Publications by authors named "Muzaffar Ali"

37 Publications

Genetic Characterization of Highly Pathogenic Avian Influenza A(H5N8) Virus in Pakistani Live Bird Markets Reveals Rapid Diversification of Clade 2.3.4.4b Viruses.

Viruses 2021 Aug 18;13(8). Epub 2021 Aug 18.

Programme in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.

The highly pathogenic (HPAI) avian influenza A(H5N1) viruses have undergone reassortment with multiple non-N1-subtype neuraminidase genes since 2008, leading to the emergence of H5Nx viruses. H5Nx viruses established themselves quickly in birds and disseminated from China to Africa, the Middle East, Europe and North America. Multiple genetic clades have successively evolved through frequent mutations and reassortment, posing a continuous threat to domestic poultry and causing substantial economic losses. Live bird markets are recognized as major sources of avian-to-human infection and for the emergence of zoonotic influenza. In Pakistan, the A(H5N1) virus was first reported in domestic birds in 2007; however, avian influenza surveillance is limited and there is a lack of knowledge on the evolution and transmission of the A(H5) virus in the country. We collected oropharyngeal swabs from domestic poultry and environmental samples from six different live bird markets during 2018-2019. We detected and sequenced HPAI A(H5N8) viruses from two chickens, one quail and one environmental sample in two markets. Temporal phylogenetics indicated that all novel HPAI A(H5N8) viruses belonged to clade 2.3.4.4b, with all eight genes of Pakistan A(H5N8) viruses most closely related to 2017 Saudi Arabia A(H5N8) viruses, which were likely introduced via cross-border transmission from neighboring regions approximately three months prior to virus detection into domestic poultry. Our data further revealed that clade 2.3.4.4b viruses underwent rapid lineage expansion in 2017 and acquired significant amino acid mutations, including mutations associated with increased haemagglutinin affinity to human α-2,6 receptors, prior to the first human A(H5N8) infection in Russian poultry workers in 2020. These results highlight the need for systematic avian influenza surveillance in live bird markets in Pakistan to monitor for potential A(H5Nx) variants that may arise from poultry populations.
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http://dx.doi.org/10.3390/v13081633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402709PMC
August 2021

Narrow complex supraventricular tachycardia. What is the mechanism?

HeartRhythm Case Rep 2021 Aug 4;7(8):525-528. Epub 2021 May 4.

Department of Cardiology, Johns Hopkins University, Baltimore, Maryland.

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http://dx.doi.org/10.1016/j.hrcr.2021.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377234PMC
August 2021

Lyme Prosthetic Joint Infection in Total Knee Arthroplasty: A Case Report.

JBJS Case Connect 2021 07 30;11(3). Epub 2021 Jul 30.

UPMC Pinnacle, Harrisburg, Pennsylvania.

Case: An 81-year-old man from the northeastern United States presented with an acute Borrelia burgdorferi prosthetic joint infection (PJI) 15 years after undergoing a right total knee arthroplasty. He had no complications until his recent presentation. He was treated with irrigation and debridement with implant retention. Synovial fluid Lyme polymerase chain reaction and serological tests were positive. Postoperatively, he received oral doxycycline and at 6 weeks was asymptomatic. Four months later, he died of neuroborreliosis vasculitis, a complication of Lyme.

Conclusion: We recommend considering Lyme disease as a cause of culture-negative PJIs in endemic regions. Early surgical treatment may mitigate adverse outcomes of Lyme.
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http://dx.doi.org/10.2106/JBJS.CC.20.00898DOI Listing
July 2021

An unusual case of Adrenocortical Adenocarcinoma with Biochemical Masquerade of Pheochromocytoma.

Pak J Med Sci 2021 Jul-Aug;37(4):1241-1243

Lubna Mirza Norman Regional Hospital, Norman, United State.

Adrenocortical carcinoma (ACC) is a rare malignancy that arises from the adrenal cortex and often presents as adrenal incidentaloma on abdominal scans with rise in the use of imaging modalities. ACC often presents as Cushing's syndrome or virilization. On the other hand, pheochromocytoma is an adrenal medullary tumor. It is rare for ACC to present as pheochromocytoma even though both may coexist. Moreover, ACC tumors have radiological and histological features suggestive of aggressive nature of the disease. We present a case of a 65-year-old lady who initially presented with a 3cm left adrenal incidentaloma. All of her adrenal hormones were in normal range. She was lost to follow up for several years and returned with a much enlarged lesion. Biochemical work up showed mildly increased catecholamines and metanephrines suggestive of pheochromocytoma. She didn't have any signs or symptoms of pheochromocytoma. She was treated with alpha blockers before surgery as a prophylactic measure. Surgical pathology was consistent with the diagnosis of primary adrenal adenocarcinoma. We recommend that adrenal incidentalomas should be followed annually for up to five years as per American association of Endocrinology and the Endocrine Society guidelines to prevent morbidity and mortality in patients.
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http://dx.doi.org/10.12669/pjms.37.4.3916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281192PMC
November 2020

Morbid Obesity Due to Prolactinoma and Significant Weight Loss After Dopamine Agonist Treatment.

AACE Clin Case Rep 2021 May-Jun;7(3):204-206. Epub 2021 Mar 11.

Department of Endocrinology, Norman Regional Hospital, Oklahoma.

Objective: Morbid obesity may be related to a prolactinoma, although uncommon, and can lead to adverse effects like insulin resistance and metabolic syndrome. Recent research suggests that hyperprolactinemia causes an abnormal lipid profile, weight gain, and cardiovascular diseases. Moreover, high prolactin levels lead to decreased testosterone production by disrupting 17-b-estradiol synthesis. Our objective was to present a case of prolactinoma with morbid obesity, hypogonadism, and then significant weight loss after dopamine agonist treatment.

Methods: The clinical course, in addition to serial laboratory and imaging results, are presented. These include prolactin levels, testosterone levels, thyroid function tests, blood sugar levels, and serial lipid profiles.

Results: In this report, we discuss a case of 30-year-old male with prolactin-secreting macroadenoma with clinical features of hypogonadism, hypothyroidism, and morbid obesity. He showed marked improvement in obesity and hypogonadism with dopamine agonist therapy supplemented with clomiphene citrate.

Conclusion: Prolactinomas with morbid obesity can be successfully treated contingent upon proper medication and compliance with medications. Insulin resistance, hypogonadism, prolactin levels, body mass index, and tumor size all improved by regular follow-up and treatment adherence.
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http://dx.doi.org/10.1016/j.aace.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165126PMC
March 2021

Prevalence and phylogenetic analysis of Crimean-Congo hemorrhagic fever virus in ticks collected from Punjab province of Pakistan.

Acta Trop 2021 Jun 19;218:105892. Epub 2021 Mar 19.

Galveston National Laboratory, Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne zoonotic disease of human that caused by CCHF virus. To study the epidemiological distribution of CCHFV, 2183 tick samples were collected from sheep, goats, cattle and buffalo of different livestock farms of ten districts of Punjab province of Pakistan. Detection of CCHFV was done using enzyme link immunosorbent assay (ELISA) after proper identification of tick samples. The partial S-segment of CCHFV from ELISA positive tick samples was amplified by PCR and sequenced to determine the genotype of CCHFV. Out of2183 collected tick samples, 1913 ticks belonged to 5 species of genus Hyalomma as H. antolicum (48%), H. marginatum (30.2%), H. rufipes (10.82%), H. impressum (5.43%) and H. dromedarii (5.27%). While 270 ticks belonged to 3 species of genus Rhipicephalus as R. microplus (44.8%), R. sanguineus (32.22%) and R. turanicus (24.8%). The overall antigenic prevalence of CCHFV was found to be 12.13% in collected tick samples and 21 tick pools were sequenced for partial S-segment of CCHFV. All of the 21 tick pools were clustered in genotype IV (Asia-1). The highest prevalence of CCHFV was found in district Chakwal (24.13%) followed by Mianwali (23.68%), Rawalpindi (23.07%), Attock (20.0%), Rajanpur (10.52%) and Lahore (8.33%). In positive tick pools, the highest prevalence of CCHFV antigen was found in H. antolicum (39.6%) followed by H. marginatum (30.18%), H. rufipes (13.2%), H. impressum (3.77%), H. dromedarii (1.88%), R. microplus (5.66%) and R. sanguineus (5.66%). The current study confirms the presence of CCHFV in the ticks population of Punjab. The CCHF virus present in Punjab belongs to Asia-1 genotype. It is important to control the tick infestation of the animals present in these areas. So that the transmission cycle of CCHF can be inhibited.
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http://dx.doi.org/10.1016/j.actatropica.2021.105892DOI Listing
June 2021

Effect of fluoroscopy frame rate on radiation exposure and in-hospital outcomes in three-dimensional electroanatomic mapping guided procedures.

J Arrhythm 2021 Feb 5;37(1):97-102. Epub 2021 Jan 5.

Department of Cardiac Electrophysiology Sri Jayadeva Institute of Cardiovascular Sciences and Research Bangalore India.

Background: Fluoroscopic imaging involves exposure of the patients and the laboratory staff to ionizing radiation. One of the strategies that reduce such exposure in an electrophysiology laboratory is using a three-dimensional electroanatomic mapping (3D EAM) system for performing these procedures. In this analysis, we have analyzed the effect of fluoroscopy frame rate on the radiation exposure and in-hospital outcomes in ablation procedures performed under 3D EAM guidance.

Methods: We retrospectively analyzed all the ablation procedures performed under 3D EAM guidance at our institute from September 2015 to December 2018. The procedures were divided into two groups based on whether the procedures were performed before (pre) or after (post) January 26, 2018. After January 2018, fluoroscopy was used at a frame rate of 3.75 frames per second (fps). Radiation exposure indices and in-hospital outcomes were compared between the two groups.

Results: Ablation procedures included in the analysis were ventricular arrhythmias (n = 192), atrial flutter (115), atrial tachycardia (AT) (43), and atrial fibrillation (AF) (30). Over the study period, there was a significant reduction in procedure time, fluoroscopy time, dose area product, and effective dose (ED) ( < .001). Except for AT and AF ablation procedures, there was a significant reduction in the radiation exposure indices when the "post" group was compared with the "pre" group ( ≤ .02). The decrease in the frame rate had no significant effect on in-hospital outcomes.

Conclusion: The use of 3D EAM combined with decreasing the fluoroscopy frame rate significantly reduced the total radiation exposure without adversely affecting in-hospital outcomes.
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http://dx.doi.org/10.1002/joa3.12496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896476PMC
February 2021

Prevalence of type 2 diabetes mellitus and association of HbA1c with severity of coronary artery disease in patients presenting as non-diabetic acute coronary syndrome.

Egypt Heart J 2020 Sep 29;72(1):66. Epub 2020 Sep 29.

Department of Cardiology, SKIMS Soura, Srinagar, Jammu and Kashmir, 190011, India.

Background: Acute coronary syndrome (ACS) indicates the serious clinical manifestation of coronary artery disease (CAD) and is closely associated with cardiovascular prognosis in patients with ACS. This study was aimed to study the prevalence of type 2 diabetes mellitus (T2DM) and the relation of HbA1c with the severity of CAD in patients presenting as non-diabetic ACS. Diabetic status of the patients was assessed with fasting blood sugar (FBS) and HbA1c levels, and coronary artery disease burden was assessed by coronary angiography.

Results: Out of 208 patients, 85.1% were males, and 14.9% were females; 73.56% cases were hypertensive. 80.77% of cases had STEMI, 17.79% had NSTEMI, and 1.44% had unstable angina. Out of 168 STEMI patients, 64.3% were thrombolysed, 21.42% presented late, 2.38% had contraindications to thrombolysis, and 11.9% underwent primary PCI. FBS in diabetic range was found in 44.23% of cases, impaired FBS in 36.54%, and 19.23% of patients had FBS in non-diabetic range. According to HbA1c, 41.8% were diabetic, 39.4% were pre-diabetic, and 18.8% were non-diabetic. A significant positive correlation was found between HbA1c and Gensini score and between HbA1c and the number of vessels involved.

Conclusion: This study emphasises the importance of evaluating the presence of diabetes in patients presenting as non-diabetic acute coronary syndrome in developing countries. Acute coronary syndrome may be considered as one of the presentations of diabetes mellitus.
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http://dx.doi.org/10.1186/s43044-020-00101-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524918PMC
September 2020

Seroprevalence of Crimean-Congo haemorrhagic fever among three selected risk human groups in disease-endemic region of Pakistan.

Zoonoses Public Health 2020 11 15;67(7):755-759. Epub 2020 Apr 15.

Department of Microbiology, University of Veterinary and Animal Sciences, Lahore, Pakistan.

The occurrence of Crimean-Congo haemorrhagic fever (CCHF) in humans is linked with animals living in close vicinity, and information on the incidence of CCHF at the human-animal interface is scarce. Therefore, the current study was designed to identify the high-risk groups of individuals linked with animals in the Chakwal district of Pakistan having a history of CCHF cases in humans. In subject matter, coupled with risk factor analysis, we performed a sero-based CCHF surveillance in three selected risk groups of humans including abattoir workers (n = 137), milkmen (n = 169) and animal handlers (n = 147). Sera samples and questionnaire-based data were collected from each of the participants and screened for anti-CCHFV IgG antibodies using enzyme-linked immunosorbent assay. The highest seroprevalence was observed in animal handlers (n = 14, 9.52%, 95% CI: 4.68-13.99) followed by abattoir workers (n = 9, 6.57%, 95% CI: 2.42-10.72) and milkmen (n = 3, 1.78%, 95% CI: 0.24-4.24). The risk of seropositivity was significantly associated with humans linked with tick-infested animals (OR: 11.0, 95% CI: 1.5-83.0, p = .002), old age >40 years (OR: 6.6, 95% CI: 2.7-16.0, p < .0001), illiteracy (OR: 4.3, 95% CI: 1.5-13.0, p = .004) and humans without knowledge about CCHF (OR: 7.6, 95% CI: 1.8-33.0, p = .0009). The findings of the current study highlighted the seroprevalence of CCHF in high-risk groups of humans living in a disease-endemic area of Pakistan and highlight the need for well-integrated disease surveillance in the future to better comprehend disease control interventions.
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http://dx.doi.org/10.1111/zph.12704DOI Listing
November 2020

Circulation of multiple subtypes (A, G and CRFs 02_AG) of human immunodeficiency virus type 1 (HIV-1) in selected districts of Punjab province, Pakistan.

Arch Virol 2019 Dec 1;164(12):3081-3087. Epub 2019 Oct 1.

Primary and Secondary Health Care Department, Government of Punjab, Lahore, 54600, Pakistan.

Owing to consistent genetic mutation and recombination, various escape mutants and/or drug-resistant mutants of human immunodeficiency virus (HIV-1) are now emerging worldwide. Therefore, an understanding of the genetic characteristics of prevailing strains, particularly with regard to drug-resistance-associated substitutions, is essential for devising and implementing treatments and disease control interventions in endemic settings such as Pakistan. We processed a total of 130 plasma samples originating from HIV-treatment centers in selected districts of Punjab province, Pakistan. The samples were first screened using an HIV-1 Ag/Ab Combo test followed by amplification of the pol gene (1084 bp) from samples that were positive either for the antigen or for both the antigen and antibodies simultaneously. Screening revealed that a total of 45 samples were positive (34.62%; 95% CI: 26.99-43.13) for either antigen or both antigen and antibodies (n = 18, 40%; 95% CI: 27.02-54.55) or for antibodies alone (n = 27, 60%; 95% CI: 45.45-72.98). A largest number of positive samples was from the district of Lahore (n = 19/43, 44.18%; 95% CI: 30.44-58.9) followed by Faisalabad (n= 12/36, 33.33%; 95% CI: 20.21-49.66), Gujranwala (n = 05/23, 21.7%; 95% CI: 9.66-41.9) and Sargodha (n = 09/28, 32.1%; 95% CI: 17.93-50.66). The probability of occurrence of HIV infection was significantly associated with individuals having a history of injecting drug use (68.08%; OR = 11.15; 95% CI: 53.84-79.61, p = 0.0001). Phylogenetic analysis based on the pol gene showed that the sequences from this study clustered into three distinct clades representing recombinant form 02_AG (n = 14, 77.0%; 95% CI: 54.79-91.00), and subtypes A (n = 2, 11.1%; 95% CI: 3.1-32.8) and G (n = 2, 11.1%; 95% CI: 3.1-32.8). Although we screened 18 samples for drug-resistance-associated mutations, except for an accessory mutation (M46K) in the protease (PR) region in one subject, we found a lack of drug-resistance-associated substitutions in the PR region. On the other hand, we found two subjects (2/18) carrying a resistance-associated mutation (V106I) conferring a low level of resistance against non-nucleoside reverse transcriptase inhibitors. The present study shows that multiple subtypes of HIV-1 are present in the affected population. Continuous disease surveillance coupled with evaluation of drug resistance at higher resolution should be done in future studies.
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http://dx.doi.org/10.1007/s00705-019-04422-7DOI Listing
December 2019

Different risk factors are associated with alcohol use versus problematic use in male Pakistani adolescents.

Int J Psychol 2020 Aug 27;55(4):585-589. Epub 2019 Aug 27.

University of Karachi, Karachi, Pakistan.

Substance abuse is a significant problem in Pakistan (Hussain, 2017), yet, there are few studies of risk factors in this population, particularly in remote areas. Male adolescents (N = 243; M = 16.9 years, SD = 1.3 years) were recruited from schools in Gilgit-Baltistan, and completed questions on demographics, substance use, and psychosocial functioning. As a Muslim country, there are strict prohibitions against alcohol use, yet 44.9% of the sample reported lifetime alcohol use. The Alcohol Use Disorders Identification Test (Babor, Higgins-Biddle, Saunders, & Monteiro, 2001), was used to quantify level of risk associated with use, and 22.6% of the sample had scores indicating significant risk levels. Logistic regression analyses indicated that lifetime alcohol use was associated with internalising problems (e.g., depression, anxiety), while risky alcohol use was associated with externalising problems (e.g., aggressive and delinquent behaviour). Attention problems were related to both outcomes. Implications for prevention are discussed.
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http://dx.doi.org/10.1002/ijop.12617DOI Listing
August 2020

Clinical and Electrophysiological Correlates of Incessant Ivabradine-Sensitive Atrial Tachycardia.

Circ Arrhythm Electrophysiol 2019 08 26;12(8):e007387. Epub 2019 Jul 26.

Cardiac Electrophysiology Unit, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India.

Background: Incessant focal atrial tachycardia (FAT), if untreated, can lead to ventricular dysfunction and heart failure (tachycardia-induced cardiomyopathy). Drug therapy of FAT is often difficult and ineffective. The efficacy of ivabradine has not been systematically evaluated in the treatment of FAT.

Methods: The study group consisted of patients with incessant FAT (lasting >24 hours) and structurally normal hearts. Patients with ventricular dysfunction as a consequence of FAT were not excluded. All antiarrhythmic drugs were discontinued at least 5 half-lives before the initiation of ivabradine. Oral ivabradine (adults, 10 mg twice 12 hours apart; pediatric patients: 0.28 mg/kg in 2 divided doses) was initiated in the intensive care unit under continuous electrocardiographic monitoring. A positive response was defined as the termination of tachycardia with the restoration of sinus rhythm or suppression of the tachycardia to <100 beats per minute without termination within 12 hours of initiating ivabradine.

Results: Twenty-eight patients (mean age, 34.6±21.5 years; women, 60.7%) were included in the study. The most common symptom was palpitation (85.7%) followed by shortness of breath (25%). The mean atrial rate during tachycardia was 170±21 beats per minute, and the mean left ventricular ejection fraction was 54.7±14.3%. Overall, 18 (64.3%) patients responded within 6 hours of the first dose of ivabradine. Thirteen of 18 ivabradine responders subsequently underwent successful catheter ablation. FAT originating in the atrial appendages was a predictor of ivabradine response compared with those arising from other atrial sites (P=0.046).

Conclusions: Ivabradine-sensitive atrial tachycardia constitutes 64% of incessant FAT in patients without structural heart disease. Incessant FAT originating in the atrial appendages is more likely to respond to ivabradine than that arising from other atrial sites. Our findings implicate the funny current in the pathogenesis of FAT.
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http://dx.doi.org/10.1161/CIRCEP.119.007387DOI Listing
August 2019

Prevalence and Phylogenetics of H9n2 in Backyard and Commercial Poultry in Pakistan.

Avian Dis 2018 12;62(4):416-424

Institute of Pure and Applied Biology, Bahauddin Zakariya University, Multan 60800, Pakistan.

Surveillance of H9N2 is currently focused on areas central to the commercial poultry industry. This study determined the prevalence of H9N2 virus in commercial and backyard poultry flocks in Punjab Province, Pakistan. Oral and tracheal swabs were collected from commercial and backyard poultry from January 2015 through June 2016. Antisera against H5, H7, H9, and Newcastle disease viruses were used for virus identification. Molecular confirmation was made by reverse transcription PCR. Avian influenza virus subtypes H5 and H7 were not detected. The H9N2 virus was isolated in 5.7% of 905 tested flocks (5-10 birds/flock). Prevalence in commercial and backyard poultry was 6.7% of 687 flocks and 2.7% of 218 flocks, respectively. Hemagglutinin and neuraminidase-gene-based phylogenetic analysis of commercial and backyard poultry isolates showed 100% homology. Within sublineage B2 of Pakistan, identity among most recent isolates (2015) was 100%, compared to 75%-99% identity with previously isolated viruses (2010-12), indicating continued virus evolution. Most of the previously reported and currently studied viruses were isolated near the Pakistan-India border. Phylogenetic analysis showed that Pakistani and Indian isolates were closely related, indicating that avian influenza virus transmission may occur across this border.
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http://dx.doi.org/10.1637/11690-062117-ResNote.1DOI Listing
December 2018

Avian Influenza A(H9N2) Virus in Poultry Worker, Pakistan, 2015.

Emerg Infect Dis 2019 01;25(1):136-139

Avian influenza A(H9N2) virus isolated from a poultry worker in Pakistan in 2015 was closely related to viruses detected in poultry farms. Observed mutations in the hemagglutinin related to receptor-binding affinity and antigenicity could affect cross-reactivity with prepandemic H9N2 vaccine strains.
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http://dx.doi.org/10.3201/eid2501.180618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302575PMC
January 2019

The ZZ domain of p300 mediates specificity of the adjacent HAT domain for histone H3.

Nat Struct Mol Biol 2018 09 27;25(9):841-849. Epub 2018 Aug 27.

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.

Human p300 is a transcriptional co-activator and a major acetyltransferase that acetylates histones and other proteins facilitating gene transcription. The activity of p300 relies on the fine-tuned interactome that involves a dozen p300 domains and hundreds of binding partners and links p300 to a wide range of vital signaling events. Here, we report a novel function of the ZZ-type zinc finger (ZZ) of p300 as a reader of histone H3. We show that the ZZ domain and acetyllysine-recognizing bromodomain of p300 play critical roles in modulating p300 enzymatic activity and its association with chromatin. The acetyllysine binding function of bromodomain is essential for acetylation of histones H3 and H4, whereas interaction of the ZZ domain with H3 promotes selective acetylation of the histone H3K27 and H3K18 sites.
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http://dx.doi.org/10.1038/s41594-018-0114-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482957PMC
September 2018

Clinical profile in arrhythmogenic cardiomyopathy and a recessive plakophilin-2 gene mutation.

Indian Heart J 2018 May - Jun;70(3):421-426. Epub 2017 Oct 20.

Department of Cardiology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K, India.

Objective: Arrhythmogenic cardiomyopathy (ACM) is not an uncommon cause of cardiac morbidity in Kashmir valley. This study was designed to document various clinical features and to sequence exons 11 and 12 of plakophilin 2 (PKP2) gene in these patients.

Methods: ACM patients who attended cardiology outpatient department of our institute from January 2014 to April 2015 were included in the study. Their records were reviewed. Controls were randomly selected, who had no history or family history of cardiac illness and had a normal cardiac examination. A blood sample was also taken from both the groups for sequencing of exon 11 and 12 of PKP2 gene. ACM patients were followed up until July 2016.

Results: Eleven ACM patients and seven controls were included in the study. Most common mode of presentation was ventricular tachycardia (VT). Two patients had left ventricular (LV) systolic dysfunction. One patient had a splice site mutation in exon 12 of PKP2 gene and one patient died during follow-up. One of the controls had an intronic variation that has no pathogenic significance vis-à-vis ACM.

Conclusion: Our study describes various clinical parameters in ACM patients and a recessive plakophilin 2 mutation after a limited PKP2 gene sequencing.
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http://dx.doi.org/10.1016/j.ihj.2017.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034022PMC
September 2018

Are the anatomy textbooks wrong? A clinical patho-anatomic study of foveal vessels in the round ligament of the hip.

Ann Transl Med 2017 Dec;5(Suppl 3):S32

Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, OH, USA.

Background: The foveal vessels of the ligamentum teres are an anterior branch of the posterior division of the obturator artery, providing blood to the capitis of the femoral head. However, the basic anatomic description of foveal vasculature in the ligamentum teres of the hip is widely variable, with some studies reporting that the vessels are not patent in roughly one third of all adults. Therefore, the purpose of this study was to evaluate the status of foveal vessels in primary total hip arthroplasty (THA) patients. Specifically, we evaluated: (I) if the foveal vessels were intact; and we (II) correlated foveal vessel status with (i) patient demographics, including gender and age; as well as (ii) perioperative data, such as operative time and blood loss.

Methods: The macroscopic status of the foveal vessels in the ligamentum teres femoris was documented in 266 patients at the time of primary unilateral THA performed between August 2015 and April 2017. The vessels were considered to be intact if active bleeding was directly visible from the acetabular stump of the severed ligamentum teres femoris. Demographics including age, gender, and preoperative diagnosis were collected. The perioperative outcome variables included estimated blood loss (EBL) and operative time. Foveal vessel status defined as intact or not intact, was also correlated with patient demographics and perioperative data. A student's -test was used to compare the continuous variables and a chi square test was used for categorical variables.

Results: The foveal vessels were intact in 161 patients (61%) and not intact in 105 patients (39%). The mean age for patients with intact foveal vessels was found to be 64 years (range, 18 to 94 years) 65 years (range, 29 to 94 years) (P>0.05) for not intact. No correlation was found between preoperative diagnosis, gender, operative time, and EBL and foveal vessel status.

Conclusions: The results of this clinical patho-anatomic study of the foveal vessels in the ligamentum teres femoris of the hip refutes the polarized claims of prior anatomy texts that document the vessels as either "absent in adults" or "always intact." Rather, the results of this study reveal an alternate option: that foveal vessels can be present and either be intact (61%) or not intact (39%). No correlation was found between age, gender, operative time, and EBL and foveal vessel status.
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http://dx.doi.org/10.21037/atm.2017.11.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750263PMC
December 2017

Structural Insight into Recognition of Methylated Histone H3K4 by Set3.

J Mol Biol 2017 06 30;429(13):2066-2074. Epub 2016 Sep 30.

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Structural Biology and Biochemistry Program, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address:

The plant homeodomain (PHD) finger of Set3 binds methylated lysine 4 of histone H3 in vitro and in vivo; however, precise selectivity of this domain has not been fully characterized. Here, we explore the determinants of methyllysine recognition by the PHD fingers of Set3 and its orthologs. We use X-ray crystallographic and spectroscopic approaches to show that the Set3 PHD finger binds di- and trimethylated states of H3K4 with comparable affinities and employs similar molecular mechanisms to form complexes with either mark. Composition of the methyllysine-binding pocket plays an essential role in determining the selectivity of the PHD fingers. The finding that the histone-binding activity is not conserved in the PHD finger of Set4 suggests different functions for the Set3 and Set4 paralogs.
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http://dx.doi.org/10.1016/j.jmb.2016.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374059PMC
June 2017

Multivalent Chromatin Engagement and Inter-domain Crosstalk Regulate MORC3 ATPase.

Cell Rep 2016 09;16(12):3195-3207

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address:

MORC3 is linked to inflammatory myopathies and cancer; however, the precise role of MORC3 in normal cell physiology and disease remains poorly understood. Here, we present detailed genetic, biochemical, and structural analyses of MORC3. We demonstrate that MORC3 is significantly upregulated in Down syndrome and that genetic abnormalities in MORC3 are associated with cancer. The CW domain of MORC3 binds to the methylated histone H3K4 tail, and this interaction is essential for recruitment of MORC3 to chromatin and accumulation in nuclear bodies. We show that MORC3 possesses intrinsic ATPase activity that requires DNA, but it is negatively regulated by the CW domain, which interacts with the ATPase domain. Natively linked CW impedes binding of the ATPase domain to DNA, resulting in a decrease in the DNA-stimulated enzymatic activity. Collectively, our studies provide a molecular framework detailing MORC3 functions and suggest that its modulation may contribute to human disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074691PMC
http://dx.doi.org/10.1016/j.celrep.2016.08.050DOI Listing
September 2016

Liposomal Bupivacaine in Total Knee Arthroplasty for Better Postoperative Analgesic Outcome and Economic Benefits.

J Knee Surg 2016 Jul 10;29(5):e2. Epub 2016 Jun 10.

Center for Joint Preservation and Replacement, Rubin Institute for Advanced Orthopedics, Baltimore, Maryland.

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http://dx.doi.org/10.1055/s-0036-1584270DOI Listing
July 2016

Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors.

Bioorg Chem 2016 Feb 31;64:85-96. Epub 2015 Dec 31.

H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia. Electronic address:

Four series of heterocyclic compounds 4-dihydropyrimidine-2-thiones 7-12 (series A), N,S-dimethyl-dihydropyrimidines 13-18 (series B), hydrazine derivatives of dihydropyrimidine 19-24 (series C), and tetrazolo dihydropyrimidine derivatives 25-30 (series D), were synthesized and evaluated for in vitro urease inhibitory activity. The series B-D were first time examined for urease inhibition. Series A and C were found to be significantly active with IC50 values between 34.7-42.9 and 15.0-26.0 μM, respectively. The structure-activity relationship showed that the free S atom and hydrazine moiety are the key pharmacophores against urease enzyme. The kinetic studies of the active series A (7-12) and C (19-24) were carried out to determine their modes of inhibition and dissociation constants Ki. Compounds of series A (7-12) and series C (19-24) showed a mixed-type of inhibition with Ki values ranging between 15.76-25.66 and 14.63-29.42 μM, respectively. The molecular docking results showed that all the active compounds of both series have significant binding interactions with the active sites specially Ni-ion of the urease enzyme. Cytotoxicity of all series A-D was also evaluated against mammalian mouse fibroblast 3T3 cell lines, and no toxicity was observed in cellular model.
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http://dx.doi.org/10.1016/j.bioorg.2015.12.007DOI Listing
February 2016

Liposomal Bupivacaine in Total Knee Arthroplasty for Better Postoperative Analgesic Outcome and Economic Benefits.

J Knee Surg 2016 Apr 29;29(3):180-7. Epub 2015 Dec 29.

Center for Joint Preservation and Replacement, Rubin Institute for Advanced Orthopedics, Baltimore, Maryland.

When orthopedists consider which analgesia to use after total knee arthroplasty (TKA), the primary objective is to relieve pain with fewer adverse side effects. Over the last decade, substantial efforts have been made to improve pain control following TKA, but it is still very challenging to obtain optimal control. Current modalities in use, such as opioids, epidurals, and nerve blocks, provide substantial pain relief, but they are associated with substantial side effects and serious complications. Recently, bupivacaine, a commonly used nonopioid analgesic, has been formulated into an aqueous suspension of multivesicular liposomes that provide long-lasting analgesia, while avoiding significant adverse effects of opioids. The purpose of this review is to analyze the use of traditional postsurgical pain management and the potential contribution of a long-acting liposomal formulation of bupivacaine as part of the analgesic regimen in TKA, including its mode of action, injection technique, efficacy on pain, and health care costs.
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http://dx.doi.org/10.1055/s-0035-1570369DOI Listing
April 2016

Immediate effect of percutaneous transvenous mitral commissurotomy on atrial electromechanical delay and P-wave dispersion in patients with severe mitral stenosis.

Indian Heart J 2015 Dec 21;67 Suppl 2:S46-54. Epub 2015 Nov 21.

DM Fellow, Dept. of Cardiology, SKIMS, Srinagar, India.

Background: Mitral stenosis (MS) is associated with prolonged inter- and intra-atrial electromechanical delays and increased P-wave dispersion, which are markers of atrial fibrillation (AF) risk. This study was conducted to assess the immediate effect of successful percutaneous transvenous mitral commissurotomy (PTMC) on these parameters.

Methods: This single center observational study included 25 patients with severe MS (aged 34.1 ± 7.1 years, with mean mitral valve area (MVA) of 0.74 ± 0.13 cm(2)), in sinus rhythm, who underwent successful PTMC at our hospital. P-wave dispersion (PWD) was calculated by subtracting minimum P-wave duration (P min) from maximum P-wave duration (Pmax), measured on a 12-lead surface ECG obtained from each patient in supine position at a paper speed of 50mm/s and 20mm/mV. Inter-atrial (AEMD), left intra-atrial (L-IAEMD), and right intra-atrial (R-IAEMD) electromechanical delays were measured on tissue Doppler imaging. PTMC was performed using the standard Inoue Balloon technique. All these parameters were evaluated and compared before and 24-48 h after PTMC.

Results: Successful PTMC led to significant reduction in AEMD (p < 0.001), L-IAEMD (p < 0.001), and R-IAEMD (p < 0.001). There were no changes in Pmax, Pmin, and PWD immediately after PTMC.

Conclusions: Successful PTMC has a favorable early impact on inter- and intra-atrial electromechanical delays, which are considered as novel parameters of atrial electromechanical remodeling in MS patients. Prospective large-scale studies are required to confirm whether improvement in these markers translates into reduced long-term AF risk.
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http://dx.doi.org/10.1016/j.ihj.2015.10.375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688442PMC
December 2015

Molecular Insights into Inhibition of the Methylated Histone-Plant Homeodomain Complexes by Calixarenes.

J Biol Chem 2015 Sep 30;290(38):22919-30. Epub 2015 Jul 30.

From the Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045,

Plant homeodomain (PHD) finger-containing proteins are implicated in fundamental biological processes, including transcriptional activation and repression, DNA damage repair, cell differentiation, and survival. The PHD finger functions as an epigenetic reader that binds to posttranslationally modified or unmodified histone H3 tails, recruiting catalytic writers and erasers and other components of the epigenetic machinery to chromatin. Despite the critical role of the histone-PHD interaction in normal and pathological processes, selective inhibitors of this association have not been well developed. Here we demonstrate that macrocyclic calixarenes can disrupt binding of PHD fingers to methylated lysine 4 of histone H3 in vitro and in vivo. The inhibitory activity relies on differences in binding affinities of the PHD fingers for H3K4me and the methylation state of the histone ligand, whereas the composition of the aromatic H3K4me-binding site of the PHD fingers appears to have no effect. Our approach provides a novel tool for studying the biological roles of methyllysine readers in epigenetic signaling.
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http://dx.doi.org/10.1074/jbc.M115.669333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4645621PMC
September 2015

Low-cost design and fabrication of an anthropomorphic robotic hand.

J Nanosci Nanotechnol 2014 Oct;14(10):7427-31

Human hand signifies a magnificent and challenging example for scientists and engineers trying to replicate its complex structure and functionality. This paper proposes a bio-mechatronic approach for the design of an anthropomorphic artificial hand capable of performing basic human hand motions with fundamental gripping functionality. The dexterity of the artificial hand is exhibited by imitating the natural motion of the human fingers. Imitation is produced according to the data acquired from the flex sensors attached to the human fingers. In order to have proper gripping, closed-loop control is implemented using the tactile sensors. Feedback for the closed-loop control is provided by force sensing resistors (FSRs), attached on the fingertips of the robotic hand. These sensors also enable handling of fragile objects. The mathematical model is derived using forward kinematics and also simulated on MATLAB to ascertain the position of robotic fingers in 3D space.
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http://dx.doi.org/10.1166/jnn.2014.9558DOI Listing
October 2014

O-GlcNAcylation of MLL5β is essential for MLL5β-AP-1 transcription complex assembly at the HPV16/18-long control region.

J Mol Cell Biol 2015 Apr 10;7(2):180-3. Epub 2015 Feb 10.

Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore 117596, Singapore

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http://dx.doi.org/10.1093/jmcb/mjv009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425831PMC
April 2015

A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response.

Cell 2014 May;157(4):869-81

Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome.
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http://dx.doi.org/10.1016/j.cell.2014.03.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038154PMC
May 2014

Diverse functions of PHD fingers of the MLL/KMT2 subfamily.

Biochim Biophys Acta 2014 Feb 28;1843(2):366-71. Epub 2013 Nov 28.

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address:

Five members of the KMT2 family of lysine methyltransferases, originally named the mixed lineage leukemia (MLL1-5) proteins, regulate gene expression during embryogenesis and development. Each KMT2A-E contains a catalytic SET domain that methylates lysine 4 of histone H3, and one or several PHD fingers. Over the past few years a growing number of studies have uncovered diverse biological roles of the KMT2A-E PHD fingers, implicating them in binding to methylated histones and other nuclear proteins, and in mediating the E3 ligase activity and dimerization. Mutations in the PHD fingers or deletion of these modules are linked to human diseases including cancer and Kabuki syndrome. In this work, we summarize recently identified biological functions of the KMT2A-E PHD fingers, discuss mechanisms of their action, and examine preference of these domains for histone and non-histone ligands.
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http://dx.doi.org/10.1016/j.bbamcr.2013.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925188PMC
February 2014

Molecular basis for chromatin binding and regulation of MLL5.

Proc Natl Acad Sci U S A 2013 Jul 24;110(28):11296-301. Epub 2013 Jun 24.

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.

The human mixed-lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle, and survival; however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3. The 1.48-Å resolution crystal structure of MLL5 plant homeodomain in complex with the H3K4me3 peptide reveals a noncanonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a unique His-Asp swapping rearrangement mediated by a C-terminal α-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, UpSET, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide first insights into the molecular basis for the recruitment, exclusion, and regulation of MLL5 at chromatin.
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http://dx.doi.org/10.1073/pnas.1310156110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710826PMC
July 2013
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