurodegeneration, and notably transcripts that identify exosomes. When we compared highly expressed genes using hierarchial cluster analysis, "Exosome" was the first and most highly significant cluster identified, p < 5 × 10-13, Benjamini correction. Exosomes are membrane-bound vesicles that package and remove toxic proteins from cells and also enable cell to cell communication. They carry genetic material, including DNA, mRNA and microRNAs, proteins, and lipids to target cells throughout the body. Exosomes are released by cortical neurons and astrocytes in culture and are present in BP vs C postmortem brain tissue. Little is known about what transcripts and proteins are targeted to neurons, how they regulate biological functions of the acceptor cell, or how that may be altered in mood disorders. Since astrocyte-derived exosomes have been suggested to promote neuronal plasticity, as well as to remove toxic proteins in the brain, alterations in their function or content may be involved in neurodevelopmental, neuropathological, and neuropsychiatric conditions. To examine exosome cargos and interactions with neural precursor cells, astrocytes were differentiated from four bipolar disorder (BP) and four control (C) iPSC lines. Culture supernatants from these astrocytes were collected, and exosomes isolated by ultra-centrifugation. Western blot analysis demonstrated the presence of the exosome markers CD9, CD81, and Hsp70. Nanosight technology was used to characterize exosomes from each astrocyte cell line, suggesting that exosomes were slightly more concentrated in culture supernatants derived from BP compared with C astrocytes but there was no difference in the mean sizes of the exosomes. Analysis of their function in neuronal differentiation is being carried out by labeling exosomes derived from bipolar patient and control astrocytes and adding them to control neural progenitor cells. Given the current interest in clearing toxic proteins from brains of patients with neurodegenerative disorders, exosomes may present similar opportunities in BP.

PMID: 32578149 [PubMed - in process]

PULMONARY ASPERGILLOMA.

QJM. 2020 Feb 20;:

Authors: Bashir A, Chauhdary WA, Rubel AR, Soe ZN, Hla Aye MT, Javed N, Mani BI, Lim KC, Chong VH

PMID: 32077956 [PubMed - as supplied by publisher]

Long-term Pulpal and Restorative Outcomes of Pulpotomy in Mature Permanent Teeth.

J Endod. 2020 Mar;46(3):383-390

Authors: Tan SY, Yu VSH, Lim KC, Tan BCK, Neo CLJ, Shen L, Messer HH

Abstract
INTRODUCTION: Pulpotomy in mature permanent cariously exposed teeth preserves the remaining pulp tissues, but long-term outcomes of the pulp and the restoration are unknown. This prospective study examined the immediate and long-term status of the pulp and the restored tooth and identified potential predictors of early and late failures in teeth that were asymptomatic or experiencing only mild symptoms at the time of treatment.
METHODS: Pulpotomy was performed using the aseptic technique and a tricalcium silicate cement under local anesthesia. Teeth were assessed for up to 5 years for pulpal and apical signs and symptoms, restorative marginal integrity, and periodontal health.
RESULTS: Fifty-two patients (61 teeth) with a median age of 40 years (range, 21-75 years) were included in this study; 17 (32.7%) men and 35 (67.3%) women were treated and reviewed. Overall pulp survival was 90.2% (95% confidence interval, 79.8%-96.3%); 6 teeth developed irreversible pulpitis or pulp necrosis when the restoration was intact. Preoperative pain was a potential predictor (P < .05) for early failure. Eleven late failures occurred between 2 and 4 years: 1 tooth with intact coronal restoration had pulp necrosis and asymptomatic apical periodontitis, 4 had recurrent caries resulting in asymptomatic apical periodontitis, 4 remained vital and only needed new restorations, 1 was unrestorable, and 1 was extracted for periodontal reasons. The type of definitive restoration was a potential predictor for late failure (P < .05).
CONCLUSIONS: Carious pulp exposures in asymptomatic mature permanent teeth can be predictably managed by pulpotomy using a tricalcium silicate cement. Short-term failures were few and managed by pulpectomy. Appropriate coronal restoration is critical to long-term success.

PMID: 31902641 [PubMed - indexed for MEDLINE]

Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 1. Amide Linked Analogs.

ACS Infect Dis. 2020 02 14;6(2):173-179

Authors: Akama T, Freund YR, Berry PW, Carter DS, Easom EE, Jarnagin K, Lunde CS, Plattner JJ, Rock F, Stefanakis R, Fischer C, Bulman CA, Lim KC, Suzuki BM, Tricoche N, Mansour A, DiCosty U, McCall S, Carson B, McCall JW, McKerrow J, Hübner MP, Specht S, Hoerauf A, Lustigman S, Sakanari JA, Jacobs RT

Abstract
A series of benzimidazole-benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness. The lead identified in this series, 8a (AN8799), was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound 8a was effective in killing Brugia malayi, B. pahangi, and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 28 days. The measurement of plasma levels of 8a at the end of the dosing period and at the time of sacrifice revealed an interesting dependence of activity on the extended exposure for both 8a and the positive control, flubendazole.

PMID: 31876154 [PubMed - in process]

Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 2. Ketone Linked Analogs.

ACS Infect Dis. 2020 02 14;6(2):180-185

Authors: Carter DS, Jacobs RT, Freund YR, Berry PW, Akama T, Easom EE, Lunde CS, Rock F, Stefanakis R, McKerrow J, Fischer C, Bulman CA, Lim KC, Suzuki BM, Tricoche N, Sakanari JA, Lustigman S, Plattner JJ

Abstract
The optimization of a series of benzimidazole-benzoxaborole hybrid molecules linked via a ketone that exhibit good activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness, is described. The lead identified in this series, 21 (AN15470), was found to have acceptable pharmacokinetic properties to enable an evaluation following oral dosing in an animal model of onchocerciasis. Compound 21was effective in killing worms implanted in Mongolian gerbils when dosed orally as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 7 days.

PMID: 31876143 [PubMed - in process]

Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models.

Int J Parasitol Drugs Drug Resist. 2020 04;12:18-27

Authors: Hübner MP, Gunderson E, Vogel I, Bulman CA, Lim KC, Koschel M, Ehrens A, Frohberger SJ, Fendler M, Tricoche N, Voronin D, Steven A, Chi V, Bakowski MA, Woods AK, Petrassi HM, McNamara CW, Beerntsen B, Chappell L, Sullivan W, Taylor MJ, Turner JD, Hoerauf A, Lustigman S, Sakanari JA

Abstract
The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16-18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10-14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days.

PMID: 31869759 [PubMed - indexed for MEDLINE]

GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through miR-126.

Development. 2019 11 05;146(21):

Authors: Mahamud MR, Geng X, Ho YC, Cha B, Kim Y, Ma J, Chen L, Myers G, Camper S, Mustacich D, Witte M, Choi D, Hong YK, Chen H, Varshney G, Engel JD, Wang S, Kim TH, Lim KC, Srinivasan RS

Abstract
Mutations in the transcription factor GATA2 cause lymphedema. GATA2 is necessary for the development of lymphatic valves and lymphovenous valves, and for the patterning of lymphatic vessels. Here, we report that GATA2 is not necessary for valvular endothelial cell (VEC) differentiation. Instead, GATA2 is required for VEC maintenance and morphogenesis. GATA2 is also necessary for the expression of the cell junction molecules VE-cadherin and claudin 5 in lymphatic vessels. We identified miR-126 as a target of GATA2, and miR-126-/- embryos recapitulate the phenotypes of mice lacking GATA2. Primary human lymphatic endothelial cells (HLECs) lacking GATA2 (HLECΔGATA2) have altered expression of claudin 5 and VE-cadherin, and blocking miR-126 activity in HLECs phenocopies these changes in expression. Importantly, overexpression of miR-126 in HLECΔGATA2 significantly rescues the cell junction defects. Thus, our work defines a new mechanism of GATA2 activity and uncovers miR-126 as a novel regulator of mammalian lymphatic vascular development.

PMID: 31582413 [PubMed - indexed for MEDLINE]

Subdural haematoma mimics.

Clin Radiol. 2019 Sep;74(9):663-675

Authors: Lim M, Kheok SW, Lim KC, Venkatanarasimha N, Small JE, Chen RC

Abstract
A subdural haematoma (SDH) is a frequently encountered pathology seen on an emergency room computed tomography (CT) head scan. An extra-axial crescentic density along the convexity of the brain or within the interhemispheric fissure is generally thought to represent a SDH; however, SDH mimics are known to occur in nature, and can be broadly classified under the subcategories of normal anatomy, artefacts, tumour, inflammation, infection, ischaemia, trauma, and iatrogenic. Understanding the typical characteristics of a SDH, knowledge of normal anatomy, close inspection of the morphology of the subdural process, changes to the adjacent structures, and rigorous attention to clinical details may reveal subtle clues that distinguish a true SDH from a mimic. This is crucial in appropriately directing clinical management. This review amalgamates most of the rare subdural processes that have been reported to mimic SDH, and discusses the imaging and clinical features that help to differentiate between them. This topic is highly valuable for radiology trainees, general radiologists, and emergency room physicians, and may serve as a refresher for the practising neuroradiologist.

PMID: 31109715 [PubMed - indexed for MEDLINE]

Gender differences in health status, quality of life, and community service needs of older adults living alone.

Arch Gerontol Geriatr. 2019 Jul - Aug;83:239-245

Authors: Ko H, Park YH, Cho B, Lim KC, Chang SJ, Yi YM, Noh EY, Ryu SI

Abstract
OBJECTIVES: The aim of this study was to identify gender differences in the health status, community service needs, and quality of life of older adults living alone in an urban city in South Korea.
METHODS: A cross-sectional descriptive correlational design was used. The study sampled 1023 older adults (≥65 years) living alone in S* City, during the period from August to October in 2018. Trained interviewers conducted face-to-face interviews with the participants, using the UCLA Loneliness Scale, Short Form Geriatric Depression Scale - Korean version, ENRICHD Social Support Instrument (ESSI), the Mini-Mental State Examination Standard Version (MMSE-2SV), and Health-Related Quality of Life (EQ-5D).
RESULTS: 77.8% were women and the mean age was 77.38 years (men = 74.65, women = 78.16). Women had lower socioeconomic and health status than men. Men felt more lonely, depressed, and had suicidal thoughts more frequently than women. Women had more needs regarding care, residential environment, movement, connection, and emergency services than men. In men, depressive symptoms, suicidal thoughts, loneliness, and right-hand grip strength were identified using the EQ-5D. The EQ-5D was also used to explain depressive symptoms, suicidal thoughts, cognitive function, and physical activity in women.
CONCLUSION: Health status and community service needs were dependent on gender; therefore interventions should be tailored according to gender. Our research found that to decrease depression and suicidal thoughts, improve physical health, and enhance quality of life for older adults living alone, interventions need to be designed to decrease male loneliness and to enhance female cognitive function.

PMID: 31102926 [PubMed - indexed for MEDLINE]

Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi.

PLoS Negl Trop Dis. 2019 01;13(1):e0006787

Authors: Fischer C, Ibiricu Urriza I, Bulman CA, Lim KC, Gut J, Lachau-Durand S, Engelen M, Quirynen L, Tekle F, Baeten B, Beerntsen B, Lustigman S, Sakanari J

Abstract
River blindness and lymphatic filariasis are two filarial diseases that globally affect millions of people mostly in impoverished countries. Current mass drug administration programs rely on drugs that primarily target the microfilariae, which are released from adult female worms. The female worms can live for several years, releasing millions of microfilariae throughout the course of infection. Thus, to stop transmission of infection and shorten the time to elimination of these diseases, a safe and effective drug that kills the adult stage is needed. The benzimidazole anthelmintic flubendazole (FBZ) is 100% efficacious as a macrofilaricide in experimental filarial rodent models but it must be administered subcutaneously (SC) due to its low oral bioavailability. Studies were undertaken to assess the efficacy of a new oral amorphous solid dispersion (ASD) formulation of FBZ on Brugia pahangi infected jirds (Meriones unguiculatus) and compare it to a single or multiple doses of FBZ given subcutaneously. Results showed that worm burden was not significantly decreased in animals given oral doses of ASD FBZ (0.2-15 mg/kg). Regardless, doses as low as 1.5 mg/kg caused extensive ultrastructural damage to developing embryos and microfilariae (mf). SC injections of FBZ in suspension (10 mg/kg) given for 5 days however, eliminated all worms in all animals, and a single SC injection reduced worm burden by 63% compared to the control group. In summary, oral doses of ASD formulated FBZ did not significantly reduce total worm burden but longer treatments, extended takedown times or a second dosing regimen, may decrease female fecundity and the number of mf shed by female worms.

PMID: 30650084 [PubMed - indexed for MEDLINE]

Oral health status of the disabled compared with that of the non-disabled in Korea: A propensity score matching analysis.

PLoS One. 2019;14(1):e0208246

Authors: Lee JY, Lim KC, Kim SY, Paik HR, Kim YJ, Jin BH

Abstract
BACKGROUND: There are many types of disabilities, and each type has a variety related to socioeconomic factors. Such factors affect to many health problems of the disabled. However, surveys of the oral health status of the disabled in Korea are rare.
OBJECTIVE: The purpose of this study was to estimate oral health disparity through comparing oral health status of the disabled to the non-disabled, adjusted for the net effect of the disability on oral health status.
METHODS: A cross-sectional study was conducted among the disabled in urban and suburban areas in Korea from June to September 2016. People with physical, mental, and multiple disabilities took part in this survey. The clinical examinations were carried out by trained dentists. Statistical analysis was performed to quantify the association between oral health and socioeconomic status after restricting the analysis using a propensity score matching method.
RESULTS: The disabled had more DMFT, DT, and MT, fewer FT, and fewer teeth than the non-disabled based on entire groups (P<0.01). No difference in the ratio of periodontitis was observed. The subjects with mental disabilities (MD) scored 3.09 (95% CI, 1.07-8.97), and those with multiple disabilities scored 4.37 (95% CI, 1.16-16.37) for edentulous status. The MD had an odds ratio of 1.34 (95% CI, 1.03-1.74), and those with multiple disabilities had an odds ratio of 1.75 (95% CI, 1.11-2.76) for the DMFT index.
CONCLUSIONS: These results represent poor oral health status of the disabled compared to the non-disabled. Consequentially, we can verify that not only the existence of disability but also the type of disability has a decisive effect on oral health condition. This comparison is necessary to widen our approach to evaluate the actual status condition of the disabled.

PMID: 30640962 [PubMed - indexed for MEDLINE]

Clinics in diagnostic imaging (193). Sporadic Creutzfeldt-Jakob disease (sCJD).

Singapore Med J. 2018 12;59(12):634-641

Authors: Li JSY, Lim KC, Lim WEH, Chen RC

Abstract
A 68-year-old man presented with a three-week history of rapidly progressive dementia, gait ataxia and myoclonus. Subsequent electroencephalography showed periodic sharp wave complexes, and cerebrospinal fluid assay revealed the presence of a 14-3-3 protein. A probable diagnosis of sporadic Creutzfeldt-Jakob disease was made, which was further supported by magnetic resonance (MR) imaging of the brain showing asymmetric signal abnormality in the cerebral cortices and basal ganglia. The aetiology, clinical features, diagnostic criteria, various MR imaging patterns and radiologic differential diagnosis of sporadic Creutzfeldt-Jakob disease are discussed in this article.

PMID: 30631881 [PubMed - indexed for MEDLINE]

Starvation-induced diplopia and weakness: a case of beriberi and Wernicke's encephalopathy.

BMJ Case Rep. 2019 Jan 03;12(1):

Authors: Tan TXZ, Lim KC, Chan Chung C, Aung T

Abstract
A 56-year-old teetotaller man with hypertension and gout presented with a week duration of painless worsening diplopia on a background of loss of weight and appetite, generalised lethargy and weakness for 1 year. On examination, he was noted to be hypothermic and tachycardic with generalised muscle wasting. Proximal myopathy, lower limb fasciculations and areflexia, restricted bilateral eye abduction and nystagmus were observed. Blood investigations demonstrated compensated lactic acidosis, acute kidney injury and leucocytosis. A nerve conduction study showed severe length-dependent axonal sensorimotor polyneuropathy. This was a diagnostic dilemma until an MRI brain revealed symmetrical signal abnormality and enhancement in the periaqueductal area indicative of Wernicke's encephalopathy, caused by thiamine deficiency from poor nutrition. Beriberi, also caused by thiamine deficiency, accounted for his tachycardia, polyneuropathy, areflexia, hypothermia and biochemical abnormalities. Both beriberi and Wernicke's encephalopathy are medical emergencies, which were treated with intravenous thiamine to good effect.

PMID: 30610031 [PubMed - indexed for MEDLINE]

TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling.

Int J Parasitol Drugs Drug Resist. 2018 12;8(3):571-586

Authors: Wolfe AR, Neitz RJ, Burlingame M, Suzuki BM, Lim KC, Scheideler M, Nelson DL, Benet LZ, Caffrey CR

Abstract
Treatment of schistosomiasis relies precariously on just one drug, praziquantel (PZQ). In the search for alternatives, 15 S-[2-(alkylamino)alkane] thiosulfuric acids were obtained from a previous research program and profiled in mice for efficacy against both mature (>42-day-old) and juvenile (21-day-old) Schistosoma mansoni using a screening dose of 100 mg/kg PO QDx4. One compound, S-[2-(tert-butylamino)-1-phenylethane] thiosulfuric acid (TPT sulfonate), was the most effective by decreasing female and male worm burdens by ≥ 90% and ≥46% (mature), and ≥89% and ≥79% (juvenile), respectively. In contrast, PZQ decreased mature female and male worm burdens by 95% and 94%, respectively, but was ineffective against juvenile stages. Against 7-day-old lung-stage worms, TPT sulfonate was only effective at twice the dose decreasing female and male burdens by 95 and 80%, respectively. Single oral doses at 400 and/or 600 mg/kg across various developmental time-points (1-, 7-, 15-, 21- and/or 42 day-old) were consistent with the QD x4 data; efficacy was strongest once the parasites had completed lung migration, and female and male burdens were decreased by at least 90% and 80%, respectively. In vitro, TPT sulfonate is inactive against the parasite suggesting a pro-drug mechanism of action. In mice, TPT sulfonate is fully absorbed and subject to rapid, non-CYP-mediated, first-pass metabolism that is initiated by desulfation and yields a series of metabolites. The initially-formed free thiol-containing metabolite, termed TP thiol, was chemically synthesized; it dose-dependently decreased S. mansoni and Schistosoma haematobium motility in vitro. Also, when administered as a single 50 mg/kg IP dose, TP thiol decreased 33-day-old S. mansoni female and male burdens by 35% and 44%, with less severe organomegaly. Overall, TPT sulfonate's efficacy profile is competitive with that of PZQ. Also, the characterization of a parasiticidal metabolite facilitates an understanding and improvement of the chemistry, and identification of the mechanism of action and/or target.

PMID: 30503203 [PubMed - indexed for MEDLINE]

BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression.

Genes Dev. 2018 12 01;32(23-24):1537-1549

Authors: Yu L, Jearawiriyapaisarn N, Lee MP, Hosoya T, Wu Q, Myers G, Lim KC, Kurita R, Nakamura Y, Vojtek AB, Rual JF, Engel JD

Abstract
Human globin gene production transcriptionally "switches" from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the ε-globin and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzyme components (e.g., DNA methyltransferase 1 [DNMT1] and lysine-specific demethylase 1 [LSD1]) that elicit DRED function. We also describe a potent new regulator of γ-globin repression: The deubiquitinase BRCA1-associated protein-1 (BAP1) is a component of the repressor complex whose activity maintains NCoR1 at sites in the β-globin locus, and BAP1 inhibition in erythroid cells massively induces γ-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate γ-globin gene repression.

PMID: 30463901 [PubMed - indexed for MEDLINE]

Multimodal assessments of Zika virus immune pathophysiological responses in marmosets.

Sci Rep. 2018 11 20;8(1):17125

Authors: Lum FM, Zhang W, Lim KC, Malleret B, Teo TH, Koh JJ, Lee KJ, Chua TK, Kam YW, Yee WX, Huen I, Tan JJL, Amrun SN, Prakash Kn B, Cozzone PJ, Renia L, Lee PTH, Ng LFP

Abstract
Animal models that recapitulate the human pathophysiology have been developed as useful research tools. Although laboratory mice are widely used, they are phylogenetically "distant" to humans. New world monkeys, such as the common marmoset (Callithrix jacchus) have steadily gained prominence. In this report, marmosets are explored as an alternate in vivo model to investigate infection and immunity of Zika virus (ZIKV). Multimodal platforms, including ultrasound and magnetic resonance imaging (MRI), flow cytometry, and multiplex microbead immunoassays were established to comprehensively decipher immune responses and pathophysiological outcomes. While ZIKV-infected marmosets had detectable ZIKV RNA load in various body fluids, animals did not develop any observable lesions in their testes and brains as shown by ultrasound and MRI. Immune-phenotyping detected differences in the numbers of B cells, CD8+ T cells and HLADR+ NK cells during the first two weeks of infection. Neutralizing ZIKV-specific antibodies were elicited to high levels and targeted epitopes in the E protein. This study presents a one-stop-shop platform to study infection and pathophysiology in marmosets. While marmoset-specific research tools are being refined, the research values of these animals present them as a good model for immune-based therapies.

PMID: 30459473 [PubMed - indexed for MEDLINE]

Understanding Educational Barriers and Needs of North Korean Defector Nursing Students: A Qualitative Descriptive Study.

J Transcult Nurs. 2019 Mar;30(2):187-194

Authors: Kong EH, Lim KC, Yu S

Abstract
INTRODUCTION: A growing number of North Korean defector students enter nursing schools in South Korea. Many of them, however, quit nursing school and fail to obtain a nurse license. The purpose of this study was to describe the educational barriers and needs of North Korean defector nursing students.
METHOD: A qualitative descriptive approach was employed. Convenience sampling was used, and 14 students participated. Qualitative content analysis was employed.
RESULTS: Five themes emerged: lack of preparation for higher education, multiple language barriers, differences in education and culture, lack of support and resources, and lack of information and understanding.
DISCUSSION: South Korean government needs to provide North Korean defector students with more practical supportive programs. South Korean nursing schools need to provide more transcultural education for South Korean students and supportive adaptation programs for North Korean defector students to produce culturally competent nurses who provide culturally congruent health care.

PMID: 30295150 [PubMed - indexed for MEDLINE]

A fatal case of Ortner's syndrome and dysphagia aortica secondary to rapidly expanding mycotic thoracic aortic aneurysm in a chronic kidney disease patient.

SAGE Open Med Case Rep. 2018;6:2050313X18799247

Authors: Kyaw WA, Lim CY, Khalil MAM, Lim KC, Chong VH, Tan J

Abstract
Ortner's syndrome or cardiovocal syndrome is a rare condition and refers to the association between cardiovascular conditions, usually cardiac enlargement from mitral stenosis, and recurrent laryngeal nerve palsy. We reported an interesting case of a patient with end-stage renal disease on regular dialysis who developed both Ortner's syndrome and dysphagia aortica as a result of an aortic arch aneurysm. The aneurysm underwent a rapid increase in size, likely as a result of Staphylococcus aureus infection (mycotic aneurysm) from an internal jugular dialysis catheter. This case highlighted the importance of cardiovascular conditions as rarer causes of dysphonia and dysphagia, particularly with the existence of an extrinsic infective source.

PMID: 30214810 [PubMed]

A Gata3 3' Distal Otic Vesicle Enhancer Directs Inner Ear-Specific Gata3 Expression.

Mol Cell Biol. 2018 11 01;38(21):

Authors: Moriguchi T, Hoshino T, Rao A, Yu L, Takai J, Uemura S, Ise K, Nakamura Y, Lim KC, Shimizu R, Yamamoto M, Engel JD

Abstract
Transcription factor GATA3 plays vital roles in inner ear development, while regulatory mechanisms controlling its inner ear-specific expression are undefined. We demonstrate that a cis-regulatory element lying 571 kb 3' to the Gata3 gene directs inner ear-specific Gata3 expression, which we refer to as the Gata3 otic vesicle enhancer (OVE). In transgenic murine embryos, a 1.5-kb OVE-directed lacZ reporter (TgOVE-LacZ) exhibited robust lacZ expression specifically in the otic vesicle (OV), an inner ear primordial tissue, and its derivative semicircular canal. To further define the regulatory activity of this OVE, we generated Cre transgenic mice in which Cre expression was directed by a 246-bp core sequence within the OVE element (TgcoreOVE-Cre). TgcoreOVE-Cre successfully marked the OV-derived inner ear tissues, including cochlea, semicircular canal and spiral ganglion, when crossed with ROSA26 lacZ reporter mice. Furthermore, Gata3 conditionally mutant mice, when crossed with the TgcoreOVE-Cre, showed hypoplasia throughout the inner ear tissues. These results demonstrate that OVE has a sufficient regulatory activity to direct Gata3 expression specifically in the otic vesicle and semicircular canal and that Gata3 expression driven by the OVE is crucial for normal inner ear development.

PMID: 30126893 [PubMed - indexed for MEDLINE]

Bacterial species associated with persistent apical periodontitis exert differential effects on osteogenic differentiation.

Int Endod J. 2019 Feb;52(2):201-210

Authors: Chow AT, Quah SY, Bergenholtz G, Lim KC, Yu VSH, Tan KS

Abstract
AIM: To determine if bacteria associated with persistent apical periodontitis induce species-specific pro-inflammatory cytokine responses in macrophages, and the effects of this species-specific microenvironment on osteogenic differentiation.
METHODOLOGY: Macrophages were exposed to Enterococcus faecalis, Streptococcus oralis, Streptococcus mitis, Fusobacterium nucleatum, Treponema denticola or Tannerella forsythia, and levels of TNF-α and IL-1β elicited were determined by immunoassay. Following treatment of MG-63 pre-osteoblasts with conditioned media from bacteria-exposed macrophages, osteogenic differentiation and viability of osteoblasts were analyzed by Alizarin Red Staining and MTS assay, respectively. Statistical analysis was carried out by one-way anova with the Tukey post-hoc test. Differences were considered to be significant if P < 0.05.
RESULTS: Macrophages exposed to Gram-positive bacteria did not produce significant amounts of cytokines. F. nucleatum-challenged macrophages produced up to four-fold more TNF-α and IL-1β compared to T. denticola or T. forsythia. Only conditioned media from macrophages treated with Gram-negative bacteria decreased mineralization and viability of osteoblasts.
CONCLUSIONS: Gram-positive bacteria did not impact osteogenic differentiation and appeared innocuous. Gram-negative bacteria, in particular F. nucleatum elicited an enhanced pro-inflammatory response in macrophages, inhibited osteogenic differentiation and reduced cell viability. The findings suggest that the presence of this organism could potentially increase the severity of persistent apical periodontitis.

PMID: 30099741 [PubMed - indexed for MEDLINE]

Fatal Vibrio vulnificus Bacteremia in Two Cirrhotic Patients with Abdominal Pain and Misty Mesentery.

Clin Pract Cases Emerg Med. 2017 Nov;1(4):326-328

Authors: Lim KC, Tan YL, Wu CC, Lin LW

Abstract
Two cirrhotic patients with unexplained abdominal pain deteriorated rapidly and fatally after presenting to our emergency department. Abdominal computed tomography in both patients showed "misty mesentery", which could not be explained by other etiologies. Both blood cultures revealed Vibrio vulnificus, which suggested the possible correlation of CT-finding and bacteremia.

PMID: 29849345 [PubMed]