Publications by authors named "Kenneth Lim"

96 Publications

Dysfunction in nonsense-mediated decay, protein homeostasis, mitochondrial function, and brain connectivity in ALS-FUS mice with cognitive deficits.

Acta Neuropathol Commun 2021 01 6;9(1). Epub 2021 Jan 6.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117549, Singapore.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of the same disease spectrum of adult-onset neurodegenerative diseases that affect the motor and cognitive functions, respectively. Multiple common genetic loci such as fused in sarcoma (FUS) have been identified to play a role in ALS and FTD etiology. Current studies indicate that FUS mutations incur gain-of-toxic functions to drive ALS pathogenesis. However, how the disease-linked mutations of FUS affect cognition remains elusive. Using a mouse model expressing an ALS-linked human FUS mutation (R514G-FUS) that mimics endogenous expression patterns, we found that FUS proteins showed an age-dependent accumulation of FUS proteins despite the downregulation of mouse FUS mRNA by the R514G-FUS protein during aging. Furthermore, these mice developed cognitive deficits accompanied by a reduction in spine density and long-term potentiation (LTP) within the hippocampus. At the physiological expression level, mutant FUS is distributed in the nucleus and cytosol without apparent FUS aggregates or nuclear envelope defects. Unbiased transcriptomic analysis revealed a deregulation of genes that cluster in pathways involved in nonsense-mediated decay, protein homeostasis, and mitochondrial functions. Furthermore, the use of in vivo functional imaging demonstrated widespread reduction in cortical volumes but enhanced functional connectivity between hippocampus, basal ganglia and neocortex in R514G-FUS mice. Hence, our findings suggest that disease-linked mutation in FUS may lead to changes in proteostasis and mitochondrial dysfunction that in turn affect brain structure and connectivity resulting in cognitive deficits.
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http://dx.doi.org/10.1186/s40478-020-01111-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789430PMC
January 2021

A case of acute vasitis mimicking an incarcerated inguinal hernia with subtle imaging findings.

Can J Urol 2020 12;27(6):10496-10499

Department of Urology, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.

Acute vasitis, or inflammation of the vas deferens, is a rare condition that classically presents with unilateral groin pain radiating into the scrotum and a bulge or induration along the inguinal canal. As a result, it mimics and is often mistaken for more common pathologies such as inguinal hernia, epididymo-orchitis or testicular torsion. A misdiagnosis may lead to unnecessary surgery and morbidity. Here, we present a case of acute vasitis which was originally diagnosed as an incarcerated inguinal hernia. Finally, we review the imaging findings, which can often be subtle and misinterpreted or missed.
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December 2020

Zanubrutinib for the treatment of Waldenström Macroglobulinemia.

Expert Rev Hematol 2020 12 9;13(12):1303-1310. Epub 2020 Dec 9.

Department of Haematology, Peter MacCallum Cancer Centre , Melbourne, Australia.

: Waldenström Macroglobulinaemia (WM) is a heterogeneous, incurable condition which often relapses after chemoimmunotherapy. Novel therapies such as Bruton tyrosine-kinase (BTK) inhibitors have shown to be efficacious in treating WM but with an established, significant toxicity profile seen in the first-generation inhibitor Ibrutinib. Zanubrutinib is a selective, potent BTK inhibitor with the potential to reduce toxicity and improve efficacy. : This review examines the activity of Zanubrutinib in treating treatment-naïve and relapsed refractory WM and it's toxicity profile when compared to Ibrutinib. Outcomes from the AU003 and ASPEN studies will be examined in detail including a particular focus on MYD88 and CXCR4 disease. Strengths and weaknesses of this treatment approach will be highlighted and future directions for research will be identified. : Zanubrutinib induces deeper responses and have greater activity in MYD88 and CXCR4 WM. Zanubrutinib also has a favorable toxicity profile when compared to Ibrutinib. This may potentially translate to lower discontinuation rates, improved quality of life and ultimately longer progression-free survival in patients with WM.
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http://dx.doi.org/10.1080/17474086.2020.1851184DOI Listing
December 2020

Impaired arterial vitamin D signaling occurs in the development of vascular calcification.

PLoS One 2020 19;15(11):e0241976. Epub 2020 Nov 19.

Department of Nephrology and Department of Acute Medicine, North Cumbria Integrated Care University Hospital NHS Trust, Carlisle, United Kingdom.

Conflicting data exists as to whether vitamin D receptor agonists (VDRa) are protective of arterial calcification. Confounding this, is the inherent physiological differences between human and animal experimental models and our current fragmented understanding of arterial vitamin D metabolism, their alterations in disease states and responses to VDRa's. Herein, the study aims to address these problems by leveraging frontiers in human arterial organ culture models. Human arteries were collected from a total of 24 patients (healthy controls, n = 12; end-stage CKD, n = 12). Cross-sectional and interventional studies were performed using arterial organ cultures treated with normal and calcifying (containing 5mmol/L CaCl2 and 5mmol/L β-glycerophosphate) medium, ex vivo. To assess the role of VDRa therapy, arteries were treated with either calcitriol or paricalcitol. We found that human arteries express a functionally active vitamin D system, including the VDR, 1α-hydroxylase and 24-hydroxylase (24-OHase) components and these were dysregulated in CKD arteries. VDRa therapy increased VDR expression in healthy arteries (p<0.01) but not in CKD arteries. Arterial 1α-OHase (p<0.05) and 24-OHase mRNA and protein expression were modulated differentially in healthy and CKD arteries by VDRa therapy. VDRa exposure suppressed Runx2 and MMP-9 expression in CKD arteries, however only paricalcitol suppressed MMP-2. VDRa exposure did not modulate arterial calcification in all organ culture models. However, VDRa reduced expression of senescence associated β-galactosidase (SAβG) staining in human aortic-smooth muscle cells under calcifying conditions, in vitro. In conclusion, maladaptation of arterial vitamin D signaling components occurs in CKD. VDRa exposure can exert vasculo-protective effects and seems critical for the regulation of arterial health in CKD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676703PMC
December 2020

Regulatory Elements Inserted into AAVs Confer Preferential Activity in Cortical Interneurons.

eNeuro 2020 Nov/Dec;7(6). Epub 2020 Dec 17.

Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California San Francisco Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158

Cortical interneuron (CIN) dysfunction is thought to play a major role in neuropsychiatric conditions like epilepsy, schizophrenia and autism. It is therefore essential to understand how the development, physiology, and functions of CINs influence cortical circuit activity and behavior in model organisms such as mice and primates. While transgenic driver lines are powerful tools for studying CINs in mice, this technology is limited in other species. An alternative approach is to use viral vectors such as AAV, which can be used in multiple species including primates and also have potential for therapeutic use in humans. Thus, we sought to discover gene regulatory enhancer elements (REs) that can be used in viral vectors to drive expression in specific cell types. The present study describes the systematic genome-wide identification of putative REs (pREs) that are preferentially active in immature CINs by histone modification chromatin immunoprecipitation and sequencing (ChIP-seq). We evaluated two novel pREs in AAV vectors, alongside the well-established enhancer, and found that they drove CIN-specific reporter expression in adult mice. We also showed that the identified pRE could drive sufficient expression of channelrhodopsin for optogenetic rescue of behavioral deficits in the mouse model of fast-spiking CIN dysfunction.
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http://dx.doi.org/10.1523/ENEURO.0211-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768279PMC
December 2020

Guideline No. 401: Sonographic Cervical Length in Singleton Pregnancies: Techniques and Clinical Applications.

J Obstet Gynaecol Can 2020 11;42(11):1394-1413.e1

St. John's, NL.

Objectives: • To assess the association between sonography-derived cervical length measurement and preterm birth. • To describe the various techniques to measure cervical length using sonography. • To review the natural history of the short cervix. • To review the clinical uses, predictive ability, and utility of sonography-measured short cervix.

Outcomes: Reduction in rates of prematurity and/or better identification of those at risk, as well as possible prevention of unnecessary interventions.

Intended Users: Clinicians involved in the obstetrical management or cervical imaging of patients at increased risk of a short cervix.

Target Population: Women at increased risk of a short cervix or at risk of preterm birth.

Evidence: Literature published up to June 2019 was retrieved through searches of PubMed and the Cochrane Library using appropriate controlled vocabulary and key words (preterm labour, ultrasound, cervix, cervical insufficiency, transvaginal, transperineal, cervical length, fibronectin). Results were restricted to general and systematic reviews, randomized controlled trials, controlled clinical trials, and observational studies. There were no date or language restrictions. Grey (unpublished) literature was identified through searching the websites of health technology assessment agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Values: The evidence and this guideline were reviewed by the Diagnostic Imaging Committee of the Society of Obstetricians and Gynaecologists of Canada, and the recommendations were made and graded according to the rankings of the Canadian Task Force on Preventive Health Care (Online Appendix Table A1).

Benefits, Harms, Costs: Preterm birth is a leading cause of perinatal morbidity and mortality. Use of the sonographic technique reviewed in this guideline may help identify women at risk of preterm birth and, in some circumstances, lead to interventions that may reduce the rate of preterm birth. SUMMARY STATEMENTS (CANADIAN TASK FORCE ON PREVENTIVE HEALTH CARE GRADING IN PARENTHESES): RECOMMENDATIONS (CANADIAN TASK FORCE ON PREVENTIVE HEALTH CARE GRADING IN PARENTHESES).
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http://dx.doi.org/10.1016/j.jogc.2019.06.002DOI Listing
November 2020

Dietary Aromatic Amino Acid Requirements During Early and Late Gestation in Healthy Pregnant Women.

J Nutr 2020 12;150(12):3224-3230

British Columbia Children's Hospital Research Institute, British Columbia Children's Hospital, Vancouver, Canada.

Background: Phenylalanine and tyrosine (referred to as total aromatic amino acids; TAAs) are essential for protein synthesis, and are precursors for important catecholamines. Current estimated average requirement (EAR) recommendations for TAA during pregnancy are 36 mg·kg-1·d-1, and has not been experimentally determined.

Objectives: The aim was to determine TAA requirements (dietary phenylalanine in the absence of tyrosine) during early and late gestation using the indicator amino acid oxidation (IAAO, with L-[1-13C]leucine) technique.

Methods: Nineteen healthy pregnant women (age 22-38 y) were studied at a range of phenylalanine intakes (5 to 100 mg·kg-1·d-1) in early (13-19 wk) and/or late (33-39 wk) pregnancy for a total of 51 study days. Graded test intakes were provided as 8 hourly isonitrogenous and isocaloric meals. Breath samples were collected for 13C enrichment analysis on an isotope ratio mass spectrometer. A plasma sample was collected and analyzed for phenylalanine and tyrosine concentrations on an amino acid analyzer. The TAA requirement in early and late pregnancy was calculated using 2-phase linear regression crossover analysis that identified breakpoints in 13CO2 production (the requirement) in response to phenylalanine intakes.

Results: TAA requirement during early pregnancy was 44 mg·kg-1·d-1 (95% CI: 28.3, 58.8) and during late pregnancy was 50 mg·kg-1·d-1 (95% CI: 36.1, 63.1). In early and late pregnancy, plasma phenylalanine and tyrosine concentrations rose linearly in response to graded phenylalanine intakes.

Conclusions: Our results suggest that the current EAR of 36 mg·kg-1·d-1 for TAAs is underestimated. When compared with results previously determined in nonpregnant adults, early pregnancy requirements were similar (43 compared with 44 mg·kg-1·d-1, respectively). During late pregnancy, a 14% higher TAA requirement was observed when compared with early pregnancy. The results from this study have potential implications for creating gestation stage-specific TAA recommendations.
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http://dx.doi.org/10.1093/jn/nxaa317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726121PMC
December 2020

Cardiovascular Functional Changes in Chronic Kidney Disease: Integrative Physiology, Pathophysiology and Applications of Cardiopulmonary Exercise Testing.

Front Physiol 2020 15;11:572355. Epub 2020 Sep 15.

Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States.

The development of cardiovascular disease during renal impairment involves striking multi-tiered, multi-dimensional complex alterations encompassing the entire oxygen transport system. Complex interactions between target organ systems involving alterations of the heart, vascular, musculoskeletal and respiratory systems occur in Chronic Kidney Disease (CKD) and collectively contribute to impairment of cardiovascular function. These systemic changes have challenged our diagnostic and therapeutic efforts, particularly given that imaging cardiac structure at rest, rather than ascertainment under the stress of exercise, may not accurately reflect the risk of premature death in CKD. The multi-systemic nature of cardiovascular disease in CKD patients provides strong rationale for an integrated approach to the assessment of cardiovascular alterations in this population. State-of-the-art cardiopulmonary exercise testing (CPET) is a powerful, dynamic technology that enables the global assessment of cardiovascular functional alterations and reflects the integrative exercise response and complex machinery that form the oxygen transport system. CPET provides a wealth of data from a single assessment with mechanistic, physiological and prognostic utility. It is an underutilized technology in the care of patients with kidney disease with the potential to help advance the field of cardio-nephrology. This article reviews the integrative physiology and pathophysiology of cardio-renal impairment, critical new insights derived from CPET technology, and contemporary evidence for potential applications of CPET technology in patients with kidney disease.
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http://dx.doi.org/10.3389/fphys.2020.572355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522507PMC
September 2020

Glycine, a Dispensable Amino Acid, Is Conditionally Indispensable in Late Stages of Human Pregnancy.

J Nutr 2021 Feb;151(2):361-369

BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.

Background: Recently, we showed that there are higher protein, lysine, and phenylalanine requirements in late stages of pregnancy compared with early stages. Animal studies have suggested an increased dietary need for specific dispensable amino acids in pregnancy; whether such a need exists in human pregnancies is unknown.

Objective: The objective of the current study was to examine whether healthy pregnant women at midgestation (20-29 wk) and late gestation (30-40 wk) have a dietary demand for glycine, a dispensable amino acid, using the indicator amino acid oxidation method and measurement of plasma 5-oxoproline concentrations.

Methods: Seventeen healthy women (aged 26-36 y) randomly received different test glycine intakes (range: 5-100 mg·kg-1·d-1) during each study day in midgestation (∼26 wk, n = 17 observations in 9 women) and late gestation (∼35 wk, n = 19 observations in 8 women). Diets were isocaloric with energy at 1.7 × resting energy expenditure. Protein was given as a crystalline amino acid mixture based on egg protein composition at current estimated average requirement (EAR; 0.88 g·kg-1·d-1). Breath samples were collected at baseline and isotopic steady state to measure oxidation of L-[1-13C]phenylalanine to 13CO2 (F13CO2). Plasma was collected at the sixth hour of the study day. Linear regression crossover analysis and simple linear regression were used to assess responses in F13CO2 and plasma 5-oxoproline concentrations to different glycine intakes.

Results: No statistically significant responses were observed in midgestation. However, in late gestation, lower glycine intakes resulted in higher rates of F13CO2 (suggesting low protein synthesis) with a breakpoint for phenylalanine oxidation at >37 mg glycine·kg-1·d-1 and higher plasma 5-oxoproline (suggesting low glycine availability) with a breakpoint >27 mg glycine·kg-1·d-1.

Conclusions: The findings suggest that glycine should be considered a "conditionally" indispensable amino acid during late gestation, especially when protein intakes are at 0.88 g·kg-1·d-1, the current EAR. This trial was registered at clinicaltrials.gov as NCT02149953.
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http://dx.doi.org/10.1093/jn/nxaa263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850138PMC
February 2021

Characteristics and outcome of patients with relapsed/refractory Hodgkin lymphoma following front-line escalated BEACOPP-based chemotherapy: a report from the Australasian Lymphoma Alliance.

Leuk Lymphoma 2020 12 28;61(14):3412-3416. Epub 2020 Aug 28.

Gold Coast University Hospital, Southport, Australia.

The optimal management of the small number of patients who experience early failure of eBEACOPP in Hodgkin lymphoma (HL) is unclear. We identified 12 patients with HL who progressed within 12 months of the front-line therapy between January 2010 and July 2019. Median time of first progression following diagnosis was 7 months (range 2.1-13.2). Nine patients proceeded to stem cell therapy following salvage therapy (8 autografts, 1 allograft). Seven patients received novel therapy after relapse, of these, 6 were alive at census, versus 2 out of 5 of those who had standard therapy alone. At the end of follow up (median 22 months), 4 were deceased from progressive disease, 6 were in complete remission and 2 in partial remission on continuing therapy. The outcome of patients with primary refractory HL to eBEACOPP therapy is better than expected and the use of a novel agents after relapse may be a contributing factor.
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http://dx.doi.org/10.1080/10428194.2020.1811273DOI Listing
December 2020

Effect of kidney donation on bone mineral metabolism.

PLoS One 2020 7;15(7):e0235082. Epub 2020 Jul 7.

Cambridge Clinical Trials Unit, University of Cambridge, Cambridge, United Kingdom.

Kidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age (53±10 vs 50±14 years, p = 0.33), BMI (26.3±2.89 vs 25.9±3.65, p = 0.59), systolic BP (128±13 vs 130±6 mmHg, p = 0.59), diastolic BP (80±9 vs 81±9 mmHg, p = 0.68) and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m2, p = 0.89). eGFR reduced from 84.4±20.2 to 52.3±17.5 ml/min/1.73m2 (p<0.001) by day 1 with incomplete recovery by 12 months (67.7±22.6; p = 0.002). Phosphate increased by day 1 (1.1(0.9-1.2) to 1.3(1.1-1.4) mmol/L, p <0.001) but declined to 0.8(0.8-1.0) mmol/L (p<0.001) before normalizing by 6 weeks. Calcium declined on day 1 (p = 0.003) but recovered at 6 weeks or 12 months. PTH and FGF-23 remained unchanged, but α-Klotho reduced by day 1 (p = 0.001) and remained low at 6 weeks (p = 0.02) and 1 year (p = 0.04). In this study, we conclude that kidney donation results in acute disturbances in mineral metabolism characterised by a reduced phosphate and circulating α-Klotho concentration without acute changes in the phosphaturic hormones FGF23 and PTH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235082PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340316PMC
September 2020

An evaluation of Ibrutinib for the treatment of Waldenstrom macroglobulinaemia.

Expert Opin Pharmacother 2020 Sep 30;21(13):1555-1564. Epub 2020 Jun 30.

Department of Haematology, Peter MacCallum Cancer Centre , Melbourne, Australia.

Introduction: Waldenstrom Macroglobulinaemia (WM) is a heterogenous condition which poses a challenge to manage. Novel therapies such as Ibrutinib have been shown to be efficacious in treating WM. The landscape of Ibrutinib's role in treating WM is everchanging with new discoveries in disease genomics and evolution together as well as through new findings in clinical trials.

Areas Covered: A systematic literature review was carried out using two databases 'Medline' and 'Embase' from 2009 to July 2019. Keywords used included 'Ibrutinib,' 'Waldenstrom Macroglobulinaemia,' and 'lymphoma.' There were four major clinical trials identified primarily describing outcomes of Ibrutinib in managing WM which this paper evaluates in detail. The authors present evidence of the role of Ibrutinib in the management of specific complications associated with WM. They also explore the recently discovered genomics of the disease affecting response to therapy.

Expert Opinion: The evidence for the use of Ibrutinib as a treatment option for relapsed/refractory WM is compelling in MYD88 mutated WM with the response and survival rates potentially better than conventional salvage chemoimmunotherapy. There is also a case for it to be used in the frontline setting in patients unfit for conventional frontline chemoimmunotherapy.
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http://dx.doi.org/10.1080/14656566.2020.1770727DOI Listing
September 2020

Klotho and the Treatment of Human Malignancies.

Cancers (Basel) 2020 Jun 23;12(6). Epub 2020 Jun 23.

The Royal Marsden NHS Foundation Trust, London SW6 6JJ, UK.

Klotho was first discovered as an anti-ageing protein linked to a number of age-related disease processes, including cardiovascular, renal, musculoskeletal, and neurodegenerative conditions. Emerging research has also demonstrated a potential therapeutic role for Klotho in cancer biology, which is perhaps unsurprising given that cancer and ageing share similar molecular hallmarks. In addition to functioning as a tumour suppressor in numerous solid tumours and haematological malignancies, Klotho represents a candidate therapeutic target for patients with these diseases, the majority of whom have limited treatment options. Here, we examine contemporary evidence evaluating the anti-neoplastic effects of Klotho and describe the modulation of downstream oncogenic signalling pathways, including Wnt/β-catenin, FGF, IGF1, PIK3K/AKT, TGFβ, and the Unfolded Protein Response. We also discuss possible approaches to developing therapeutic Klotho and consider technological advances that may facilitate the delivery of Klotho through gene therapy.
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http://dx.doi.org/10.3390/cancers12061665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352559PMC
June 2020

Complication rates and lymph node count between two different skin incisions at time of inguino-femoral lymph node dissection in vulvar cancer.

Int J Gynecol Cancer 2020 08 4;30(8):1113-1117. Epub 2020 May 4.

Gynaecological Oncology, University Hospital of Wales, Cardiff, UK.

Introduction: Inguino-femoral lymph node dissection plays a crucial role in the management of vulvar cancer. The procedure is associated with high complication rates, including infection, lymphocysts/lymphoedema and wound dehiscence. Several skin incision techniques exist and practice among gynecology oncologists is variable. Little evidence exists to guide surgeons regarding the optimal surgical approach. This study aimed to determine the difference in 30-day complication rates, number of lymph nodes and length of stay between patients undergoing the modified oblique and classical 'lazy S' skin incision.

Methods: A retrospective review between January 2014 and September 2018 was performed in the University Hospital of Wales, Cardiff. All cases of inguino-femoral lymph node dissection performed for vulvar cancer were included in the study without exclusion. Data collected included age, body mass index (BMI), incision type, suture material, length of hospital stay, complication rates, cancer stage, lymph node count, lymph node positivity rate and recurrence rates. Data were analyzed using SPSS software and clinical significance was set as p<0.05.

Results: Thirty-five cases of classical 'lazy S' and 14 cases of modified oblique were included in the analysis. The mean patient age was 65 years (range 41-86) in the classical 'lazy S' group and 58 years (range 19-81) in the modified oblique group. The mean BMI was 28 kg/m (range 18-45) in the classical 'lazy S' group and 29 kg/m (range 20-36) in the modified oblique group. In the classical 'lazy S' group, the stage classification was as follows: stage IB (18), II (2), IIIA (3), IIIB (4), IIIC (8). In the modified oblique group, the stage classification was: stage IB (8), II (4), IIIA (2). Grade 3-4 complications were statistically significantly more common after the classical 'lazy S' versus the modified oblique operation (20/35, 57.1% vs 2/14, 14.3%, p<0.02). Mean number of nodes harvested was statistically significantly higher in the classical 'lazy S' group compared with the modified oblique group (11.1 nodes, range 6-17 vs 7 nodes, range 4-11, p<0.001). Node positivity rate was higher in the classical 'lazy S' group compared with the modified oblique group (28.6% vs 10%, p=0.08). Mean hospital stay was statistically significantly longer in patients undergoing classical 'lazy S' versus modified oblique (10.7 vs 4.5 days, p=0.02). One case of groin node recurrence occurred and this patient was in the classical 'lazy S' arm.

Conclusion: The rate of overall and serious complications was lower after modified oblique skin incision compared with classical 'lazy S'. However, the absolute lymph node count and lymph node positivity rate were higher in the 'lazy S' group.
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http://dx.doi.org/10.1136/ijgc-2019-001014DOI Listing
August 2020

Multimodal Photoplethysmography-Based Approaches for Improved Detection of Hypertension.

J Clin Med 2020 Apr 22;9(4). Epub 2020 Apr 22.

Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Elevated blood pressure (BP) is a major cause of death, yet hypertension commonly goes undetected. Owing to its nature, it is typically asymptomatic until later in its progression when the vessel or organ structure has already been compromised. Therefore, noninvasive and continuous BP measurement methods are needed to ensure appropriate diagnosis and early management before hypertension leads to irreversible complications. Photoplethysmography (PPG) is a noninvasive technology with waveform morphologies similar to that of arterial BP waveforms, therefore attracting interest regarding its usability in BP estimation. In recent years, wearable devices incorporating PPG sensors have been proposed to improve the early diagnosis and management of hypertension. Additionally, the need for improved accuracy and convenience has led to the development of devices that incorporate multiple different biosignals with PPG. Through the addition of modalities such as an electrocardiogram, a final measure of the pulse wave velocity is derived, which has been proved to be inversely correlated to BP and to yield accurate estimations. This paper reviews and summarizes recent studies within the period 2010-2019 that combined PPG with other biosignals and offers perspectives on the strengths and weaknesses of current developments to guide future advancements in BP measurement. Our literature review reveals promising measurement accuracies and we comment on the effective combinations of modalities and success of this technology.
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http://dx.doi.org/10.3390/jcm9041203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230564PMC
April 2020

Detection of an IGH- fusion in a patient with BRAF Val600Glu negative hairy cell leukemia.

Leuk Lymphoma 2020 08 22;61(8):2024-2026. Epub 2020 Apr 22.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.

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http://dx.doi.org/10.1080/10428194.2020.1753045DOI Listing
August 2020

Vitamin D Toxicity.

J Bras Nefrol 2020 Apr;42(2):238-244

Harvard Medical School, Massachusetts General Hospital, Division of Nephrology, Department of Medicine, Boston, MA, EUA.

Fortification of food products with vitamin D was central to the eradication of rickets in the early parts of the 20th century in the United States. In the subsequent almost 100 years since, accumulating evidence has linked vitamin D deficiency to a variety of outcomes, and this has paralleled greater public interest and awareness of the health benefits of vitamin D. Supplements containing vitamin D are now widely available in both industrialized and developing countries, and many are in the form of unregulated formulations sold to the public with little guidance for safe administration. Together, this has contributed to a transition whereby a dramatic global increase in cases of vitamin D toxicity has been reported. Clinicians are now faced with the challenge of managing this condition that can present on a spectrum from asymptomatic to acute life-threatening complications. This article considers contemporary data on vitamin D toxicity, and diagnostic and management strategies relevant to clinical practice.
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http://dx.doi.org/10.1590/2175-8239-JBN-2019-0192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427646PMC
April 2020

Cuffless Single-Site Photoplethysmography for Blood Pressure Monitoring.

J Clin Med 2020 Mar 7;9(3). Epub 2020 Mar 7.

Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

One in three adults worldwide has hypertension, which is associated with significant morbidity and mortality. Consequently, there is a global demand for continuous and non-invasive blood pressure (BP) measurements that are convenient, easy to use, and more accurate than the currently available methods for detecting hypertension. This could easily be achieved through the integration of single-site photoplethysmography (PPG) readings into wearable devices, although improved reliability and an understanding of BP estimation accuracy are essential. This review paper focuses on understanding the features of PPG associated with BP and examines the development of this technology over the 2010-2019 period in terms of validation, sample size, diversity of subjects, and datasets used. Challenges and opportunities to move single-site PPG forward are also discussed.
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http://dx.doi.org/10.3390/jcm9030723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141397PMC
March 2020

Acceptability and appropriateness of a perinatal depression preventive group intervention: a qualitative analysis.

BMC Health Serv Res 2020 Mar 7;20(1):189. Epub 2020 Mar 7.

Center for Community Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, 750 N Lake Shore Drive, Suite 680, Chicago, IL, 60611, USA.

Background: Perinatal depression is a prevalent public health concern. Although preventive interventions exist, there is limited literature on the acceptability and appropriateness of these interventions, especially those delivered by paraprofessionals. The Mothers and Babies Program (MB) is a group-based perinatal depression preventive intervention delivered prenatally. A cluster-randomized controlled trial examined the acceptability, appropriateness, and effectiveness of MB delivered by mental health professionals compared to paraprofessional staff from home visiting programs.

Methods: The full study enrolled 874 pregnant women. Fifty-three facilitators were trained and delivered the MB intervention to women in one of seven states in the United States. Semi-structured interviews were attempted with a randomly-selected subset of the full sample of pregnant women who received the MB intervention and with all facilitators. Specifically, interviews were conducted with 88 women who received the MB group intervention (45 in the paraprofessional-led arm and 43 in the mental health professional-led arm) and 46 women who facilitated the groups (27 home visiting staff and 19 mental health professionals). Interviews were conducted over the phone in English or Spanish and audio recorded. The recordings were translated into English, as needed, and transcribed. Thematic analysis was conducted using NVIVO to identify key themes related to intervention acceptability and appropriateness. Similarities and differences between study arms were explored.

Results: Clients and facilitators found the MB content and group format acceptable. Challenges included maintaining group attendance, transportation issues, and managing group discussion. Overall, facilitators found the intervention appropriate for pregnant clients with some challenges presented for clients in crisis situations, experiencing housing instability, and with literacy and learning challenges. Participants provided suggestions for improvement, both for the course content and implementation. There were no significant differences found between study arms.

Conclusions: Overall, clients and facilitators enjoyed MB irrespective of study arm, and facilitators found the intervention appropriate for the population. These findings add to the qualitative literature on perinatal depression preventive interventions, specifically those delivered by paraprofessionals.

Trial Registration: This trial is registered on ClinicalTrials.gov (Initial post: December 1, 2016; identifier: NCT02979444).
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http://dx.doi.org/10.1186/s12913-020-5031-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060621PMC
March 2020

Cardiovascular Functional Reserve Before and After Kidney Transplant.

JAMA Cardiol 2020 04;5(4):420-429

Cambridge Clinical Trials Unit and School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.

Importance: Restitution of kidney function by transplant confers a survival benefit in patients with end-stage renal disease. Investigations of mechanisms involved in improved cardiovascular survival have relied heavily on static measures from echocardiography or cardiac magnetic resonance imaging and have provided conflicting results to date.

Objectives: To evaluate cardiovascular functional reserve in patients with end-stage renal disease before and after kidney transplant and to assess functional and morphologic alterations of structural-functional dynamics in this population.

Design, Setting, And Participants: This prospective, nonrandomized, single-center, 3-arm, controlled cohort study, the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) study, included patients with stage 5 chronic kidney disease (CKD) who underwent kidney transplant (KTR group), patients with stage 5 CKD who were wait-listed and had not undergone transplant (NTWC group), and patients with hypertension only (HTC group) seen at a single center from April 1, 2010, to January 1, 2013. Patients were followed up longitudinally for up to 1 year after kidney transplant. Clinical data collection was completed February 2014. Data analysis was performed from June 1, 2014, to March 5, 2015. Further analysis on baseline and prospective data was performed from June 1, 2017, to July 31, 2019.

Main Outcomes And Measures: Cardiovascular functional reserve was objectively quantified using state-of-the-art cardiopulmonary exercise testing in parallel with transthoracic echocardiography.

Results: Of the 253 study participants (mean [SD] age, 48.5 [12.7] years; 141 [55.7%] male), 81 were in the KTR group, 85 in the NTWC group, and 87 in the HTC group. At baseline, mean (SD) maximum oxygen consumption (V̇O2max) was significantly lower in the CKD groups (KTR, 20.7 [5.8] mL · min-1 · kg-1; NTWC, 18.9 [4.7] mL · min-1 · kg-1) compared with the HTC group (24.9 [7.1] mL · min-1 · kg-1) (P < .001). Mean (SD) cardiac left ventricular mass index was higher in patients with CKD (KTR group, 104.9 [36.1] g/m2; NTWC group, 113.8 [37.7] g/m2) compared with the HTC group (87.8 [16.9] g/m2), (P < .001). Mean (SD) left ventricular ejection fraction was significantly lower in the patients with CKD (KTR group, 60.1% [8.6%]; NTWC group, 61.4% [8.9%]) compared with the HTC group (66.1% [5.9%]) (P < .001). Kidney transplant was associated with a significant improvement in V̇O2max in the KTR group at 12 months (22.5 [6.3] mL · min-1 · kg-1; P < .001), but the value did not reach the V̇O2max in the HTC group (26.0 [7.1] mL · min-1 · kg-1) at 12 months. V̇O2max decreased in the NTWC group at 12 months compared with baseline (17.7 [4.1] mL · min-1 · kg-1, P < .001). Compared with the KTR group (63.2% [6.8%], P = .02) or the NTWC group (59.3% [7.6%], P = .003) at baseline, transplant was significantly associated with improved left ventricular ejection fraction at 12 months but not with left ventricular mass index.

Conclusions And Relevance: The findings suggest that kidney transplant is associated with improved cardiovascular functional reserve after 1 year. In addition, cardiopulmonary exercise testing was sensitive enough to detect a decline in cardiovascular functional reserve in wait-listed patients with CKD. Improved V̇O2max may in part be independent from structural alterations of the heart and depend more on ultrastructural changes after reversal of uremia.
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http://dx.doi.org/10.1001/jamacardio.2019.5738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042833PMC
April 2020

miR-218 Expressed in Endothelial Progenitor Cells Contributes to the Development and Repair of the Kidney Microvasculature.

Am J Pathol 2020 03 20;190(3):642-659. Epub 2020 Jan 20.

Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Ischemia due to hypoperfusion is one of the most common forms of acute kidney injury. We hypothesized that kidney hypoxia initiates the up-regulation of miR-218 expression in endothelial progenitor cells (EPCs) to guide endocapillary repair. Murine renal artery-derived EPCs (CD34/CD105) showed down-regulation of mmu-Mir218-5p/U6 RNA ratio after ischemic injury, while in human renal arteries, MIR218-5p expression was up-regulated after ischemic injury. MIR218 expression was clarified in cell culture experiments in which increases in both SLIT3 and MIR218-2-5p expressions were observed after 5 minutes of hypoxia. ROBO1 transcript, a downstream target of MIR218-2-5p, showed inverse expression to MIR218-2-5p. EPCs transfected with a MIR218-5p inhibitor in three-dimensional normoxic culture showed premature capillary formation. Organized progenitor cell movement was reconstituted when cells were co-transfected with Dicer siRNA and low-dose Mir218-5p mimic. A Mir218-2 knockout was generated to assess the significance of miR-218-2 in a mammalian model. Mir218-2-5p expression was decreased in Mir218-2 embryos at E16.5. Mir218-2 decreased CD34 angioblasts in the ureteric bud at E16.5 and were nonviable. Mir218-2 decreased peritubular capillary density at postnatal day 14 and increased serum creatinine after ischemia in adult mice. Systemic injection of miR-218-5p decreased serum creatinine after injury. These experiments demonstrate that miR-218 expression can be triggered by hypoxia and modulates EPC migration in the kidney.
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http://dx.doi.org/10.1016/j.ajpath.2019.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068533PMC
March 2020

Association between gestational weight gain and severe adverse birth outcomes in Washington State, US: A population-based retrospective cohort study, 2004-2013.

PLoS Med 2019 12 30;16(12):e1003009. Epub 2019 Dec 30.

Department of Obstetrics and Gynaecology, University of British Columbia, BC Children's Hospital, and BC Women's Hospital and Health Centre, Vancouver, British Columbia, Canada.

Background: Suboptimal weight gain during pregnancy is a potentially modifiable risk factor. We aimed to investigate the association between suboptimal gestational weight gain and severe adverse birth outcomes by pre-pregnancy body mass index (BMI) categories, including obesity class I to III.

Methods And Findings: We conducted a population-based study of pregnant women with singleton hospital births in Washington State, US, between 2004 and 2013. Optimal, low, and excess weight gain in each BMI category was calculated based on weight gain by gestational age as recommended by the American College of Obstetricians and Gynecologists and the Institute of Medicine. Primary composite outcomes were (1) maternal death and/or severe maternal morbidity (SMM) and (2) perinatal death and/or severe neonatal morbidity. Logistic regression was used to obtain adjusted odds ratios (AORs) and 95% confidence intervals. Overall, 722,839 women with information on pre-pregnancy BMI were included. Of these, 3.1% of women were underweight, 48.1% had normal pre-pregnancy BMI, 25.8% were overweight, and 23.0% were obese. Only 31.5% of women achieved optimal gestational weight gain. Women who had low weight gain were more likely to be African American and have Medicaid health insurance, while women with excess weight gain were more likely to be non-Hispanic white and younger than women with optimal weight gain in each pre-pregnancy BMI category. Compared with women who had optimal weight gain, those with low gestational weight gain had a higher rate of maternal death, 7.97 versus 2.63 per 100,000 (p = 0.027). In addition, low weight gain was associated with the composite adverse maternal outcome (death/SMM) in women with normal pre-pregnancy BMI and in overweight women (AOR 1.12, 95% CI 1.04-1.21, p = 0.004, and AOR 1.17, 95% CI 1.04-1.32, p = 0.009, respectively) compared to women in the same pre-pregnancy BMI category who had optimal weight gain. Similarly, excess gestational weight gain was associated with increased rates of death/SMM among women with normal pre-pregnancy BMI (AOR 1.20, 95% CI 1.12-1.28, p < 0.001) and obese women (AOR 1.12, 95% CI 1.01-1.23, p = 0.019). Low gestational weight gain was associated with perinatal death and severe neonatal morbidity regardless of pre-pregnancy BMI, including obesity classes I, II, and III, while excess weight gain was associated with severe neonatal morbidity only in women who were underweight or had normal BMI prior to pregnancy. Study limitations include the ascertainment of pre-pregnancy BMI using self-report, and lack of data availability for the most recent years.

Conclusions: In this study, we found that most women do not achieve optimal weight gain during pregnancy. Low weight gain was associated with increased risk of severe adverse birth outcomes, and in particular with maternal death and perinatal death. Excess gestational weight gain was associated with severe adverse birth outcomes, except for women who were overweight prior to pregnancy. Weight gain recommendations for this group may need to be reassessed. It is important to counsel women during pregnancy about specific risks associated with both low and excess weight gain.
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http://dx.doi.org/10.1371/journal.pmed.1003009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936783PMC
December 2019

The Role of Nonenzymatic Post-translational Protein Modifications in Uremic Vascular Calcification.

Adv Chronic Kidney Dis 2019 11;26(6):427-436

Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA. Electronic address:

Considerable technological advances have enabled the identification and linkage of nonenzymatic post-translationally modified proteins to the pathogenesis of cardiovascular disease (CVD) in patients with kidney failure. Through processes such as the nonenzymatic carbamylation reaction as well as the formation of advanced glycation end products, we now know that protein modifications are invariably associated with the development of CVD beyond a mere epiphenomenon and this has become an important focus of nephrology research in recent years. Although the specific mechanisms by which protein modifications occurring in kidney failure that may contribute to CVD are diverse and include pathways such as inflammation and fibrosis, vascular calcification has emerged as a distinct pathological sequelae of protein modifications. In this review, we consider the biological mechanisms and clinical relevance of protein carbamylation and advanced glycation end products in CVD development with a focus on vascular calcification.
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http://dx.doi.org/10.1053/j.ackd.2019.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993873PMC
November 2019

Dietary phenylalanine requirements during early and late gestation in healthy pregnant women.

Am J Clin Nutr 2020 02;111(2):351-359

BC Children's Hospital Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada.

Background: Phenylalanine is an indispensable amino acid and, via tyrosine, is the precursor for the neurotransmitters dopamine, norepinephrine, and epinephrine. Currently, dietary requirements for phenylalanine during pregnancy are unknown.

Objectives: This study's aim was to determine phenylalanine requirements (in the presence of excess tyrosine) during early and late gestation using direct amino acid oxidation (DAAO; with l-[1-13C]phenylalanine) and indicator amino acid oxidation (IAAO; with l-[1-13C]leucine).

Methods: Twenty-three healthy women (age: 30.4 ± 3.1 y, mean ± SD) were studied at a range of phenylalanine intakes (5.5-30.5 mg · kg-1 · d-1 in early and late pregnancy using DAAO, and 2.5-30.5 mg · kg-1 · d-1 in late pregnancy using IAAO) for a total of 76 study days. Test intakes were provided as 8 isocaloric and isonitrogenous meals with 1.5 g · kg-1 · d-1 protein and energy at 1.7 times the measured resting energy expenditure. Breath samples were analyzed on an isotope ratio mass spectrometer for 13C enrichment. Phenylalanine requirement was determined using a 2-phase linear regression crossover model to identify a breakpoint in 13CO2 production (representing the mean requirement) in response to phenylalanine intakes.

Results: Phenylalanine requirement during early pregnancy was determined to be 15 mg · kg-1 · d-1 (95% CI: 10.4, 19.9 mg · kg-1 · d-1); during late pregnancy, it was determined to be 21 mg · kg-1 · d-1 by DAAO (95% CI: 17.4, 24.7 mg · kg-1 · d-1) and IAAO (95% CI: 10.5, 32.2 mg · kg-1 · d-1).

Conclusions: Our results suggest a higher requirement (40%) for phenylalanine during late pregnancy than during early pregnancy. Moreover, the early pregnancy requirements are higher than the previous adult male requirement (9.1 mg · kg-1 · d-1; 95% CI: 4.6, 13.6 mg · kg-1 · d-1), although the 95% CIs overlap. Both DAAO and IAAO methods provided similar breakpoints in late pregnancy, showing that the DAAO method was appropriate even though low phenylalanine intakes could not be tested. These results have potential implications for gestation stage-specific dietary phenylalanine recommendations in future.This trial was registered at clinicaltrials.gov as NCT02669381.
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http://dx.doi.org/10.1093/ajcn/nqz288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997087PMC
February 2020

Directive clinique N 388 - Détermination de l'âge gestationnel par échographie.

J Obstet Gynaecol Can 2019 Oct;41(10):1508-1520

Vancouver (C.-B.). Electronic address:

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http://dx.doi.org/10.1016/j.jogc.2019.04.011DOI Listing
October 2019

Guideline No. 388-Determination of Gestational Age by Ultrasound.

J Obstet Gynaecol Can 2019 Oct;41(10):1497-1507

Vancouver, BC. Electronic address:

Objective: To assist clinicians in assigning gestational age based on ultrasound biometry.

Outcomes: To determine whether ultrasound dating provides more accurate gestational age assessment than menstrual dating with or without the use of ultrasound. To provide maternity health care providers and researchers with evidence-based guidelines for the assignment of gestational age. To determine which ultrasound biometric parameters are superior when gestational age is uncertain. To determine whether ultrasound gestational age assessment is cost effective.

Evidence: Published literature was retrieved through searches of PubMed or MEDLINE and The Cochrane Library in 2013 using appropriate controlled vocabulary and key words (gestational age, ultrasound biometry, ultrasound dating). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to July 31, 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).

Benefits, Harms, And Costs: Accurate assignment of gestational age may reduce post-dates labour induction and may improve obstetric care through allowing the optimal timing of necessary interventions and the avoidance of unnecessary ones. More accurate dating allows for optimal performance of prenatal screening tests for aneuploidy. A national algorithm for the assignment of gestational age may reduce practice variations across Canada for clinicians and researchers. Potential harms include the possible reassignment of dates when significant fetal pathology (such as fetal growth restriction or macrosomia) result in a discrepancy between ultrasound biometric and clinical gestational age. Such reassignment may lead to the omission of appropriate-or the performance of inappropriate-fetal interventions.

Summary Statements: RECOMMENDATIONS.
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http://dx.doi.org/10.1016/j.jogc.2019.04.010DOI Listing
October 2019

Klotho: A Major Shareholder in Vascular Aging Enterprises.

Int J Mol Sci 2019 Sep 19;20(18). Epub 2019 Sep 19.

The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.

Accelerated vascular aging is a condition that occurs as a complication of several highly prevalent inflammatory conditions such as chronic kidney disease, cancer, HIV infection and diabetes. Age-associated vascular alterations underlie a continuum of expression toward clinically overt cardiovascular disease. This has contributed to the striking epidemiologic transition whereby such noncommunicable diseases have taken center stage as modern-day global epidemics and public health problems. The identification of α-Klotho, a remarkable protein that confers powerful anti-aging properties has stimulated significant interest. In fact, emerging data have provided fundamental rationale for Klotho-based therapeutic intervention for vascular diseases and multiple other potential indications. However, the application of such discoveries in Klotho research remains fragmented due to significant gaps in our molecular understanding of Klotho biology, as well as hurdles in clinical research and experimental barriers that must first be overcome. These advances will be critical to establish the scientific platform from which future Klotho-based interventional trials and therapeutic enterprises can be successfully launched.
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http://dx.doi.org/10.3390/ijms20184637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770519PMC
September 2019

FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits.

Hum Mol Genet 2019 11;28(22):3777-3791

Department of Physiology, National University of Singapore, 117549, Singapore.

Pathological fused in sarcoma (FUS) inclusions are found in 10% of patients with frontotemporal dementia and those with amyotrophic lateral sclerosis (ALS) carrying FUS mutations. Current work indicates that FUS mutations may incur gain-of-toxic functions to drive ALS pathogenesis. However, how FUS dysfunction may affect cognition remains elusive. Using a mouse model expressing wild-type human FUS mimicking the endogenous expression pattern and level within the central nervous system, we found that they developed hippocampus-mediated cognitive deficits accompanied by an age-dependent reduction in spine density and long-term potentiation in their hippocampus. However, there were no apparent FUS aggregates, nuclear envelope defects and cytosolic FUS accumulation. These suggest that these proposed pathogenic mechanisms may not be the underlying causes for the observed cognitive deficits. Unbiased transcriptomic analysis identified expression changes in a small set of genes with preferential expression in the neurons and oligodendrocyte lineage cells. Of these, we focused on Sema5a, a gene involved in axon guidance, spine dynamics, Parkinson's disease and autism spectrum disorders. Critically, FUS binds directly to Sema5a mRNA and regulates Sema5a expression in a FUS-dose-dependent manner. Taken together, our data suggest that FUS-driven Sema5a deregulation may underlie the cognitive deficits in FUS transgenic mice.
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http://dx.doi.org/10.1093/hmg/ddz217DOI Listing
November 2019

The use of photoplethysmography for assessing hypertension.

NPJ Digit Med 2019 26;2:60. Epub 2019 Jun 26.

1School of Electrical and Computer Engineering, University of British Columbia, Vancouver, Canada.

The measurement of blood pressure (BP) is critical to the treatment and management of many medical conditions. High blood pressure is associated with many chronic disease conditions, and is a major source of mortality and morbidity around the world. For outpatient care as well as general health monitoring, there is great interest in being able to accurately and frequently measure BP outside of a clinical setting, using mobile or wearable devices. One possible solution is photoplethysmography (PPG), which is most commonly used in pulse oximetry in clinical settings for measuring oxygen saturation. PPG technology is becoming more readily available, inexpensive, convenient, and easily integrated into portable devices. Recent advances include the development of smartphones and wearable devices that collect pulse oximeter signals. In this article, we review (i) the state-of-the-art and the literature related to PPG signals collected by pulse oximeters, (ii) various theoretical approaches that have been adopted in PPG BP measurement studies, and (iii) the potential of PPG measurement devices as a wearable application. Past studies on changes in PPG signals and BP are highlighted, and the correlation between PPG signals and BP are discussed. We also review the combined use of features extracted from PPG and other physiological signals in estimating BP. Although the technology is not yet mature, it is anticipated that in the near future, accurate, continuous BP measurements may be available from mobile and wearable devices given their vast potential.
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http://dx.doi.org/10.1038/s41746-019-0136-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594942PMC
June 2019