Publications by authors named "Gabrielle Britton"

34 Publications

Critical Review of the Alzheimer's Disease Non-Transgenic Models: Can They Contribute to Disease Treatment?

J Alzheimers Dis 2020 Nov 20. Epub 2020 Nov 20.

Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá, República de Panamá.

Alzheimer's disease (AD) is a growing neurodegenerative disease without effective treatments or therapies. Despite the use of different approaches and an extensive variety of genetic amyloid based models, therapeutic strategies remain elusive. AD is characterized by three main pathological hallmarks that include amyloid-β plaques, neurofibrillary tangles, and neuroinflammatory processes; however, many other pathological mechanisms have been described in the literature. Nonetheless, the study of the disease and the screening of potential therapies is heavily weighted toward the study of amyloid-β transgenic models. Non-transgenic models may aid in the study of complex pathological states and provide a suitable complementary alternative to evaluating therapeutic biomedical and intervention strategies. In this review, we evaluate the literature on non-transgenic alternatives, focusing on the use of these models for testing therapeutic strategies, and assess their contribution to understanding AD. This review aims to underscore the need for a shift in preclinical research on intervention strategies for AD from amyloid-based to alternative, complementary non-amyloid approaches.
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http://dx.doi.org/10.3233/JAD-200870DOI Listing
November 2020

Apolipoprotein ɛ4 Affects Multiple Domains of Neuropsychological Functioning in a Sample of Elderly Hispanics.

J Alzheimers Dis 2020 Oct 10. Epub 2020 Oct 10.

Centro de Neurociencia y Unidad de Investigación Clínica, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá.

Apolipoprotein ɛ4 allele (APOEɛ4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), but inconsistencies have arisen in studies with Hispanics. The objective of this study was to explore APOEɛ4 expression and cognitive function in a sample of Panamanian older adults, including healthy controls, mild cognitive impairment, and AD. Participants with at least one copy of APOEɛ4 had a significantly lower performance in global cognition, verbal memory, executive functions, visuospatial abilities, regardless of diagnosis. The present study contributes to the understanding of the association of APOEɛ4 and impairment in specific cognitive domains in elderly Hispanics.
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http://dx.doi.org/10.3233/JAD-200921DOI Listing
October 2020

Intestinal volvulus in the pump twin of a twin reversed arterial perfusion (TRAP) sequence after laser therapy at 18 weeks: a case report.

J Med Case Rep 2020 Aug 8;14(1):123. Epub 2020 Aug 8.

Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Ciudad del Saber, Panamá, Panamá.

Background: Twin reversed arterial perfusion sequence is a rare and potentially lethal condition affecting approximately 1% of monochorionic twin pregnancies and 1 in 35,000 pregnancies overall. An apparently normal (pump) twin perfuses its severely malformed cotwin with deoxygenated blood via retrograde flow in direct arterioarterial anastomoses between the umbilical arteries of each twin. Fetal intestinal volvulus is a rare condition usually manifesting after birth. We report a unique case of twin reversed arterial perfusion sequence in association with intestinal volvulus in the surviving pump twin.

Case Presentation: A 32-year-old Hispanic primigravida was referred to our clinic after a fetoscopy procedure of laser photocoagulation of anastomoses at 18 weeks of gestation. Follow up scans in the ex-pump twin revealed dilated bowel loops and a typical "whirlpool sign" at 26 weeks of gestation, and intrauterine intestinal volvulus was suspected. At 29 weeks of gestation, preterm premature rupture of membranes occurred, and an emergency cesarean section was performed. The newborn was diagnosed in the early neonatal period with intestinal perforation. The diagnosis was postnatally confirmed by surgery and histopathology.

Conclusions: The type of fetal intervention and late gestational age of the procedure increase the risk of complications. This case alerts health providers to be vigilant in the follow-up of patients with complicated monochorionic pregnancies.
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http://dx.doi.org/10.1186/s13256-020-02444-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414987PMC
August 2020

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017.

Authors:
Roy Burstein Nathaniel J Henry Michael L Collison Laurie B Marczak Amber Sligar Stefanie Watson Neal Marquez Mahdieh Abbasalizad-Farhangi Masoumeh Abbasi Foad Abd-Allah Amir Abdoli Mohammad Abdollahi Ibrahim Abdollahpour Rizwan Suliankatchi Abdulkader Michael R M Abrigo Dilaram Acharya Oladimeji M Adebayo Victor Adekanmbi Davoud Adham Mahdi Afshari Mohammad Aghaali Keivan Ahmadi Mehdi Ahmadi Ehsan Ahmadpour Rushdia Ahmed Chalachew Genet Akal Joshua O Akinyemi Fares Alahdab Noore Alam Genet Melak Alamene Kefyalew Addis Alene Mehran Alijanzadeh Cyrus Alinia Vahid Alipour Syed Mohamed Aljunid Mohammed J Almalki Hesham M Al-Mekhlafi Khalid Altirkawi Nelson Alvis-Guzman Adeladza Kofi Amegah Saeed Amini Arianna Maever Loreche Amit Zohreh Anbari Sofia Androudi Mina Anjomshoa Fereshteh Ansari Carl Abelardo T Antonio Jalal Arabloo Zohreh Arefi Olatunde Aremu Bahram Armoon Amit Arora Al Artaman Anvar Asadi Mehran Asadi-Aliabadi Amir Ashraf-Ganjouei Reza Assadi Bahar Ataeinia Sachin R Atre Beatriz Paulina Ayala Quintanilla Martin Amogre Ayanore Samad Azari Ebrahim Babaee Arefeh Babazadeh Alaa Badawi Soghra Bagheri Mojtaba Bagherzadeh Nafiseh Baheiraei Abbas Balouchi Aleksandra Barac Quique Bassat Bernhard T Baune Mohsen Bayati Neeraj Bedi Ettore Beghi Masoud Behzadifar Meysam Behzadifar Yared Belete Belay Brent Bell Michelle L Bell Dessalegn Ajema Berbada Robert S Bernstein Natalia V Bhattacharjee Suraj Bhattarai Zulfiqar A Bhutta Ali Bijani Somayeh Bohlouli Nicholas J K Breitborde Gabrielle Britton Annie J Browne Sharath Burugina Nagaraja Reinhard Busse Zahid A Butt Josip Car Rosario Cárdenas Carlos A Castañeda-Orjuela Ester Cerin Wagaye Fentahun Chanie Pranab Chatterjee Dinh-Toi Chu Cyrus Cooper Vera M Costa Koustuv Dalal Lalit Dandona Rakhi Dandona Farah Daoud Ahmad Daryani Rajat Das Gupta Ian Davis Nicole Davis Weaver Dragos Virgil Davitoiu Jan-Walter De Neve Feleke Mekonnen Demeke Gebre Teklemariam Demoz Kebede Deribe Rupak Desai Aniruddha Deshpande Hanna Demelash Desyibelew Sagnik Dey Samath Dhamminda Dharmaratne Meghnath Dhimal Daniel Diaz Leila Doshmangir Andre R Duraes Laura Dwyer-Lindgren Lucas Earl Roya Ebrahimi Soheil Ebrahimpour Andem Effiong Aziz Eftekhari Elham Ehsani-Chimeh Iman El Sayed Maysaa El Sayed Zaki Maha El Tantawi Ziad El-Khatib Mohammad Hassan Emamian Shymaa Enany Sharareh Eskandarieh Oghenowede Eyawo Maha Ezalarab Mahbobeh Faramarzi Mohammad Fareed Roghiyeh Faridnia Andre Faro Ali Akbar Fazaeli Mehdi Fazlzadeh Netsanet Fentahun Seyed-Mohammad Fereshtehnejad João C Fernandes Irina Filip Florian Fischer Nataliya A Foigt Masoud Foroutan Joel Msafiri Francis Takeshi Fukumoto Nancy Fullman Silvano Gallus Destallem Gebremedhin Gebre Tsegaye Tewelde Gebrehiwot Gebreamlak Gebremedhn Gebremeskel Bradford D Gessner Birhanu Geta Peter W Gething Reza Ghadimi Keyghobad Ghadiri Mahsa Ghajarzadeh Ahmad Ghashghaee Paramjit Singh Gill Tiffany K Gill Nick Golding Nelson G M Gomes Philimon N Gona Sameer Vali Gopalani Giuseppe Gorini Bárbara Niegia Garcia Goulart Nicholas Graetz Felix Greaves Manfred S Green Yuming Guo Arvin Haj-Mirzaian Arya Haj-Mirzaian Brian James Hall Samer Hamidi Hamidreza Haririan Josep Maria Haro Milad Hasankhani Edris Hasanpoor Amir Hasanzadeh Hadi Hassankhani Hamid Yimam Hassen Mohamed I Hegazy Delia Hendrie Fatemeh Heydarpour Thomas R Hird Chi Linh Hoang Gillian Hollerich Enayatollah Homaie Rad Mojtaba Hoseini-Ghahfarokhi Naznin Hossain Mostafa Hosseini Mehdi Hosseinzadeh Mihaela Hostiuc Sorin Hostiuc Mowafa Househ Mohamed Hsairi Olayinka Stephen Ilesanmi Mohammad Hasan Imani-Nasab Usman Iqbal Seyed Sina Naghibi Irvani Nazrul Islam Sheikh Mohammed Shariful Islam Mikk Jürisson Nader Jafari Balalami Amir Jalali Javad Javidnia Achala Upendra Jayatilleke Ensiyeh Jenabi John S Ji Yash B Jobanputra Kimberly Johnson Jost B Jonas Zahra Jorjoran Shushtari Jacek Jerzy Jozwiak Ali Kabir Amaha Kahsay Hamed Kalani Rohollah Kalhor Manoochehr Karami Surendra Karki Amir Kasaeian Nicholas J Kassebaum Peter Njenga Keiyoro Grant Rodgers Kemp Roghayeh Khabiri Yousef Saleh Khader Morteza Abdullatif Khafaie Ejaz Ahmad Khan Junaid Khan Muhammad Shahzeb Khan Young-Ho Khang Khaled Khatab Amir Khater Mona M Khater Alireza Khatony Mohammad Khazaei Salman Khazaei Maryam Khazaei-Pool Jagdish Khubchandani Neda Kianipour Yun Jin Kim Ruth W Kimokoti Damaris K Kinyoki Adnan Kisa Sezer Kisa Tufa Kolola Soewarta Kosen Parvaiz A Koul Ai Koyanagi Moritz U G Kraemer Kewal Krishan Kris J Krohn Nuworza Kugbey G Anil Kumar Manasi Kumar Pushpendra Kumar Desmond Kuupiel Ben Lacey Sheetal D Lad Faris Hasan Lami Anders O Larsson Paul H Lee Mostafa Leili Aubrey J Levine Shanshan Li Lee-Ling Lim Stefan Listl Joshua Longbottom Jaifred Christian F Lopez Stefan Lorkowski Sameh Magdeldin Hassan Magdy Abd El Razek Muhammed Magdy Abd El Razek Azeem Majeed Afshin Maleki Reza Malekzadeh Deborah Carvalho Malta Abdullah A Mamun Navid Manafi Ana-Laura Manda Morteza Mansourian Francisco Rogerlândio Martins-Melo Anthony Masaka Benjamin Ballard Massenburg Pallab K Maulik Benjamin K Mayala Mohsen Mazidi Martin McKee Ravi Mehrotra Kala M Mehta Gebrekiros Gebremichael Meles Walter Mendoza Ritesh G Menezes Atte Meretoja Tuomo J Meretoja Tomislav Mestrovic Ted R Miller Molly K Miller-Petrie Edward J Mills George J Milne G K Mini Seyed Mostafa Mir Hamed Mirjalali Erkin M Mirrakhimov Efat Mohamadi Dara K Mohammad Aso Mohammad Darwesh Naser Mohammad Gholi Mezerji Ammas Siraj Mohammed Shafiu Mohammed Ali H Mokdad Mariam Molokhia Lorenzo Monasta Yoshan Moodley Mahmood Moosazadeh Ghobad Moradi Masoud Moradi Yousef Moradi Maziar Moradi-Lakeh Mehdi Moradinazar Paula Moraga Lidia Morawska Abbas Mosapour Seyyed Meysam Mousavi Ulrich Otto Mueller Atalay Goshu Muluneh Ghulam Mustafa Behnam Nabavizadeh Mehdi Naderi Ahamarshan Jayaraman Nagarajan Azin Nahvijou Farid Najafi Vinay Nangia Duduzile Edith Ndwandwe Nahid Neamati Ionut Negoi Ruxandra Irina Negoi Josephine W Ngunjiri Huong Lan Thi Nguyen Long Hoang Nguyen Son Hoang Nguyen Katie R Nielsen Dina Nur Anggraini Ningrum Yirga Legesse Nirayo Molly R Nixon Chukwudi A Nnaji Marzieh Nojomi Mehdi Noroozi Shirin Nosratnejad Jean Jacques Noubiap Soraya Nouraei Motlagh Richard Ofori-Asenso Felix Akpojene Ogbo Kelechi E Oladimeji Andrew T Olagunju Meysam Olfatifar Solomon Olum Bolajoko Olubukunola Olusanya Mojisola Morenike Oluwasanu Obinna E Onwujekwe Eyal Oren Doris D V Ortega-Altamirano Alberto Ortiz Osayomwanbo Osarenotor Frank B Osei Aaron E Osgood-Zimmerman Stanislav S Otstavnov Mayowa Ojo Owolabi Mahesh P A Abdol Sattar Pagheh Smita Pakhale Songhomitra Panda-Jonas Animika Pandey Eun-Kee Park Hadi Parsian Tahereh Pashaei Sangram Kishor Patel Veincent Christian Filipino Pepito Alexandre Pereira Samantha Perkins Brandon V Pickering Thomas Pilgrim Majid Pirestani Bakhtiar Piroozi Meghdad Pirsaheb Oleguer Plana-Ripoll Hadi Pourjafar Parul Puri Mostafa Qorbani Hedley Quintana Mohammad Rabiee Navid Rabiee Amir Radfar Alireza Rafiei Fakher Rahim Zohreh Rahimi Vafa Rahimi-Movaghar Shadi Rahimzadeh Fatemeh Rajati Sree Bhushan Raju Azra Ramezankhani Chhabi Lal Ranabhat Davide Rasella Vahid Rashedi Lal Rawal Robert C Reiner Andre M N Renzaho Satar Rezaei Aziz Rezapour Seyed Mohammad Riahi Ana Isabel Ribeiro Leonardo Roever Elias Merdassa Roro Max Roser Gholamreza Roshandel Daem Roshani Ali Rostami Enrico Rubagotti Salvatore Rubino Siamak Sabour Nafis Sadat Ehsan Sadeghi Reza Saeedi Yahya Safari Roya Safari-Faramani Mahdi Safdarian Amirhossein Sahebkar Mohammad Reza Salahshoor Nasir Salam Payman Salamati Farkhonde Salehi Saleh Salehi Zahabi Yahya Salimi Hamideh Salimzadeh Joshua A Salomon Evanson Zondani Sambala Abdallah M Samy Milena M Santric Milicevic Bruno Piassi Sao Jose Sivan Yegnanarayana Iyer Saraswathy Rodrigo Sarmiento-Suárez Benn Sartorius Brijesh Sathian Sonia Saxena Alyssa N Sbarra Lauren E Schaeffer David C Schwebel Sadaf G Sepanlou Seyedmojtaba Seyedmousavi Faramarz Shaahmadi Masood Ali Shaikh Mehran Shams-Beyranvand Amir Shamshirian Morteza Shamsizadeh Kiomars Sharafi Mehdi Sharif Mahdi Sharif-Alhoseini Hamid Sharifi Jayendra Sharma Rajesh Sharma Aziz Sheikh Chloe Shields Mika Shigematsu Rahman Shiri Ivy Shiue Kerem Shuval Tariq J Siddiqi João Pedro Silva Jasvinder A Singh Dhirendra Narain Sinha Malede Mequanent Sisay Solomon Sisay Karen Sliwa David L Smith Ranjani Somayaji Moslem Soofi Joan B Soriano Chandrashekhar T Sreeramareddy Agus Sudaryanto Mu'awiyyah Babale Sufiyan Bryan L Sykes P N Sylaja Rafael Tabarés-Seisdedos Karen M Tabb Takahiro Tabuchi Nuno Taveira Mohamad-Hani Temsah Abdullah Sulieman Terkawi Zemenu Tadesse Tessema Kavumpurathu Raman Thankappan Sathish Thirunavukkarasu Quyen G To Marcos Roberto Tovani-Palone Bach Xuan Tran Khanh Bao Tran Irfan Ullah Muhammad Shariq Usman Olalekan A Uthman Amir Vahedian-Azimi Pascual R Valdez Job F M van Boven Tommi Juhani Vasankari Yasser Vasseghian Yousef Veisani Narayanaswamy Venketasubramanian Francesco S Violante Sergey Konstantinovitch Vladimirov Vasily Vlassov Theo Vos Giang Thu Vu Isidora S Vujcic Yasir Waheed Jon Wakefield Haidong Wang Yafeng Wang Yuan-Pang Wang Joseph L Ward Robert G Weintraub Kidu Gidey Weldegwergs Girmay Teklay Weldesamuel Ronny Westerman Charles Shey Wiysonge Dawit Zewdu Wondafrash Lauren Woyczynski Ai-Min Wu Gelin Xu Abbas Yadegar Tomohide Yamada Vahid Yazdi-Feyzabadi Christopher Sabo Yilgwan Paul Yip Naohiro Yonemoto Javad Yoosefi Lebni Mustafa Z Younis Mahmoud Yousefifard Hebat-Allah Salah A Yousof Chuanhua Yu Hasan Yusefzadeh Erfan Zabeh Telma Zahirian Moghadam Sojib Bin Zaman Mohammad Zamani Hamed Zandian Alireza Zangeneh Taddese Alemu Zerfu Yunquan Zhang Arash Ziapour Sanjay Zodpey Christopher J L Murray Simon I Hay

Nature 2019 10 16;574(7778):353-358. Epub 2019 Oct 16.

Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA, USA.

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2-to end preventable child deaths by 2030-we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000-2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations.
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http://dx.doi.org/10.1038/s41586-019-1545-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800389PMC
October 2019

The Panama Aging Research Initiative Longitudinal Study.

MEDICC Rev 2019 Apr-Jul;21(2-3):54-58

The Panama Aging Research Initiative is a cohort study of 423 adults aged ≥65 years recruited from an outpatient geriatric department of Panama's largest public hospital, the Social Security Fund's Dr Arnulfo Arias Madrid Hospital Complex (Complejo Hospitalario Dr Arnulfo Arias Madrid de la Caja de Seguro Social). The study provides the first reports of modifiable and non-modifiable risk factors of cognitive impairment and dementia, as well as various health conditions common among older adults in Panama, including chronic illnesses, polypharmacy and rates of comorbidity. The initial study, conducted September 2012-May 2016, included a clinical interview; physical assessments of body mass index and handgrip strength; and cognitive testing, plus non-fasting blood draws for measurements of genetic (Apolipoprotein E genotype) and blood-based biological markers. Information was collected regarding limitations in activities of daily living, symptoms of depression and fall incidents. A subsample of participants provided cerebrospinal fluid to measure proteins related to Alzheimer's disease; another subsample underwent ultrasonography and electroencephalography. This report describes the general study design and highlights lessons learned and future directions. In particular, drawing on lessons learned from this clinical research, a community-based prospective cohort study is currently under way among older adults in Panama to validate a blood-based biomarker profile for detecting mild cognitive impairment and Alzheimer's disease, as well as risk factors for cognitive decline. KEYWORDS: Dementia, biomarkers, Latin America, aging, cognition, chronic disease, Panama.
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February 2020

Inflammatory Biomarkers, Depressive Symptoms and Falls Among the elderly in Panama.

Curr Aging Sci 2019 ;11(4):236-241

Neurosciences Center and Clinical Research Unit, Institute of Scientific Research and High Technology Services (INDICASAT AIP), City of Knowledge, Panama.

Background: Falls are common among elderly adults, and are predictors of hospitalization, institutionalization and mortality.

Objective: The objective of the present study was to examine the relationship between blood-based markers of inflammation and fall events in a sample of elderly Hispanic adults.

Method: Data were collected from 190 participants enrolled in the Panama Aging Research Initiative study who completed baseline clinical and cognitive assessments. A non-fasting blood sample was obtained. Self-reported falls were classified as no falls, single falls or recurrent (two or more) falls reported in the 12 months prior to baseline evaluations. Serum levels of C Reactive Protein (CRP), T-lymphocyte secreting protein (I-309), interleukin 10 (IL-10), interleukin 6 (IL-6) and interleukin 7 (IL-7) were measured. Global cognition was assessed with the Mini Mental State Examination and depressive symptoms were assessed with the Geriatric Depression Scale (GDS-30). Multinomial logistic regression was used to assess the link between inflammation and fall events.

Results: Depressive symptoms, limitations in Instrumental Activities of Daily Living (IADL), IL-7 and I-309 were significantly related to fall events. Elevated levels of IL-7 increased the likelihood of single and recurrent falls, while increased levels of I-309 were associated only with recurrent falls. Greater IADL limitations and depressive symptoms were associated with an increased likelihood of recurrent falls.

Conclusion: There is a lack of research investigating the relationship between inflammatory biomarkers and fall events. These results provide evidence of risk factors for falls in Hispanic older adults, and could serve to guide public health professionals to establish clinical guidelines to reduce fall risks.
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http://dx.doi.org/10.2174/1874609812666190215125104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635419PMC
March 2020

Vascular biomarkers and ApoE4 expression in mild cognitive impairment and Alzheimer's disease.

AIMS Neurosci 2018 16;5(2):148-161. Epub 2018 Jun 16.

Centro de Neurociencias y Unidad de Investigación Clínica, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá.

Vascular pathology and genetic markers such as apolipoprotein E allele ε4 (ApoE ε4) are risk factors for the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). In Panama, a high prevalence of vascular risk factors and an increase in the aging population, generate the need to investigate biomarkers using specific, sensitive, non-invasive and cost-efficient methods that could be used in primary care. The main objective of this study was to explore the association between vascular biomarkers such as intima-media thickness (IMT) and stenosis, ApoΕ ε4 and cognitive function in a sample of older adults, including healthy controls ( = 41), MCI ( = 33), and AD ( = 12). A descriptive and cross-sectional study was conducted. Participants were part of the Panama Aging Research Initiative (PARI), the first prospective study in aging in Panama. Assessments included a neuropsychological battery, ApoΕ ε4 genotyping and a Doppler ultrasound of the left carotid artery to examine the presence of vascular risk factors. Neuropsychological tests were combined to form six cognitive domains: Global cognition, language, visuospatial abilities, learning and memory, attention and executive functions. Multivariable analyses (using age, education, and ApoE ε4 expression as covariates) were conducted. Participants with increased IMT showed poorer performance in memory and those with carotid stenosis showed poorer performance in language, visuospatial abilities and attention, independent of age, education or ApoΕ ε4 expression. The results support the use of vascular markers in cognitive assessments of aged individuals.
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http://dx.doi.org/10.3934/Neuroscience.2018.2.148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181887PMC
June 2018

Individual and sex differences in high and low responder phenotypes.

Behav Processes 2017 Mar 11;136:20-27. Epub 2017 Jan 11.

Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Ciudad del Saber, Panama. Electronic address:

Individual differences in responses to a novel environment are an important tool to predict predisposition to neuropsychiatric disorders. One way to examine individual differences involves classifying animals based on locomotion in a novel context. In this study we focused on individual and sex differences by categorizing female and male mice as high (HR) or low responders (LR) on the basis of open field locomotion. We then assessed whether groups differed on behavioral measures of spontaneous alternations, anxiety, depression and contextual fear conditioning. In the Y-maze, we observed no differences across HR/LR or sex on spontaneous alternations, but HR displayed more locomotion. HR male mice showed less anxiety-like behavior in the light-dark test but not the elevated plus maze. We observed no differences in the forced swim test across HR/LR, although males exhibited greater depression-like behavior overall. HR mice exhibited less contextual fear memory compared to LR regardless of sex. Principal component analyses suggested sex-specific patterns of behaviors across tests, with female responses within individual tests tending to load together. In females anxiety- and depression-like behaviors explained a large part of the variance observed across tests in our battery, whereas male behavior was primarily explained by variables related to locomotion.
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http://dx.doi.org/10.1016/j.beproc.2017.01.006DOI Listing
March 2017

Blood-based biomarkers of adverse perinatal outcomes in maternal obesity.

J Matern Fetal Neonatal Med 2017 Dec 12;30(24):2991-2997. Epub 2017 Jan 12.

c Centro de Neurociencias y Unidad de Investigación Clínica , Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP) , Clayton , Panamá.

Objective: Increasing maternal weight has been shown to predict adverse perinatal outcome, including increases in the relative risk of fetal death, stillbirth, neonatal death, perinatal death and infant death. In order to better understand the pathophysiological factors associated with obesity during pregnancy, the role of biomarkers associated with adverse outcomes in obese pregnant women is under investigation. The purpose of this review study was to examine potential biomarkers that could serve as effective screening strategies in obese pregnant women to reduce fetal and neonatal morbidity, as well as maternal morbidity.

Methods: Electronic databases (Pubmed, Embase) were searched for previously published research studies that investigated biomarkers associated with perinatal outcomes in obese pregnant women and the putative mechanisms underlying biomarker effects on pregnancy outcomes.

Results: It is evident that while several biomarkers predict perinatal complications in obese pregnant women, none fulfilled the criteria to be considered clinically useful.

Conclusion: There is a critical need for reliable blood-based biomarkers associated with an increased risk of adverse perinatal outcomes in obese pregnant women.
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http://dx.doi.org/10.1080/14767058.2016.1271406DOI Listing
December 2017

Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.

Alzheimers Dement 2017 01 18;13(1):45-58. Epub 2016 Nov 18.

AXA Research Fund and UPMC Chair, Paris, France; Department de Neurologie, Institut de la Memorie et de la Maladie d'Alzheimer (IM2A) et Institut du Cerveau et du la Moelle epiniere (ICM), Hospital de la Pitie-Salpetriere, Sorbonne Universites, Universite Pierre et Marie Curie, Paris, France.

The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.jalz.2016.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218961PMC
January 2017

Characterization of Alzheimer's Disease and Mild Cognitive Impairment in Older Adults in Panama.

J Alzheimers Dis 2016 10;54(3):897-901

Centro de Neurociencias y Unidad de Investigación Clínica, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Ciudad del Saber, Clayton, Apartado Postal 0843-01103, Panamá.

Research on age-related cognitive impairment is scarce in Central America. We report factors associated with cognitive impairment among a sample of older adults in Panama diagnosed with Alzheimer's disease (AD, n = 31), mild cognitive impairment (MCI, n = 43), or no cognitive impairment (controls, n = 185). Apolipoprotein E (ApoE) genotype was assessed in a subset of cases (n = 135). Age (OR = 2.53, 95% CI = 1.03-6.17) and ApoE ɛ4 (OR = 5.14, 95% CI = 2.11-12.52) were significantly related to cognitive impairment (AD/MCI combined). Results underscore the potential of genetic screening in Panama for identifying those at risk of dementia.
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http://dx.doi.org/10.3233/JAD-160402DOI Listing
October 2016

A blood screening test for Alzheimer's disease.

Alzheimers Dement (Amst) 2016 25;3:83-90. Epub 2016 Jun 25.

Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.

Introduction: This study combined data across four independent cohorts to examine the positive and negative predictive values of an Alzheimer's disease (AD) blood test if implemented in primary care.

Methods: Blood samples from 1329 subjects from multiple independent, multiethnic, community-based, and clinic-based cohorts were analyzed. A "locked-down" referent group of 1128 samples was generated with 201 samples randomly selected for validation purposes. Random forest analyses were used to create the AD blood screen. Positive (PPV) and negative (NPV) predictive values were calculated.

Results: In detecting AD, PPV was 0.81, and NPV was 0.95 while using the full AD blood test. When detecting mild cognitive impairment, PPV and NPV were 0.74 and 0.93, respectively. Preliminary analyses were conducted to detect any "neurodegenerative disease". The full 21-protein AD blood test yielded a PPV of 0.85 and NPV of 0.94.

Discussion: The present study creates the first-ever multiethnic referent sample that spans community-based and clinic-based populations for implementation of an AD blood screen.
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http://dx.doi.org/10.1016/j.dadm.2016.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941038PMC
July 2016

Serum-based protein profiles of Alzheimer's disease and mild cognitive impairment in elderly Hispanics.

Neurodegener Dis Manag 2016 06 27;6(3):203-13. Epub 2016 May 27.

Centro de Neurociencias y Unidad de Investigación Clínica, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Ciudad del Saber 219, Clayton, Apartado Postal 0843-01103, República de Panamá

Aim: To describe the biomarker profiles in elderly Panamanians diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI) or no impairment using serum-based biomarkers.

Methods: Twenty-four proteins were analyzed using an electrochemiluminescence-based multiplex biomarker assay platform. A biomarker profile was generated using random forest analyses.

Results: Two proteins differed among groups: IL-18 and T-lymphocyte-secreted protein I-309. The AD profile was highly accurate and independent of age, gender, education and Apolipoprotein E ε4 status. AD and MCI profiles had substantial overlap among the top markers, suggesting common functions in AD and MCI but differences in their relative importance.

Conclusion: Our results underscore the potential influence of genetic and environmental differences within Hispanic populations on the proteomic profile of AD.
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http://dx.doi.org/10.2217/nmt-2015-0009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066121PMC
June 2016

Sex differences and estrous cycle effects on foreground contextual fear conditioning.

Physiol Behav 2016 09 16;163:305-311. Epub 2016 May 16.

Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Ciudad del Saber, Panama. Electronic address:

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http://dx.doi.org/10.1016/j.physbeh.2016.05.026DOI Listing
September 2016

Cognitive Impairment, Depression, and Cooccurrence of Both among the Elderly in Panama: Differential Associations with Multimorbidity and Functional Limitations.

Biomed Res Int 2015 21;2015:718701. Epub 2015 Dec 21.

Centro de Neurociencias y Unidad de Investigación Clínica, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Ciudad del Saber, Panama.

Cognitive impairment and depression are common mental health problems among the elderly, although few studies have examined their cooccurrence in older adults in Latin America. The purpose of this study was to examine cognitive impairment, depression, and cooccurrence of the two conditions and associated factors in a sample of older adults in Panama. This study included 304 community-dwelling elderly (≥ 65 years) individuals. Participants underwent a clinical interview and assessments of cognitive function by the Minimental State Examination and depressive symptoms by the Geriatric Depression Scale. Limitations in basic (BADL) and instrumental (IADL) activities in daily living and the presence of chronic illnesses were recorded. Multinomial regression analysis revealed that cooccurrence of cognitive impairment and depressive symptoms was explained by increasing age (OR: 3.2, 95% CI: 1.20, 8.30), low education (OR: 3.3, 95% CI: 1.33, 8.38), having four or more chronic conditions (OR: 11.5, 95% CI: 2.84, 46.63), and BADL limitations (OR: 5.0, 95% CI: 1.26, 19.68). Less education and limitations in BADL and IADL increased the odds of cognitive impairment alone, while less education and three or more chronic conditions increased the odds of depression alone. These findings underscore the relevance of assessing cognitive impairment in the elderly as part of a long-term approach to managing depression and vice versa.
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http://dx.doi.org/10.1155/2015/718701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698525PMC
October 2016

NMDA receptor dysregulation in chronic state: a possible mechanism underlying depression with BDNF downregulation.

Neurochem Int 2014 Dec 30;79:88-97. Epub 2014 Sep 30.

Center for Neuroscience, INDICASAT AIP, Ciudad del Saber, Edificio #219, Apartado Postal 0843-01103, Panamá, República de Panamá

Several lines of evidence indicate that chronic stress and downregulation of brain-derived neurotrophic factor (BNDF) are the key components of depression pathology. Evidence from animal models of depression demonstrates that chronic stress impairs hippocampal BDNF expression and that antidepressant drug effects correlate with increased BDNF synthesis and activity in the hippocampus. Studies with human carriers of BDNF Met-allele polymorphism link stress vulnerability and risk for depression. The mechanism by which chronic stress downregulates BDNF and promotes depressive-like responses is not established yet. It has been reported that chronic stress mediates alterations in several calcium-related components involved in BDNF synthesis, including CAMKII, CAMKIV and cAMP-response element-binding protein (CREB), and glutamatergic neurotransmission through N-Methyl-D-Aspartate receptors (NMDAR). Treatments with NMDAR antagonists like ketamine modulate glutamate signals, upregulate CREB and BDNF expression, and correct stress-induced cognitive and behavioral alterations. With the increasing interest to develop NMDAR modulators, it is crucial to understand the conditions that lead to depression pathology in order to develop rational therapies aimed at reestablishing proper neuronal function. We present here the current knowledge regarding the relation between chronic stress, BDNF and NMDARs and its implications in depression. We discuss a plausible mechanism where chronic stress induced NMDAR stimulation could lead to dysregulated calcium signaling and decreased BDNF activity. In these circumstances, neurons become vulnerable to the effects of stress, leading to dysfunctional neurotransmission and behavioral alterations. We propose that treatment with NMDAR antagonists may help to return the balance of calcium signaling, promote proper BDNF signaling and correct depressive symptoms.
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http://dx.doi.org/10.1016/j.neuint.2014.09.007DOI Listing
December 2014

First trimester screening using ultrasound and serum markers in Panamanians: Factors associated with adverse pregnancy outcomes.

J Res Med Sci 2014 May;19(5):451-6

Center for Neuroscience and Clinical Research Unit, Institute for Scientific Research and Technological Services (INDICASAT AIP), Panamá

Background: There is no published data on the association between serum biochemical and ultrasonographic markers and adverse pregnancy outcomes. Therefore, the aim of this study was to determine the factors associated with perinatal outcomes in singleton pregnancies using ultrasound and maternal serum markers during the first trimester in Panamanians.

Materials And Methods: This was a prospective observational study of 468 first trimester singleton pregnancies conducted over a 7-year period. All women attending a prenatal screening clinic during the study period were informed of the study and the option to participate. Two maternal serum markers, free β-human chorionic gonadotropin (β-hCG) and pregnancy associated plasma protein-A (PAPP-A), and four fetal ultrasound markers, nuchal translucency thickness, nasal bone, flow across the tricuspid valve, and flow in the ductus venosus (DV), were measured by certified maternal fetal medicine specialists. Adverse outcomes included miscarriage, major structural defects, genetic disorders, and major fetal cardiac defects.

Results: A total of 454 (97%) pregnancies were unaffected. Median maternal age was 31.5 years (range: 18-50). Maternal age was significantly greater in cases of adverse outcome (P = 0.007). The number of adverse outcomes associated with an absent or hypoplastic nasal bone, tricuspid valve regurgitation, and abnormal flow in the DV were significantly greater relative to unaffected pregnancies (Ps < 0.001). No differences were found in fetal crown-rump length or maternal serum levels of β-hCG or PAPP-A.

Conclusion: Abnormal ultrasound markers are associated with adverse outcomes. Women with normal ultrasound and serum markers should be reassured of low risk of adverse pregnancy outcomes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116578PMC
May 2014

The effects of impaired cerebral circulation on Alzheimer's disease pathology: evidence from animal studies.

J Alzheimers Dis 2014 ;42(3):707-22

Center for Neuroscience, INDICASAT AIP, City of Knowledge, Republic of Panama.

Persistent systemic hypoxia, a direct consequence of alterations in vascular function, can compromise the brain by increasing the risk of developing dementias such as Alzheimer's disease (AD). Vascular contributions to cognitive impairment and AD in aged individuals are common, and several vascular risk factors for AD are linked to hypoxia. Clinical evidence confirms that structural and functional changes characteristic of AD pathology also occur following hypoxic-ischemic events such as stroke and traumatic brain injury. Studies with transgenic and non-transgenic mouse models reliably show that hypoxia increases the levels of amyloid-β peptides that form the characteristic plaques in AD brains. Moreover, some studies suggest that vascular lesions also promote tau phosphorylation, modulate apolipoprotein E expression, and have more profound effects in aged animals, but additional evidence is needed to establish these findings. Although the mechanisms underlying hypoxia-related effects remain unclear, controlled animal studies continue to reveal mechanistic aspects of the relationship between hypoxia and AD pathology that are necessary for therapeutic developments. The present review summarizes evidence from rodent studies regarding the effects of hypoxia on AD-related pathology and evaluates its impact on understanding human disease.
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http://dx.doi.org/10.3233/JAD-140144DOI Listing
August 2015

Factors associated to depression in renal transplant recipients in Panama.

Indian J Psychiatry 2013 Jul;55(3):273-8

Department of Psychiatry, Complejo Hospitalario Dr. Arnulfo Arias Madrid, Social Security, Panama, Panama.

Aim: High rates of affective disorders have been reported in kidney transplant recipients treated for end-stage renal disease. Latin America has experienced a significant increase in transplant activity in recent decades, but there is a dearth of data regarding psychosocial issues following kidney transplantation. The aim of this study was to measure the prevalence of depression and the demographic factors associated to depression among renal transplant recipients in Panama.

Materials And Methods: This cross-sectional study was conducted between March to May 2010 in a hospital setting during routine outpatient evaluations. The study included 119 renal transplant recipients (58 males, 61 females). Depressive symptoms were measured using the self-report Hospital Anxiety and Depression Scale and diagnoses were established by a trained psychiatrist using the Mini-International Neuropsychiatric Interview. Regression models were used to explore the association between depression and sociodemographic variables.

Results: The prevalence of depression was 11.8% among transplant recipients. Linear regression indicated that the presence of an anxiety disorder, increasing age, and lower education levels were significantly and independently associated with depressive symptoms. Logistic regression analysis confirmed that anxiety and a perception of negative social support significantly increased the likelihood of depression.

Conclusions: These findings have important clinical implications. Depression after kidney transplantation has been shown to affect health outcomes adversely. Our results underscore the need to assess depressive symptoms as well as other affective disorders as part of the screening and treatment of renal transplant patients in Panama.
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http://dx.doi.org/10.4103/0019-5545.117148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777350PMC
July 2013

Antioxidant activity and polyphenol content in cultivated and wild edible fruits grown in Panama.

J Pharm Bioallied Sci 2012 Oct;4(4):313-7

Department of Biochemistry, Faculty of Natural, Exact Sciences and Technology, University of Panama, Panama.

Objectives: The present research was undertaken to determine the antioxidant activity and total polyphenol content of cultivated and wild edible fruits consumed in Panama.

Materials And Methods: 39 cultivated and wild edible fruits antioxidant activity and total polyphenol content was assessed by using the DPPH and the Folin-Ciocalteu assays, respectively.

Results And Discussion: The antioxidant composition of the fruits varied between 1083.33 and 16.22 mg TEAC/100 g fresh weight. On the other hand, the total phenolic content of the 39 fruits tested ranged from 604.80 to 35.10 mg GAE/100 g FW. Ziziphus mauritania presented the highest antioxidant activity and the largest phenolic content, whereas most fruits had a moderate TEAC value.

Conclusion: Fruits polyphenol content was strongly correlated with antioxidant properties, which pointed out the important role of these compounds in the prevention of many types of cancer, neurological ailments, and cardiovascular diseases through diverse antioxidant mechanisms.
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http://dx.doi.org/10.4103/0975-7406.103261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523527PMC
October 2012

Potential immunotargets for Alzheimer's disease treatment strategies.

J Alzheimers Dis 2013 ;33(2):297-312

Instituto de Investigaciones Científicas y Servicios de Alta Tecnologia, Ciudad de Panamá, Panamá.

Alzheimer's disease (AD) exerts a profound burden on public health worldwide. AD etiology is unknown, and research to understand its underlying pathology has produced agents for the management of symptoms, but not a cure for the disease. Most AD drugs were developed in response to research implicating fibrillar amyloid-β (Aβ) in AD neuropathology but result in only modest short-term improvements in cognitive function, so there is agreement that additional targets need to be investigated. Evidence has implicated the immune system in AD and immunotherapy as a potential approach to AD treatment. Accumulation of microglia and astrocytes has been observed around Aβ deposits and several reports implicate inflammatory mediators in AD pathology. Importantly, Aβ deposition has been found in the brains of AD patients and in aged people without dementia, but signs of neuroinflammation are found only in AD patients and not in normal aged individuals. Animal models suggest a complex role for immunomodulators in AD, namely, these mechanisms are likely to promote the same pathogenic processes that gave rise to them. To date, clinical trials with anti-inflammatories and other immunoregulators have not been successful, but available data strongly favor immunomodulation as a promising disease intervention strategy. This article reviews data that implicate various immunomodulators in AD and considers their potential application in the development of novel AD therapeutics. Currently, a deeper understanding of nervous-immune interactions during normal aging and at all stages of AD is needed. Continued research in AD inflammatory and immunoregulatory processes will increase both our understanding of disease mechanisms and the likelihood of discovering new therapeutic targets for AD.
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http://dx.doi.org/10.3233/JAD-2012-121222DOI Listing
May 2013

New evidence on α-synuclein and Tau binding to conformation and sequence specific GC* rich DNA: Relevance to neurological disorders.

J Pharm Bioallied Sci 2012 Apr;4(2):112-7

Department of Neuroscience, Medical University of South Carolina, Charleston, USA.

Background: Deoxyribonucleic acid (DNA) topology plays a critical role in maintaining the integrity of the genome and cellular functions. Although changes in DNA conformation and structural dynamics in the brain have been associated with various neurological disorders, its precise role in the pathogenesis is still unclear. Previous studies from our laboratory have shown that there is a conformational change in the genomic DNA of Parkinson's disease (PD) (B to altered B-DNA) and Alzheimer's disease brain (B to Z-DNA). However, there is limited information on the mechanism on DNA dynamics changes in brain.

Objective: In the present study, we have investigated the DNA conformation and sequence specific binding ability of α-Synuclein and Tau with reference to B-DNA and Z-DNA using oligonucleotide (CGCGCGCG)(2) as a novel model DNA system. This sequence is predominantly present in the promoter region of the genes of biological relevance.

Materials And Methods: Natively, (CGCGCGCG)(2) sequence exists in B-DNA conformation, but in the presence of high sodium concentration (4 M NaCl), the oligo converts into Z-DNA form. We used circular dichroism, melting temperature and fluorescence studies to understand protein-DNA interactions.

Results: CD studies indicated that both α-Synuclein and Tau bind to B-DNA conformation of (CGCGCGCG)(2) and induce altered B-form. Further, these proteins increased the melting temperature and decreased the number of EtBr molecules bound per base pair of DNA in B-form indicating that DNA stability is favored to alter B-DNA conformation, which could be an intermediate form favoring Z-DNA conformation. Moreover, both α-Synuclein and Tau also bound to disease-linked Z-DNA conformation of (CGCGCGCG)(2) and further stabilized the Z-conformation.

Conclusions: The present study provides vital mechanistic information on Synuclein and Tau binding to DNA in a conformation-specific manner causing conformational transition. Furthermore, both the proteins stabilize Z-DNA conformation. These have altered minor and major groove patterns and thus may have significant biological implications in relevance to gene expression pattern in neurodegeneration. We discuss the implications of α-Synuclein/Tau binding to DNA and stabilizing the altered conformations of DNA in neuronal cell dysfunction.
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http://dx.doi.org/10.4103/0975-7406.94811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341714PMC
April 2012

Randomised controlled trial of informal team sports for cardiorespiratory fitness and health benefit in Pacific adults.

J Prim Health Care 2011 Dec 1;3(4):269-77. Epub 2011 Dec 1.

Department of Sport and Exercise Science, The University of Auckland, Auckland, New Zealand.

Introduction: Rates of obesity, Type 2 diabetes and cardiovascular disease are high among Pacific people in New Zealand. Physical activity is recommended in the prevention and management of these conditions. Community-based, 'small-sided game' group activities may be an effective and culturally appropriate way to promote physical activity within Pacific communities.

Aim: To assess the effectiveness of small-sided games-based exercise on fitness and health parameters among Pacific adults over four weeks.

Methods: Twenty untrained (13 female) Pacific adults were randomised to intervention or control. Intervention participants were offered 45 minutes of small-sided games three times per week for four weeks. Control participants were offered one-month gym membership after the trial. Primary outcomes included cardiorespiratory fitness (VO₂peak) and leg strength (maximal concentric force of quadriceps at 60°/second) measured at baseline and four weeks. Secondary outcomes included glycaemia, lipid profile, blood pressure (BP), and inflammatory markers. Multivariable regression models were used to assess differences between groups, adjusting for baseline values, age and gender.

Results: At baseline, mean age was 34.8 years (SD 12.6), BMI 36.3 (6.7), systolic BP 127.7 mmHg (12.1), HbA1c 6.1% (1.9), VO₂peak 2.5 L/min (0.6) and leg strength 170.0 N.m (57.4). Sixteen participants completed the trial. Change in outcomes were greater in intervention than control participants in absolute VO₂peak (0.9 L/min (p=0.003)), leg strength (17.8 N.m (p=0.04)) and HDL (0.12 mmol/L (p=0.02)). There were no other significant differences.

Discussion: Small-sided games appear to be a promising means for improving the health and cardiorespiratory fitness and reducing the risk of diabetes and cardiovascular disease in Pacific adults.
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December 2011

Sex-dependent effects of long-term oral methylphenidate treatment on spontaneous and learned fear behaviors.

Neurosci Lett 2011 May 1;496(1):30-4. Epub 2011 Apr 1.

Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panama.

In previous studies, chronic low-dose methylphenidate (MPH) administration during early development has been shown to increase emotional responding in adulthood. However, most studies employed male subjects, which generally show enhanced fear relative to females in laboratory tests of anxious behaviors. The present study examined the sex-dependent effects of MPH treatment on innate and learned fear behaviors. Rats were treated for 4 weeks from periadolescence through early adulthood with oral MPH. In open field testing, females showed greater levels of activity than males, and MPH (5mg/kg) decreased locomotion relative to control and 2mg/kg treatment in both sexes. In contextual fear conditioning, females exhibited less freezing than males at all retention intervals. Both sexes treated with 5mg/kg MPH showed increased fear to the shock context, although MPH treatment did not interfere with contextual discrimination in either sex. Upon reexposure to the shock context at 24h, only females treated with 5mg/kg MPH exhibited increases in freezing. MPH treatment did not disrupt extinction of contextual fear (48 h post-conditioning) in either sex. These findings illustrate subtle sex differences in the effects of prolonged MPH exposure on fear behaviors, and highlight the need to examine further the underlying mechanisms in both sexes.
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http://dx.doi.org/10.1016/j.neulet.2011.03.080DOI Listing
May 2011

Targeting oligomers in neurodegenerative disorders: lessons from α-synuclein, tau, and amyloid-β peptide.

J Alzheimers Dis 2011 ;24 Suppl 2:223-32

Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, TX 75390-9070, USA.

Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Prion disease, Huntington's disease, and amyotrophic lateral sclerosis are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation in selected brain regions. The aggregates usually consist of insoluble fibrillar aggregates containing misfolded protein with β-sheet conformation. The most probable explanation is that inclusions and the aggregates symbolize an end stage of a molecular cascade of several events, and that earlier event in the cascade may be more directly tied up to pathogenesis than the inclusions themselves. Small intermediates termed as 'soluble oligomers' in the aggregation process might influence synaptic dysfunction, whereas large, insoluble deposits might function as reservoir of the bioactive oligomers. Compelling evidence suggests the role of misfolded proteins in the form of oligomers might lead to synaptic dysfunction, neuronal apoptosis and brain damage. However, the mechanism by which oligomers trigger neurodegeneration still remains mysterious. The aim of this article is to review the literature around the molecular mechanism and role of oligomers in neurodegeneration and leading approaches toward rational therapeutics.
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http://dx.doi.org/10.3233/JAD-2011-110182DOI Listing
September 2011

Cognitive and emotional behavioural changes associated with methylphenidate treatment: a review of preclinical studies.

Int J Neuropsychopharmacol 2012 Feb 25;15(1):41-53. Epub 2011 Mar 25.

Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Cognición, Cerebro y Conducta, Panamá

There is evidence from animal studies that repeated exposure to methylphenidate (MPH), a widely used psychostimulant for the treatment of attention deficit hyperactivity disorder (ADHD), produces behavioural, structural and neurochemical changes that persist long after drug administration has ended. However, the translational utility of much of this work is compromised by the use of drug doses and routes of administration that produce plasma and brain MPH levels that fall outside the clinical range, i.e. experimental parameters more relevant to drug abuse than ADHD. We used PubMed to identify pre-clinical studies that employed repeated MPH administration at low doses in young rodents and examined long-term effects on cognition, emotion, and brain structure and function. A review of this work suggests that repeated MPH treatment during early development can modify a number of cognitive, behavioural and brain processes, but these are reduced when low therapeutic doses are employed. Moreover, MPH sites of action extend beyond those implicated in ADHD. Studies that combined neurobiological and behavioural approaches provide important insights into the mechanisms underlying MPH-produced effects on cognitive and behavioural processes, which may be relevant to MPH therapeutic efficacy. There is an emerging consensus that pharmacological treatment of childhood psychiatric disorders produces persistent neuroadaptations, highlighting the need for studies that assess long-term effects of early developmental pharmacotherapy. In this regard, studies that mimic clinical therapy with rodents are useful experimental approaches for defining the behavioural and neural plasticity associated with stimulant therapy in paediatric populations.
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http://dx.doi.org/10.1017/S1461145711000472DOI Listing
February 2012

Cognitive aging and early diagnosis challenges in Alzheimer's disease.

J Alzheimers Dis 2011 ;24 Suppl 2:153-9

Center for Neuroscience, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología, Panamá, República de Panamá.

Despite the profound burden of Alzheimer's disease (AD) on public health, research to understand its underlying pathology has not yet produced new therapeutic approaches to improve symptoms or halt disease progression. AD is characterized by early cognitive deficits, particularly in short-term memory, followed by a gradual decline in other cognitive functions. Functional imaging studies indicate that hippocampal and medial temporal lobe cortices are the sites of early pathology underlying the initial memory impairments. Behaviors that rely on hippocampal integrity have been the focus of extensive research using animal models and represent useful functional endpoints in pre-clinical AD research. In this review, we argue that relevant information can be derived from studying normal, aging animals performing hippocampal-sensitive tasks. Because age is the greatest risk factor for developing clinical AD, the aspects of cognitive decline occurring in normal, aging animals that resemble those seen in aging humans are reliable endpoints that can be applied to improving human therapies. Ultimately, pre-clinical studies that employ tasks sensitive to hippocampal function can be applied toward novel hypotheses in AD intervention and could provide important insights for developing early detection devices for AD patients.
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http://dx.doi.org/10.3233/JAD-2011-110239DOI Listing
September 2011

Cognitive aging and early diagnosis challenges in Alzheimer's disease.

J Alzheimers Dis 2011 ;24 Suppl 2:153-9

Center for Neuroscience, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología, Panamá, República de Panamá.

Despite the profound burden of Alzheimer's disease (AD) on public health, research to understand its underlying pathology has not yet produced new therapeutic approaches to improve symptoms or halt disease progression. AD is characterized by early cognitive deficits, particularly in short-term memory, followed by a gradual decline in other cognitive functions. Functional imaging studies indicate that hippocampal and medial temporal lobe cortices are the sites of early pathology underlying the initial memory impairments. Behaviors that rely on hippocampal integrity have been the focus of extensive research using animal models and represent useful functional endpoints in pre-clinical AD research. In this review, we argue that relevant information can be derived from studying normal, aging animals performing hippocampal-sensitive tasks. Because age is the greatest risk factor for developing clinical AD, the aspects of cognitive decline occurring in normal, aging animals that resemble those seen in aging humans are reliable endpoints that can be applied to improving human therapies. Ultimately, pre-clinical studies that employ tasks sensitive to hippocampal function can be applied toward novel hypotheses in AD intervention and could provide important insights for developing early detection devices for AD patients.
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http://dx.doi.org/10.3233/JAD-2011-110239DOI Listing
September 2011

Estimated prevalence of attention-deficit/hyperactivity disorder in a sample of Panamanian school-aged children.

Child Psychiatry Hum Dev 2011 Apr;42(2):243-55

Clínica Neuropsicológica, Panamá, República de Panamá.

The present study investigated the prevalence of ADHD in a school sample of children ages 6-11 years in the city of Panama. The assessment battery included the Conners' Parent and Teacher Rating Scales, the Structured Developmental History of the Behavioral Assessment System for Children (BASC-2), and the Wechsler Intelligence Scale for Children (WISC-III). The prevalence of ADHD (N = 229) was 7.4%, with an estimate of 1.8% for the predominantly inattentive subtype, 3.1% for the predominantly hyperactive/impulsive subtype, and 2.6% for the combined subtype. The prevalence rate of ADHD is relatively low in Panama compared to those reported for samples in neighboring countries. Moreover, ADHD children were unlikely to have been identified or referred to psychological or special education assessments. Our findings confirm that ADHD is overlooked in some cultures and that a significant number of children with ADHD-related impairments are not receiving optimal intervention.
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http://dx.doi.org/10.1007/s10578-010-0213-2DOI Listing
April 2011

Characterization of anxiety-related responses in male rats following prolonged exposure to therapeutic doses of oral methylphenidate.

Pharmacol Biochem Behav 2009 Oct 21;93(4):451-9. Epub 2009 Jun 21.

Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Cognición, Cerebro y Conducta, Ciudad del Saber, Panamá.

Increases in the rates of attention-deficit/hyperactivity disorder (ADHD) diagnosis and the prescribed use of methylphenidate (MPH) in recent years have raised concerns over the potential effects of early MPH exposure on brain structure and function in adulthood. Animal studies have shown that long-term MPH exposure can modify anxiety-related behaviors and related neural circuitry in adulthood. The present study employed a battery of behavioral tests and repeated testing to assess the long-term effects of MPH exposure on anxious responding. Male Wistar rats beginning on post-natal day 27 were exposed to 4 or 7 weeks of twice daily MPH administration at doses of 2, 3, or 5 mg/kg. MPH was administered orally and on weekdays only in order to approximate drug treatment in clinical populations. Behavioral testing began 18 days following the last drug administration. Our results indicate that prolonged oral MPH treatment at therapeutic doses has little or no enduring effects on anxious behaviors. However, a comparison of MPH groups that received treatment for 4 or 7 weeks suggests that the two treatment periods influenced anxious behaviors in observably different manners in adulthood; namely, a more prolonged period of exposure produced less anxiety relative to the shorter period of MPH exposure as indicated by behaviors in the light-dark transition, elevated plus-maze, and fear conditioning tests. These findings were interpreted as evidence of the importance of considering length of drug exposure in pre-clinical studies aimed at investigating the effects of MPH exposure in ADHD populations.
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http://dx.doi.org/10.1016/j.pbb.2009.06.007DOI Listing
October 2009